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

Abstract

Niclosamide is an FDA-approved anthelmintic that is being studied in clinical trials as a chemotherapeutic and broad-spectrum antiviral. Additionally, several other applications are currently in the preclinical stage. Unfortunately, niclosamide is a poorly water soluble molecule, with reduced oral bioavailability, which hinders its use for new indications. Moreover, niclosamide is a poor glass former; in other words, the molecule has a high tendency to recrystallize, and it is virtually impossible to generate a stable amorphous solid employing the neat molecule. Previously, our group reported the development of an amorphous solid dispersion (ASD) of niclosamide (niclosamide ASD) that generates nanoparticles during its dissolution, not only increasing niclosamide’s apparent solubility from 6.6 ± 0.4 to 481.7 ± 22.2 µg/mL in fasted state simulated intestinal fluid (FaSSIF) but also its oral bioavailability 2.6-fold in Sprague–Dawley rats after being administered as a suspension. Nevertheless, niclosamide ASD undergoes recrystallization in acidic media, and an enteric oral dosage form is needed for its translation into the clinic. In this work, we further characterized the nanoparticles that generated during the dissolution of the niclosamide ASD. Cryogenic transmission electron microscopy (Cryo-TEM) and wide-angle X-ray scattering (WAXS) revealed that the nanoparticles were amorphous and had a particle size of ~150 nm. The oral dosage forms of niclosamide ASD were formulated using commercial enteric capsules (Capsuline® and EudracapTM) and as enteric-coated tablets. The enteric dosage forms were tested using pH-shift dissolution and acid-uptake tests, using the USP type II dissolution apparatus and the disintegration apparatus, respectively. The capsules exhibited a higher percentage of weight gain, and visual rupture of the Capsuline capsules was observed. Eudracap capsules protected the formulation from the acidic media, but polymer gelling and the formation of a nondispersible plug were noted during dissolution testing. In contrast, enteric-coated tablets protected the formulation from acid ingress and maintained the performance of niclosamide ASD granules during dissolution in FaSSIF media. These enteric-coated tablets were administered to beagle dogs at a niclosamide dose of 75 mg/kg, resulting in plasma concentrations of niclosamide higher than those reported in the literature using solubilized niclosamide at a higher dose (i.e., 100 mg/kg). In summary, an enteric oral dosage form of niclosamide ASD was formulated without hindering the generation of nanoparticles while maintaining the increase in the niclosamide’s apparent solubility. The enteric-coated tablets successfully increased the niclosamide plasma levels in dogs when compared to a niclosamide solution prepared using organic solvents.

Clinical safety and pharmacokinetics of a novel oral niclosamide formulation compared with marketed niclosamide chewing tablets in healthy volunteers: a three-part randomized, double-blind, placebo-controlled trial

“…PEG-400 was used here as a solvent to increase absorption in the intestine. However, PEG has an osmotic effect and is the basis of some laxatives used in gastroenterology, known to cause GI side effects that could affect absorption [15, 17].…”

“…We developed the drug as a drinking solution consisting of polyethyleneglycol 400 g/mol (PEG 400) as a solvent for niclosamide, aiming to increase intestinal absorption and to ensure more reproducible uptake [15, 16]. We hypothesized that the niclosamide solution would reduce the high variability of plasma levels and increase systemic availability, making it more suitable for the clinical treatment of systemic diseases.…”

Enteric coating of tablets containing an amorphous solid dispersion of an enteric polymer and a weakly basic drug: A strategy to enhance in vitro release

“…In terms of using coatings to prevent drug crystallization of ASDs, both enteric and non-enteric coatings have been evaluated. ASDs of niclosamide with copovidone (60% DL) exhibited crystallization in a simulated gastric medium (pH 2.0) after immersion for 30 min which could be circumvented by formulating as enteric-coated tablets which delayed drug release until the higher pH environment of the intestine, where crystallization was less favorable due to ionization of the drug ( Jara et al, 2022 ). Non-enteric coatings have also been used to reduce amorphous drug crystallization during storage of the solid formulation ( Boel and Van den Mooter, 2023 , Li et al, 2019 , Zeng et al, 2019 ).…”

“…Riekes and co-workers used Eudragit® L100 for fixed-dose combinations of an ezetimibe and lovastatin ASD with Soluplus (5:5:90, w/w/w) to avoid the formation of the active metabolite of lovastatin in gastric environments ( Riekes et al, 2017 , Riekes et al, 2016 ). Enteric-coated formulations were also noted to prevent drug crystallization in acidic media for ASDs of niclosamide with copovidone at a 60% DL ( Jara et al, 2022 ). In another study, enteric-coated darunavir-HPMC ASD nanoparticles were fabricated in a single step using electrospraying ( Nguyen et al, 2016 ).…”

3D-Printed Gastroretentive Tablets Loaded with Niclosamide Nanocrystals by the Melting Solidification Printing Process (MESO-PP)

“…In a previous work performed by Tharmalingam et al [ 14 ], it was verified that Niclosamide was stable at acid pH, being effective, in vitro and in vivo, against antimicrobial forms of H. pylori with a Minimum Inhibitory Concentration (MIC) and a Minimum Bactericidal Concentration (MBC) of 0.25 µg/mL and 0.5 µg/mL, respectively. Despite the accumulated evidence that positions Niclosamide for use in the treatment of H. pylori , this drug belongs to the class II of the biopharmaceutical classification system (BCS), being very low in solubility and dissolution in aqueous media, especially at acidic pH [ 15 ]. To obtain a successful antimicrobial treatment for H. pylori infection, drugs must be stable and active at acidic pH and have the capacity to penetrate the gastric mucosa to reach and maintain the minimum concentrations (MIC and MBC) in this region.…”