In Search of Optimal Migraine Relief

In Search of Optimal Migraine Relief

Summary: Oral transmucosal administration of eletriptan hydrobromide provides faster and more effective relief for migraine sufferers.

Source: Malmo University

For migraine medications to be effective, it is essential that the active substance is immediately released into the bloodstream. The pills currently on the market go through the body’s metabolism, which means that effectiveness is reduced and there is a delay in relief.

A research team from the University of Malmö thinks they can circumvent this problem by means of a shortcut in the mucous membrane of the mouth.

The active substances in migraine medicine are called triptans. It is a collective name for tryptamine-based drugs that react with serotonin receptors and thereby inhibit certain signaling substances in the brain that can cause the experience of pain. Serotonin is one of the most important signaling substances in the human nervous system and affects, among other things, sexual behavior, appetite, sleep and pain.

In the Oral Transmucosal Administration of Eletriptan for Neurological Diseases research project, Sabrina Valetti and her research colleagues chose to work with eletriptan hydrobromide (EB), which is the triptan with the least toxic effect on the heart.

“A regular triptan pill must pass through both the stomach and the liver, where much of the metabolism takes place. Studies show that more than half of the triptan dose is broken down before it reaches the blood. We investigated the possibility of introducing EB directly into blood vessels in the mouth through the mucosa under the tongue,” says Valetti, who leads the project at the Biofilm Research Center for Biointerfaces.

It shows a brain
Serotonin is one of the most important signaling substances in the human nervous system and affects, among other things, sexual behavior, appetite, sleep and pain. Image is in public domain

“We know from patient studies that it is important for the substance to reach maximum concentration in the blood within two hours to have an effect. We therefore studied what was the expected concentration of EB with our method after this period. We saw that the expected concentration was higher in 3D human cells than that provided by regular migraine pills. This was also the case for pig mucosa, but only if the pH value was increased,” she says, and continues:

“Our body has a buffer system that regulates and balances temporary pH variations and we did not see any toxic effects on the mucosa for a period of four hours when the pH value changed from 6.8 to 10.4. But what we don’t know is whether it feels unpleasant in the mouth or not.

The biggest challenge lies in the fact that the mucosa is a relatively thick tissue and a barrier that must protect us from the most diverse external attacks. They therefore carried out tests last fall where they examined in detail the lipids, which are thought to play a determining role in the mucous membrane of pigs, in order to better understand this particular barrier effect.

The results are expected in the spring.

About this migraine and neuropharmacology research news

Author: Press office
Source: Malmo University
Contact: Press office – University of Malmö
Picture: Image is in public domain

Original research: Free access.
“Oral transmucosal administration of eletriptan for neurological diseases” by Sabrina Valetti et al. International Journal of Pharmaceuticals


Oral transmucosal administration of eletriptan for neurological diseases

Migraine is a very common neurological disease that affects approximately 1 billion patients worldwide and presents with severe disabling symptoms, which significantly decreases the quality of life. As a self-medication practice, oral administration of triptans is the most common option, despite its relatively slow therapeutic onset and low drug bioavailability.

To overcome these problems, we present here, to our knowledge, the first study on the possibility of oral transmucosal administration of one of the safest triptans, namely eletriptan hydrobromide (EB).

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Based on a comprehensive set of in vitro and ex vivo experiments, we highlight the conditions required for oral transmucosal administration, which may result in similar or even higher plasma drug concentrations expected from administration. conventional oral.

With histology and tissue integrity studies, we conclude that EB does not induce morphological changes or impair the integrity of the mucosal barrier after 4 h of exposure.

At the cellular level, EB is internalized in human oral keratinocytes within the first 5 minutes without inducing toxicity at concentrations relevant for transmucosal administration. Whereas the pKa of EB is within the physiological range, we have systematically investigated the effect of pH on both solubility and transmucosal permeation.

As the pH is increased from 6.8 to 10.4, the drug solubility decreases dramatically from 14.7 to 0.07 mg/mL. At pH 6.8, EB resulted in the highest drug flux and total amount permeated through the mucosa, while at pH 10.4 EB shows a higher permeability coefficient and hence a higher ratio of drug impregnated with respect to the drug applied. Permeation experiments with model membranes confirmed the pH-dependent permeation profile of EB.

The distribution of EB in the different cellular compartments of keratinocytes is pH-dependent. Briefly, high drug ionization leads to higher association with the cell membrane, suggesting ionic interactions between EB and phospholipid headgroups. Additionally, we show that the chemical permeation enhancer DMSO can be used to significantly improve drug permeation (i.e., a 12- to 36-fold increase).

Taken together, this study presents important findings on transmucosal administration of eletriptan via the oral cavity and paves the way for clinical investigations for prompt and safe treatment of migraine.

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