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. 2022 Aug 31;27(17):5600.
doi: 10.3390/molecules27175600.

Preparation and Characterization of Disulfiram and Beta Cyclodextrin Inclusion Complexes for Potential Application in the Treatment of SARS-CoV-2 via Nebulization

Ana Maria Pereira  1   2 , Ayse Kaya  1 , Dan Alves  1 , Niusha Ansari-Fard  1 , Ibrahim Tolaymat  1 , Basel Arafat  1 , Mohammad Najlah  1
Affiliations

Preparation and Characterization of Disulfiram and Beta Cyclodextrin Inclusion Complexes for Potential Application in the Treatment of SARS-CoV-2 via Nebulization

Ana Maria Pereira et al. Molecules. .

Abstract

Disulfiram (DS), known as an anti-alcoholism drug, has shown a potent antiviral activity. Still, the potential clinical application of DS is limited by its low water solubility and rapid metabolism. Cyclodextrins (CDs) have been widely used to improve the solubility of drugs in water. In this study, five concentrations of hydroxypropyl β-cyclodextrin (HP) and sulfobutyl ether β-cyclodextrin (SBE) were used to form inclusion complexes of DS for enhanced solubility. Solutions were freeze-dried, and the interaction between DS and CD was characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FTIR). In addition, the nebulization properties of the DS-CD solutions were studied. The aqueous solubility of DS increased significantly when loaded to either of both CDs. The phase solubility of both complexes was a linear function of the CD concentration (AL type). Furthermore, physicochemical characterization studies showed a potent inclusion of the drug in the CD-DS complexes. Aerosolization studies demonstrated that these formulations are suitable for inhalation. Overall, the CD inclusion complexes have great potential for the enhancement of DS solubility. However, further studies are needed to assess the efficacy of DS-CD inclusion complexes against SARS-CoV-2 via nebulization.

Keywords: SARS-CoV-19; disulfiram; nebulization; solubility; β-cyclodextrin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of disulfiram (DS).
Figure 2
Figure 2
Chemical structure of hydroxypropyl β-cyclodextrin and sulfobutyl ether β-cyclodextrin, adapted from [17]. HP-β-CD: R = -CH2CHOHCH3; SBE-β-CD: R = -(CH2)4SO3-Na+.
Figure 3
Figure 3
(a) DS solubility in assorted CD solutions; (b) phase solubility diagrams of DS and CD (mean ± SD, n = 3).
Figure 4
Figure 4
Differential Scanning Calorimetry (DSC) thermographs of (a) DS, HP-CD, and freeze-dried formulation (HP20); (b) DS, SBE-CD, and the freeze-dried formulation SBE20.
Figure 5
Figure 5
Thermogravimetric Analysis (TGA) thermographs of (a) DS, HP-CD, and HP-CD freeze-dried formulation; (b) DS, SBE-CD, and SBE-CD freeze-dried formulation.
Figure 6
Figure 6
Fourier Transform Infrared Spectroscopy (FTIR) spectra of (a) DS, physical mixture of DS with HP-CD, raw HP-CD, and HP-CD freeze-dried formulation; (b) DS, physical mixture of DS with SBE-CD, raw SBE-CD, and SBE-CD freeze-dried formulation.
Figure 7
Figure 7
Aerosol output of each empty CD (10% and 15%), and each CD (10% and 15%) loaded with DS (mean ± SD, n = 3).
Figure 8
Figure 8
FPF of each empty CD (10% and 15%), and each CD (10% and 15%) loaded with DS (mean ± SD, n = 3).
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