Encapsulation of Metronidazole in Biocompatible Macrocycles and Structural Characterization of Its Nano Spray-Dried Nanostructured Composite.

Mirella Mirankó,Tivadar Feczkó,László Biczók,Mónika Megyesi,Judit Tóth,Zsombor Miskolczy

doi:10.3390/molecules26237335

Abstract

Due to the great potential of biocompatible cucurbit[7]uril (CB7) and 4-sulfonatocalix[4]arene (SCX4) macrocycles in drug delivery, the confinement of the pharmaceutically important metronidazole as an ionizable model drug has been systematically studied in these cavitands. Absorption and fluorescence spectroscopic measurements gave 1.9 × 105 M−1 and 1.0 × 104 M−1 as the association constants of the protonated metronidazole inclusion in CB7 and SCX4, whereas the unprotonated guests had values more than one order of magnitude lower, respectively. The preferential binding of the protonated metronidazole resulted in 1.91 pH unit pKa diminution upon encapsulation in CB7, but the complexation with SCX4 led to a pKa decrease of only 0.82 pH unit. The produced protonated metronidazole–SCX4 complex induced nanoparticle formation with protonated chitosan by supramolecular crosslinking of the polysaccharide chains. The properties of the aqueous nanoparticle solutions and the micron-sized solid composite produced therefrom by nano spray drying were unraveled. The results of the present work may find application in the rational design of tailor-made self-assembled drug carrier systems.

Highlights

The formulation of active pharmaceutical ingredients is a significant challenge in the development of stable and bioavailable dosage forms with improved therapeutic efficacy
The preferential binding of the protonated metronidazole resulted in 1.91 pH unit pKa diminution upon encapsulation in CB7, but the complexation with SCX4 led to a pKa decrease of only 0.82 pH unit
Both CB7 and SCX4 macrocycles can serve as molecular containers for the encapsulation of the protonated form of the medically important metronidazole

Summary

Introduction

The formulation of active pharmaceutical ingredients is a significant challenge in the development of stable and bioavailable dosage forms with improved therapeutic efficacy. Water-soluble macrocycles possessing a large hydrophobic interior, e.g., cyclodextrins, calixarenes and cucurbiturils, are widely used as functional excipients because the inclusion of drugs in their cavity can lead to enhanced solubility, a modified release rate, prolonged chemical or thermal stability, improved delivery and reduced side effects [1,2,3]. The dynamic nature of noncovalent interactions allows the fabrication of stimuli-responsive nanostructures for a targeted and controlled release of the biologically active constituent [7,8,9]. These potential benefits of host–guest complex formation may be exploited in the formulation of ionizable model drug, metronidazole (Met), a widely used synthetic antibiotic and antiprotozoal agent [10]. Various approaches have been reported to enhance its bioactivity and poor water-solubility, but its encapsulation has not been studied in cucurbit[7]uril

Methods

Results

Conclusion