Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin

Abstract

Abstract:We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy ( = −9.98 kcal·mol drug's overall aqueous solubility, it is important to concern the different forms and ionization states of this anesthetic. All mean values are indicated with their standard deviations.

Evaluation of the potential toxicity of unmodified and modified cyclodextrins on murine blood-brain barrier endothelial cells

“…In vitro cytotoxicity study for unmodified and modified cyclodextrins on endothelial cells Taking into consideration the previously published concentrations of either some cyclodextrin-formulated drugs, such as sevoflurane in the concentration of 20 -40 μg*mL -1 (Nitzschke et al, 2013) complexed with α-CD (relative inclusion content [w%] = 94%) and midazolam with TRI-MEB in the concentration of 40 mg*L -1 (Shityakov et al, 2014), or HPβCD, functionalized with calcium carbonate microparticles in the concentration of 50 μg*mL -1 (Zhang et al, 2015), the CellTiter-Glo® luminescent cell viability assay was used to determine the CD cytotoxicity effect on endothelial cells in DMEM and heat-inactivated human serum. Although the high purification of TRIMEB and HPβCD was achieved with a significantly improved aqueous solubility (31 g and > 50 g in 100 mL at 25°C), in comparison to α-CD (15 g in 100 mL at 25°C), the TRI-MEB and HPβCD powder might incorporate some traces (< 0.25%) of undermethylated and unpropylated products (unpublished data).…”

“…They are oligosaccharides produced through the enzymatic degradation of starch and typically exist as hexameric α-, heptameric β-and octomeric γ-CDs (Zidovetzki and Levitan, 2007). CDs are also known to enhance the solubility of lipophilic biologically active compounds and thus have the potential to integrate into sophisticated drug-delivery systems to enhance the permeation of substances through different barriers, such as the blood-brain barrier (BBB) (Shityakov et al, 2014;Shityakov et al, 2015). The permeation of CDs through the BBB could be an especially important issue in the case of some neurological diseases, such as Niemann-Pick type C, which is currently cured by some modified CDs administered intrathecally to avoid the BBB (Vecsernyés et al, 2014).…”

Non-ionic thiolated cyclodextrins &mdash; the next generation

“…33 Due to the addition of cholesterol to final formulations, however, this toxic effect might be compensated. 11…”

“…Beta CD (β-CD) was chosen for this study as various derivatives of this type of CD have already shown great potential in drug delivery. 8,11 In order to obtain non-ionic thiolated CDs without a ring opening, hydroxyl groups on the glucose subunits of β-CD are replaced by thiol groups via bromination followed by reaction with thiourea. 5 The resulting non-ionic thiolated CDs are investigated regarding cytotoxicity, mucoadhesive properties, and their ability to incorporate miconazole, serving as a hydrophobic model drug.…”

Carvedilol Solubility Enhancement by Inclusion Complexation and Solid Dispersion: Review

“…derivatives is generally proceed through formation of inclusion complexes. Cyclodextrins serve as host and form compound with different drug molecules [6,7] ( Fig.1).Each drug molecule is enclosed by a Cyclodextrin molecule. Cyclodextrins have been widely used to enhance the aqueous solubility and dissolution rate of poorly water-soluble drugs [8,9] .…”