In every drug, no matter whether it comes as a pill or as an injection, we can always find two kinds of ingredients: the molecule with a therapeutic effect, called active principle, and a series of substances that go along with this active compound, called excipients. These additional components may have no therapeutic action, but they are essential for the drug to work, as they provide the physical and chemical characteristics that the active principle needs to act as it did in the laboratory testing. Therefore, in the road to develop a brand-new treatment for a disease, finding a molecule that can provide the therapeutic effect is vital, but if there is no adequate formulation of the product, the drug will probably fail.
In the New Deal project, our partner Eurofins Amatsigroup ensures that the therapeutic molecule is administered in the most suitable way. The New Deal project aims to treat intestinal bowel disease (IBD) using molecules called siRNAs which target genes involved in intestinal inflammation. “Our role is to work on the formulation parts. For example, designing a synthetic coating and ensuring that there is a correct delivery of the final product,” says Jo Vercammen, Director of Technical Business Management at Eurofins Amatsigroup.
There are many issues that are important when deciding the perfect formulation for a drug, and one of them is the dose strength. As we discussed in a previous post, a drug can prove useful to treat a disease in the lab, but if the dose required to make this effect produces harmful side effects which are worse than the disease itself, then the drug may be useless. “It really influences how we should make the formulation,” says Celine Van Vooren, Senior Scientist in Eurofins Amatsigroup. “Do we need a high load of the compounds or a low load?”
“That’s something we need to know from the beginning,” Vercammen points out. In the case of IBD, the drug must reach the intestine to reduce its inflammation. For this purpose, the New Deal project is developing lipid nanoparticles that can carry the siRNAs, enter the intestinal cells, and deliver the cargo. But, even if in the laboratory this concept works, the ultimate goal is to make the therapy work in patients. “The challenge with nanoparticles is about the assembly of the molecule with the nanoparticles: to check that the therapeutic molecule still has the correct conformation after the process,” says Vercammen.
Therefore, another characteristic that must be checked is the stability of the resulting product. Parameters such as the solubility, the reactivity and other physical and chemical characteristics can affect the integrity of the drug, but also the way it behaves within the body. “For example, in the first stage we screened two different polymers to see which excipients give the best reconstitution or the best release of the drug molecule,” Van Vooren recalls. These experiments are key to find the most adequate polymers that will help the nanoparticles to act as intended. It quickly turns into a race to test many different formulation strategies searching for the best one. “We look in an in vitro model to have an idea of how nanoparticles will dissolve, depending on parameters such as the pH composition of the medium,” Vercammen explains. This is key to choose the best delivery route for your drug. “If you target the intestinal tract, you have to make sure that the formulation doesn’t dissolve in the stomach region and stays stable, but then at the point of the colon, it starts to dissolve,” Van Vooren adds.
Finally, considering that nanoparticles are the vehicle that will carry the siRNA molecules to their destination, morphology also plays a role. “The size is quite important. Particles aggregate together and if the integrity is damaged, delivering the nucleic acids would be difficult. Therefore, one of the main things we check if the lipid nanoparticles still have the same size after the formulation process.”, explains Van Vooren. Even if nanoparticles’ size is microns -̶ one millionth of a metre̶ a shift in the form of these tiny vehicles can hamper the adequate release of the therapeutic drug in the intestine.
These are just a few aspects that formulation activities must consider when designing a drug delivery system. Even if a certain molecule looks like a perfect therapeutic answer to a disease, it may not behave as expected or the chosen delivery route may not be effective. At the end of the day, the final goal of formulation is clear, as Vercammen states: “Our responsibility is to deliver a formulation that can be used to in the clinic and in patients in the end”.