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Cyclodextrin Complexation Studies as the First Step for Repurposing of Chlorpromazine
- Source :
- International Journal of Pharmaceutics, International Journal of Pharmaceutics, 2020, 584, pp.119391. ⟨10.1016/j.ijpharm.2020.119391⟩, International Journal of Pharmaceutics, Elsevier, 2020, 584, pp.119391. ⟨10.1016/j.ijpharm.2020.119391⟩
- Publication Year :
- 2020
- Publisher :
- HAL CCSD, 2020.
-
Abstract
- International audience; The antipsychotic drug chlorpromazine (CPZ) has potential for the treatment of acute myeloid leukemia, if central nervous system side-effects resulting from its passage through the blood-brain barrier can be prevented. A robust drug delivery system for repurposed CPZ would be drug-in-cyclodextrin-in-liposome that would redirect the drug away from the brain while avoiding premature release in the circulation. As a first step, CPZ complexation with cyclodextrin (CD) has been studied. The stoichiometry, binding constant, enthalpy, and entropy of complex formation between CPZ and a panel of CDs was investigated by isothermal titration calorimetry (ITC). All the tested CDs were able to include CPZ, in the form of 1:1, 1:2 or a mixture of 1:1 and 1:2 complexes. In particular, a substituted γ-CD, sugammadex (the octasodium salt of octakis(6-deoxy-6-S-(2-carboxyethyl)-6-thio)cyclomaltooctaose), formed exclusively 1:2 complexes with an extremely high association constant of 6.37 × 10 9 M −2. Complexes were further characterized by heat capacity changes, one-and twodimensional (ROESY) nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulations. Finally, protection of CPZ against photodegradation by CDs was assessed. This was accelerated rather than reduced by complexation with CD. Altogether these results provide a molecular basis for the use of CD in delayed release formulations for CPZ.
- Subjects :
- Magnetic Resonance Spectroscopy
Chlorpromazine
Chemistry, Pharmaceutical
Enthalpy
Pharmaceutical Science
02 engineering and technology
Molecular Dynamics Simulation
030226 pharmacology & pharmacy
Repurposin
Sugammadex
03 medical and health sciences
Molecular dynamics
0302 clinical medicine
Drug Stability
Cyclodextrin,Chlorpromazine, Inclusion complex, Sugammadex, Photodegradation, Repurposin
Photodegradation
[CHIM] Chemical Sciences
medicine
Cyclodextrin
[CHIM]Chemical Sciences
chemistry.chemical_classification
Cyclodextrins
Drug Carriers
Inclusion complex
Chemistry
beta-Cyclodextrins
Drug Repositioning
Isothermal titration calorimetry
021001 nanoscience & nanotechnology
Binding constant
Combinatorial chemistry
3. Good health
Delayed-Action Preparations
Drug delivery
Liposomes
Thermodynamics
0210 nano-technology
CSOB
medicine.drug
gamma-Cyclodextrins
Subjects
Details
- Language :
- English
- ISSN :
- 03785173
- Database :
- OpenAIRE
- Journal :
- International Journal of Pharmaceutics, International Journal of Pharmaceutics, 2020, 584, pp.119391. ⟨10.1016/j.ijpharm.2020.119391⟩, International Journal of Pharmaceutics, Elsevier, 2020, 584, pp.119391. ⟨10.1016/j.ijpharm.2020.119391⟩
- Accession number :
- edsair.doi.dedup.....58a4611434b864637d4be196e24fbef0