In search of the optimal migraine medicine

Abstract: The use of oral transmucosal administration of eletriptan hydrobromide provides faster and more effective relief for migraine sufferers.

Source: Malmo University

In order for anti-migraine drugs to be effective, it is important that the active substance is immediately released into the bloodstream. The pills that are currently on the market go through the body’s metabolism which means that the effectiveness is reduced and there is a delay in the relief.

A research team from Malmö University believes it can bypass this by using a shortcut in the lining of the mouth.

Active substances in the treatment of migraine are known as triptans. This is a collective name for tryptamine-based drugs that react with serotonin receptors and thereby inhibit certain signaling substances in the brain that can trigger 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 research project Oral transmucosal delivery of eletriptan for neurological diseases, 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.

“An ordinary triptan tablet must pass through both the stomach and the liver, where a large part of the metabolism takes place. Studies show that more than half of a triptan dose is broken down on the way before it reaches the blood. We investigated the possibility of getting EB directly into blood vessels in the mouth through the mucosa under the tongue,” explains Valetti, who leads the project at the Biofilms Research Center for Biointerfaces.

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

“Our body has a buffer system that regulates and balances temporary pH variations and we saw no toxic effect on the mucosa during the four-hour period when the pH value was increased from 6.8 to 10.4. But what we don’t know is whether it’s perceived as unpleasant in the mouth or not.”

The biggest challenge lies in the fact that the mucous membrane is a relatively thick tissue and a barrier that should protect us from various external attacks. Last autumn they therefore carried out tests in which they examined in detail the lipids, which are believed to play a decisive role in the mucous membranes of pigs, in order to better understand this special barrier effect.

The results are expected in the spring.

About this news about migraine and neuropharmacology

Author: Press office
Source: Malmo University
Contact: Press office – Malmo University
Picture: The image is in the public domain

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

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Abstract

Oral transmucosal administration of eletriptan for neurological diseases

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

In order to overcome these problems, we present here, as far as we know, the first study on the possibility of oral transmucosal administration of one of the safest triptans, namely eletriptan hydrobromide (EB).

Based on an extensive set of in vitro and ex vivo experiments, we outline the conditions required for oral transmucosal administration, potentially leading to similar or even higher plasma drug concentrations expected from conventional oral administration.

Through studies of histology and tissue integrity, we conclude that EB does not cause morphological changes or damage the integrity of the mucosal barrier after 4 hours of exposure.

At the cellular level, EB is internalized in human oral keratinocytes within the first 5 minutes without inducing toxicity at relevant concentrations for transmucosal delivery. Given that pK_And EB belongs to the physiological range, we systematically investigated the effect of pH on solubility and transmucosal permeation.

When the pH increases from 6.8 to 10.4, the solubility of the drug drops drastically from 14.7 to 0.07 mg/mL. At pH 6.8, EB led to the highest drug flow and the total amount passed through the mucosa, while at pH 10.4, EB showed a higher permeability coefficient and thus a higher ratio of the drug passed in relation to the administered drug. Permeability experiments with model membranes confirmed the pH-dependent permeability profile of EB.

The distribution of EB in different cell compartments of keratinocytes depends on pH. In summary, high ionization of the drug leads to greater association with the cell membrane, indicating ionic interactions between EBs and phospholipid heads. Moreover, we show that the chemical permeability enhancer DMSO can be used to significantly increase drug permeability (ie, a 12- to 36-fold increase).

Taken together, this study presents important findings on oral transmucosal delivery of eletriptan and paves the way for clinical research for the rapid and safe treatment of migraine.