An in press paper on detailed ITC and NMR study of chlorpromazin complexation with various cyclodextrins reports on an unexpected result: an extremely high association constant was determined for sugammadex/chlorpromazine complex of 1:2 molar ratio (6.37 ± 0.25) x 10(9) M(-2).
The aim of the study was to develop a new formulation of chlorpromazin, an antipsychotic drug for the treatment of myeloid leukemia. The repurposing of this long-known drug requires a delivery system preventing the passage through the blood-brain barrier to avoid the central nervous system side-effects. As a first step the interaction with the native cyclodextrins as well as with their derivatives was studied. Complexes were further characterized by heat capacity changes, one- and two-dimensional (ROESY) NMR spectroscopy and molecular dynamics simulations. Finally, protection of chlorpromazin against photodegradation by CDs was also assessed. Structural investigation (1D 1H NMR and 2D ROESY) of the inclusion complexes, complemented by molecular dynamics simulations in some cases, revealed that the different CDs included different regions or orientations of the chlorpromazin molecule within the CD cavity. However, all investigated CDs also accelerated photodegradation of the drug.
The following CDs were involved in the study: α-CD (Cavamax® W6 Pharma), RAME-β-CD (Cavasol® W7 M Pharma), HP-β-CD (Cavasol® W7 HP Pharma), γ-CD (Cavamax® W8 Pharma) and HP-γ-CD (Cavasol® W8 HP Pharma), β-CD (KLEPTOSE®), CRYSME-β-CD (KLEPTOSE® CRYSMEB EXP), DIME-β-CD (CycloLab), TRIME-β-CD (BioCydex), SBE-β-CD (Captisol®), SBE-γ-CD (Ligand) and sugammadex (Bridion®).
Fig. 1 shows the structure of chlorpromazin (CPZ) complexes obtained by molecular dynamic simulations.
Prposed molecular structure of β-CD/CPZ (1:1), DIME-β-CD/CPZ (1:1) and sugammadex/CPZ (1:2) complexes
Z. Wang, D. Landy, C. Sizun, C. Cézard, A. Solgadi, C. Przybylski, L. de Chaisemartin, L. Herfindal, G. Barratt, F.-X. Legrand (2020) Cyclodextrin complexation studies as the first step for repurposing of chlorpromazine. International Journal of Pharmaceutics
Available online 4 May 2020, 119391