Development and Characterization of the Neuroregenerative Xanthohumol C/Hydroxypropyl-β-cyclodextrin Complex Suitable for Parenteral Administration

Michael Kirchinger; Lara Bieler; Julia Tevini; Michael Vogl; Elisabeth Haschke-Becher; Thomas K. Felder; Sebastien Couillard-Després; Herbert Riepl; Corinna Urmann

doi:10.1055/a-1013-1276

Planta Medica, Table of Contents

Planta Med 2019; 85(16): 1233-1241
DOI: 10.1055/a-1013-1276

Biological and Pharmacological Activity

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

Development and Characterization of the Neuroregenerative Xanthohumol C/Hydroxypropyl-β-cyclodextrin Complex Suitable for Parenteral Administration

Michael Kirchinger‡

¹Organic-Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, Straubing, Germany

²TUM Campus Straubing, Straubing, Germany

,

Lara Bieler‡

³Institute of Experimental Neuroregeneration, Paracelsus Medical University Salzburg, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria

,

Julia Tevini

⁴Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria

,

Michael Vogl

³Institute of Experimental Neuroregeneration, Paracelsus Medical University Salzburg, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria

,

Elisabeth Haschke-Becher

⁴Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria

,

Thomas K. Felder

⁴Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria

⁵Obesity Research Unit, Paracelsus Medical University, Salzburg, Austria

,

Sebastien Couillard-Després

³Institute of Experimental Neuroregeneration, Paracelsus Medical University Salzburg, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria

⁶Austrian Cluster for Tissue Regeneration, Salzburg, Austria

,

Herbert Riepl

¹Organic-Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, Straubing, Germany

²TUM Campus Straubing, Straubing, Germany

,

Corinna Urmann

¹Organic-Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, Straubing, Germany

²TUM Campus Straubing, Straubing, Germany

› Author Affiliations

Abstract

The chroman-like chalcone Xanthohumol C, originally found in hops, was demonstrated to be a potent neuroregenerative and neuroprotective natural product and therefore constitutes a strong candidate for further pharmaceutical research. The bottleneck for in vivo experiments is the low water solubility of this chalcone. Consequently, we developed and validated a suitable formulation enabling in vivo administration. Cyclodextrins were used as water-soluble and nontoxic complexing agents, and the complex of Xanthohumol C and 2-hydroxypropyl-β-cyclodextrin was characterized using HPLC, HPLC-MS, NMR, and differential scanning calorimetry. The water solubility of Xanthohumol C increases with increasing concentrations of cyclodextrin. Using 50 mM 2-hydroxypropyl-β-cyclodextrin, solubility was increased 650-fold. Furthermore, in vitro bioactivity of Xanthohumol C in free and complexed form did not significantly differ, suggesting the release of Xanthohumol C from 2-hydroxypropyl-β-cyclodextrin. Finally, a small-scaled in vivo experiment in a rat model showed that after i. p. administration of the complex, Xanthohumol C can be detected in serum, the brain, and the cerebrospinal fluid at 1 and 6 h post-administration. Mean (± SD) Xanthohumol C serum concentrations after 1, 6, and 12 h were determined as 463.5 (± 120.9), 61.9 (± 13.4), and 9.3 (± 0.8) ng/mL upon i. v., and 294.3 (± 22.4), 45.5 (± 0.7), and 13 (± 1.0) ng/mL after i. p. application, respectively. Accordingly, the formulation of Xanthohumol C/2-hydroxypropyl-β-cyclodextrin is suitable for further in vivo experiments and further pharmaceutical research aiming for the determination of its neuroregenerative potential in animal disease models.

Key words

Xanthohumol C - drug solubilization - bioavailability - cyclodextrin - Cannabaceae

Full Text

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