The hormone also exists in percutaneous gels and patches that allow the first-pass effect in the liver to be circumvented while providing stable and prolonged concentrations in the blood stream, contrary to the sought-after effect. The transdermal route could also be excluded then.

In fact, the Canadian company Trimel Pharmaceuticals, which initiated the Tefina project, had already chosen the transnasal route of administration. “It’s not a new route”, Brigitte Evrard reminds us. “It’s already used for other active ingredients such as sumatriptan and dihydroergotamine (drugs to treat migraine) or for hormones such as ocytocin, calcitonin, and the antidiuretic hormone (ADH). Like the transdermal route, it bypasses the liver, but its effect is much shorter. The transnasal route gives a rapid and transitory plasmatic peak, which is exactly what the manufacturer was looking for.” 

The Canadians therefore came to Liège with a product whose development was already quite advanced. “Contrary to what was said in certain newspapers, Tefina wasn’t developed entirely here”, Brigitte Evrard points out. “What happened was that the Canadian researchers encountered problems in making the appropriate amount of active ingredient soluble in the excipients they had chosen. Therefore, they came to us with this specific problem and our role was simply to help them choose the right excipient and find the method of manufacturing that would allow them to obtain the desired results.”

Spray technology

What are the requirements for a good nasal spray? “The product has to adhere well to the mucous membrane to maintain contact for a certain amount of time and therefore improve absorption. An aqueous solution would seep out immediately with the nasal secretions. Therefore, it’s necessary to use a viscous liquid, what we call a gel, which is administered in a finely dispersed spray."

Therefore, to develop a nasal form, you would first have to find excipients that are well tolerated by the nose’s fragile mucous membrane to avoid damaging the cilia. And that isn’t easy: while some excipients are known for being toxic to the nose’s mucous membrane, they can nevertheless be safely used in eye drops for instance. The nasal mucous membrane also imposes isotonic and pH rules: solutions that are too acid or too alkaline can't be applied inside the nose... but it is also necessary to remain compatible with the active molecule, which often has its own requirements. It is equally essential to find the optimum level of viscosity, to allow the longest possible adhesion to the mucous membrane without blocking the cilia, which must remain functional. In this precise case, the solution was found in agents that increase the product’s viscosity.