Amorphous Solid Dispersions and the Contribution of Nanoparticles to In Vitro Dissolution and In Vivo Testing: Niclosamide as a Case Study.

Miguel O Jara,Robert O Williams,Zachary N Warnken

doi:10.3390/pharmaceutics13010097

Miguel O Jara, Robert O Williams + Show 1 more

Open Access

https://doi.org/10.3390/pharmaceutics13010097

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Journal: Pharmaceutics	Publication Date: Jan 14, 2021
Citations: 36	License type: CC BY 4.0

Affiliation: The University of Texas at Austin

Abstract

We developed an amorphous solid dispersion (ASD) of the poorly water-soluble molecule niclosamide that achieved a more than two-fold increase in bioavailability. Notably, this niclosamide ASD formulation increased the apparent drug solubility about 60-fold relative to the crystalline material due to the generation of nanoparticles. Niclosamide is a weakly acidic drug, Biopharmaceutics Classification System (BCS) class II, and a poor glass former with low bioavailability in vivo. Hot-melt extrusion is a high-throughput manufacturing method commonly used in the development of ASDs for increasing the apparent solubility and bioavailability of poorly water-soluble compounds. We utilized the polymer poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP–VA) to manufacture niclosamide ASDs by extrusion. Samples were analyzed based on their microscopic and macroscopic behavior and their intermolecular interactions, using differential scanning calorimetry (DSC), X-ray diffraction (XRD), nuclear magnetic resonance (NMR), Fourier-transform infrared (FTIR), and dynamic light scattering (DLS). The niclosamide ASD generated nanoparticles with a mean particle size of about 100 nm in FaSSIF media. In a side-by-side diffusion test, these nanoparticles produced a four-fold increase in niclosamide diffusion. We successfully manufactured amorphous extrudates of the poor glass former niclosamide that showed remarkable in vitro dissolution and diffusion performance. These in vitro tests were translated to a rat model that also showed an increase in oral bioavailability.

Highlights

Niclosamide is an FDA-approved anthelmintic drug that is one of the Model List of Essential Medicines produced by the World Health Organization (WHO) [1,2]
In order to understand the mechanism of solubility and bioavailability improvement of niclosamide amorphous solid dispersion (ASD), we evaluated the in vitro and in vivo performance of a niclosamide
The niclosamide was considered amorphous at the limit of X-ray diffraction (XRD) sensitivity

Summary

Introduction

Niclosamide is an FDA-approved anthelmintic drug that is one of the Model List of Essential Medicines produced by the World Health Organization (WHO) [1,2]. The water solubility of niclosamide has been reported to be about 13.32 μg/mL in its anhydrous form, but this falls to about 0.61 or 0.96 μg/mL for its monohydrate forms [9]. Several clinical trials have attempted to repurpose niclosamide. One of the clearest examples is the clinical trial NCT02532114, which was terminated early due to the low oral bioavailability of niclosamide, which exhibited Cmax values between 35.7 and 182 ng/mL after the oral administration of 500 mg three times daily. The authors stated that any attempt to repurpose the previously approved niclosamide product as a cancer therapy should be avoided, and efforts should be directed toward developing analogs that have higher bioavailability [10]. The efforts to increase niclosamide’s bioavailability include the use of co-crystals [8,11,12], solid lipid nanoparticles [13], dendrimer-like mate-

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