Intranasal formulation helps edaravone reach brain: Early study

Approach might offer patients more convenient option with fewer side effects

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Illustration of intranasal spray.

An into-the-nose (intranasal) formulation of edaravone — the active ingredient in the amyotrophic lateral sclerosis (ALS) medication Radicava — may enhance the medication’s ability to reach brain tissue, according to a recent study.

The formulation, which was made by packaging edaravone into tiny carriers called nanoparticles, was found to ease toxicity in cell cultures, and showed good brain distribution with limited accumulation in other organs when delivered via the intranasal route in mice.

Researchers believe this approach might eventually offer patients an alternate mode of delivery for edaravone with fewer side effects, but could also be used to formulate other ALS medications that have a hard time getting into the brain.

“This study is the first of its kind to develop an ALS drug in a nanoparticulate formulation for nose-to-brain delivery raising hope to ALS patients where currently treatment options are limited,” researchers wrote.

The study, “Intranasal administration of edaravone nanoparticles improves its stability and brain bioavailability,” was published in the Journal of Controlled Release.

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Radicava designed to combat oxidative stress

Radicava works to slow functional decline in ALS by combating oxidative stress, a type of cellular damage that’s implicated in the nerve cell death that characterizes the disease.

It is available to patients in a number of countries as an into-the-vein (intravenous) infusion, but an oral formulation called Radicava ORS is also approved in the U.S. and Canada. Neither formulation has been cleared in the European Union.

Intranasal formulations of medications are thought to offer certain advantages for treating neurological conditions, but such a formulation of Radicava does not currently exist.

With this approach, medications are often packaged into nanoparticles, which have characteristics that help to bypass the selective blood-brain barrier (BBB) and efficiently reach the brain tissue when inhaled through the nose. The BBB is a tight-knit collection of cells that works to keep unwanted molecules out of the brain. A consequence of this is that certain medications, when delivered into the bloodstream, have a hard time getting in.

In addition to helping medications reach the brain in higher concentrations, intranasal therapies are thought to help avoid side effects that arise when a medication accumulates in various organs after a systemic mode of delivery.

This study is the first of its kind to develop an ALS drug in a nanoparticulate formulation for nose-to-brain delivery raising hope to ALS patients where currently treatment options are limited.

Researchers develop new nanoparticle-encapsulated version of edaravone

As such, researchers in the U.K. and China developed a new nanoparticle-encapsulated version of edaravone, referred to as NP-EDV and examined its properties in cell cultures and mice.

Results indicated that edaravone could be efficiently loaded into the nanoparticles and had better shelf-life stability than the molecule normally has on its own.

Moreover, NP-EDV exhibited favorable pharmacological properties and reduced signs of oxidative stress and associated cellular toxicity in an oxidative stress cell culture model.

The encapsulated treatment was then tagged with a fluorescent marker and administered to healthy mice via intranasal or intravenous delivery. The fluorescent marker can be imaged to look at the distribution of the medication throughout the body.

While both modes of delivery enabled NP-EDV to reach the brain, similar concentrations were reached with a much lower dose of the intranasal treatment, suggesting “smaller drug doses can be given without compromising drug concentrations in the brain,” the researchers wrote.

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Intranasal route limited uptake of medication largely to brain, GI tract

On the other hand, distribution of NP-EDV was more widespread throughout the body with the intravenous infusion, showing accumulation in several organs including the liver, whereas the intranasal route limited uptake of the medication largely to the brain and gastrointestinal tract.

“Altogether the imaging study … suggested that the [intranasal] route offers a more ‘brain targeting’ approach with relative lower accumulation in the rest of the body,” the researchers wrote.

Avoiding accumulation in these other organs might help to prevent side effects.

In addition to supporting the potential benefits of an intranasal edaravone formulation, the scientists believe the study’s findings have broader applications. The nanoparticles they developed could also be used to package other potential ALS therapies that have a limited ability to reach the brain on their own.

“The current approach also opens up new opportunities for repurposed drugs for treatment of ALS which could otherwise be limited due to poor BBB crossing and brain bioavailability,” the team concluded.