Aqueous cannabidiol β-cyclodextrin complexed polymeric micelle nasal spray to attenuate in vitro and ex vivo SARS-CoV-2-induced cytokine storms

Int J Pharm. 2023 Jun 10:640:123035. doi: 10.1016/j.ijpharm.2023.123035. Epub 2023 May 12.


Cannabidiol (CBD) has a number of biological effects by acting on the cannabinoid receptors CB1 and CB2. CBD may be involved in anti-inflammatory processes via CB1 and CB2 receptors, resulting in a decrease of pro-inflammatory cytokines. However, CBD's poor aqueous solubility is a major issue in pharmaceutical applications. The aim of the present study was to develop and evaluate a CBD nasal spray solution. A water-soluble CBD was prepared by complexation with β-cyclodextrin (β-CD) at a stoichiometric ratio of 1:1 and forming polymeric micelles using poloxamer 407. The mixture was then lyophilized and characterized using FT-IR, DSC, and TGA. CBD-β-CD complex-polymeric micelles were formulated for nasal spray drug delivery. The physicochemical properties of the CBD-β-CD complex-polymeric micelle nasal spray solution (CBD-β-CDPM-NS) were assessed. The results showed that the CBD content in the CBD-β-CD complex polymeric micelle powder was 102.1 ± 0.5% labeled claim. The CBD-β-CDPM-NS was a clear colorless isotonic solution. The particle size, zeta potential, pH value, and viscosity were 111.9 ± 0.7 nm, 0.8 ± 0.1 mV, 6.02 ± 0.02, and 12.04 ± 2.64 cP, respectively. This formulation was stable over six months at ambient temperature. The CBD from CBD-β-CDPM-NS rapidly released to 100% within 1 min. Ex vivo permeation studies of CBD-β-CDPM-NS through porcine nasal mucosa revealed a permeation rate of 4.8 μg/cm2/min, which indicated that CBD was effective in penetrating nasal epithelial cells. CBD-β-CDPM-NS was tested for its efficacy and safety in terms of cytokine production from nasal immune cells and toxicity to nasal epithelial cells. The CBD-β-CDPM-NS was not toxic to nasal epithelial at the concentration of CBD equivalent to 3.125-50 μg/mL. When the formulation was subjected to bioactivity testing against monocyte-like macrophage cells, it proved that the CBD-β-CDPM-NS has the potential to inhibit inflammatory cytokines. CBD-β-CDPM-NS demonstrated the formulation's ability to reduce the cytokine produced by S-RBD stimulation in ex vivo porcine nasal mucosa in both preventative and therapeutic modes.

Keywords: Cannabidiol; Nasal spray solution; Polymeric micelles; Pro-inflammatory cytokine; SARS-CoV-2; β-Cyclodextrin.

MeSH terms

  • Animals
  • COVID-19*
  • Cannabidiol* / chemistry
  • Cytokine Release Syndrome
  • Micelles
  • Nasal Sprays
  • SARS-CoV-2
  • Spectroscopy, Fourier Transform Infrared
  • Swine
  • beta-Cyclodextrins* / chemistry


  • Cannabidiol
  • Micelles
  • Nasal Sprays
  • beta-Cyclodextrins