Oral Delivery of Niclosamide as an Amorphous Solid Dispersion That Generates Amorphous Nanoparticles during...

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Materials Science

Background:

• Niclosamide, an anthelmintic, shows potential as a chemotherapeutic and antiviral agent but suffers from poor water solubility and low oral bioavailability.
• The molecule's tendency to recrystallize prevents the formation of stable amorphous solids, hindering its therapeutic development.
• Previous work established an amorphous solid dispersion (ASD) of niclosamide that enhances solubility and bioavailability but requires an enteric dosage form to prevent acid-mediated recrystallization.

Purpose of the Study:

• To characterize nanoparticles formed during niclosamide ASD dissolution.
• To develop and evaluate enteric oral dosage forms of niclosamide ASD for improved clinical translation.
• To assess the in vivo performance of the optimized enteric dosage form in beagle dogs.

Main Methods:

• Nanoparticle characterization using cryogenic transmission electron microscopy (Cryo-TEM) and wide-angle X-ray scattering (WAXS).
• Formulation of enteric capsules and enteric-coated tablets using niclosamide ASD.
• In vitro evaluation of enteric dosage forms using pH-shift dissolution and acid-uptake tests.
• In vivo pharmacokinetic study in beagle dogs.

Main Results:

• Nanoparticles generated from niclosamide ASD were amorphous with a particle size of approximately 150 nm.
• Enteric-coated tablets effectively protected the niclosamide ASD from acid ingress and maintained nanoparticle generation during dissolution.
• Enteric-coated tablets in beagle dogs resulted in higher niclosamide plasma concentrations compared to literature values for solubilized niclosamide at a higher dose.

Conclusions:

• Enteric-coated tablets represent a viable oral dosage form for niclosamide ASD, overcoming limitations of poor solubility and recrystallization.
• This formulation strategy enhances niclosamide's apparent solubility and bioavailability, supporting its advancement for new indications.
• The developed enteric-coated tablets demonstrate superior in vivo performance, paving the way for clinical applications of niclosamide.