Autophagy-Inducing Inhalable Co-crystal Formulation of Niclosamide-Nicotinamide for Lung Cancer Therapy

Ray, Eupa; Vaghasiya, Kalpesh; Sharma, Ankur; Shukla, Rahul; Khan, Rehan; Kumar, Anil; Verma, Rajkumar

doi:10.1208/s12249-020-01803-z

Cited by 40 publications

(17 citation statements)

References 59 publications

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“…Interestingly, this PVP–VA carbonyl stretching (amide) even shifted in the physical mixture. This indicates a strong interaction, a phenomenon that has been seen in other studies with niclosamide and other excipients [27]. Solidstate NMR was conducted to gather further evidence about these interactions between niclosamide and PVP–VA.…”

Section: Resultsmentioning

confidence: 57%

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Amorphous solid dispersions and the confounding effect of nanoparticles in in vitro dissolution and in vivo testing: Niclosamide as a case of study

Jara

Warnken

2020

Preprint

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We developed an amorphous solid dispersion (ASD) of the poorly water soluble molecule niclosamide that achieved more than a 2 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, 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 polyvinylpyrrolidone vinyl acetate (PVPVA) to manufacture niclosamide ASDs by extrusion. Samples were analyzed based on their microscopic and macroscopic behavior and their intermolecular interactions, using DSC, XRD, NMR, FTIR, and 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 4 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.

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Section: Resultsmentioning

confidence: 57%

“…The peaks of niclosamide and PVP–VA were assigned as described in previous studies [7,27–29]. As can be seen in Figure 4, noticeable changes were observed when comparing niclosamide ASD and its physical mixture throughout the spectra.…”

Section: Resultsmentioning

confidence: 83%

Amorphous solid dispersions and the confounding effect of nanoparticles in in vitro dissolution and in vivo testing: Niclosamide as a case of study

Jara

Warnken

2020

Preprint

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show abstract

“…Interestingly, this PVP-VA carbonyl stretching (amide) even shifted in the physical mixture. This indicates a strong interaction, a phenomenon that has been seen in other studies with niclosamide and other excipients [27]. Solid-state NMR was conducted to gather further evidence about these interactions between niclosamide and PVP-VA.…”

Section: Ftirmentioning

confidence: 57%

“…The peaks of niclosamide and PVP-VA were assigned as described in previous studies [7,[27][28][29]. As can be seen in Error!…”

Section: Ftirmentioning

confidence: 99%

Amorphous Solid Dispersions and the Confounding Effect of Nanoparticles in in Vitro Dissolution and in Vivo Testing: Niclosamide as a Case Study

Williams¹,

Warnken²,

Jara³

2020

Preprint

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We developed an amorphous solid dispersion (ASD) of the poorly water-soluble molecule niclosamide that achieved more than a 2-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, 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 polyvinylpyrrolidone–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 DSC, XRD, NMR, FTIR, and 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 4-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.

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“…The aerosol performance of the niclosamide inhalation powder was determined by NGI, as shown in Table 2. The powder had an FPF (delivered dose) of 86.0 ± 2.7%, which is particularly high when compared with other niclosamide inhalers manufactured by technologies such as spray-drying [15,27]. Remarkably, the inhaled powder achieved an MMAD of about 1 μm and was able to reach the last stage of the cascade impactor ( Error!…”

Section: Resultsmentioning

confidence: 99%

Niclosamide Inhalation Powder Made by Thin-Film Freezing: Pharmacokinetic and Toxicology Studies in Rats and Hamsters

Jara

Warnken

Sahakijpijarn

et al. 2021

Preprint

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In this work, we have developed and tested in vivo a dry powder form of niclosamide made by thin-film freezing (TFF) and administered it by inhalation to rats and hamsters. The niclosamide dry powder, suitable for inhalation, is being developed as a therapeutic agent against COVID-19 infection. Niclosamide, a poorly water-soluble drug, is an interesting drug candidate because it was approved over 60 years ago for use as an anthelmintic medication, but recent studies demonstrated its potential as a broad-spectrum antiviral with a specific pharmacological effect against SARS-CoV-2 infection. In the past, clinical trials for other indications were terminated prior to completion due to low and highly variable oral bioavailability. In order to quickly address the current pandemic, targeting niclosamide directly to the lungs is rational to address the COVID-19 main clinical complications. Thin-film freezing technology was used to develop a niclosamide inhalation powder composition that exhibited acceptable aerosol performance with a fine particle fraction (FPF) of 86.0% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 1.11 μm and 2.84, respectively. This formulation not only proved to be safe after an acute three-day, multi-dose pharmacokinetic study in rats as evidenced by histopathology analysis, but also was able to achieve lung concentrations above the required IC50 and IC90 levels for at least 24 h after a single administration in a Syrian hamster model. To conclude, we successfully developed a niclosamide dry powder inhalation formulation by thin-film freezing for further scale-up and clinical testing against the COVID-19 infection. This approach overcomes niclosamide’s limitation of poor oral bioavailability by targeting the drug directly to the primary site of infection, the lungs.

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Autophagy-Inducing Inhalable Co-crystal Formulation of Niclosamide-Nicotinamide for Lung Cancer Therapy

Cited by 40 publications

References 59 publications

Amorphous solid dispersions and the confounding effect of nanoparticles in in vitro dissolution and in vivo testing: Niclosamide as a case of study

Amorphous solid dispersions and the confounding effect of nanoparticles in in vitro dissolution and in vivo testing: Niclosamide as a case of study

Amorphous Solid Dispersions and the Confounding Effect of Nanoparticles in in Vitro Dissolution and in Vivo Testing: Niclosamide as a Case Study

Niclosamide Inhalation Powder Made by Thin-Film Freezing: Pharmacokinetic and Toxicology Studies in Rats and Hamsters

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