The secrets of female Viagra

The announcement of the development of a testosterone nasal spray (a ‘Female Viagra’!) by a team from Liège, aimed at improving women’s sex life, was lucky enough to attract the attention of the media. But for the researchers, for whom Tefina (its name) only represents a small part of their activity, an experiment such as this is almost routine: the University of Liège’s Laboratory of pharmaceutical technology and biopharmacy carries out a great deal of innovative research that is far more complex than the development of this nasal spray. But why this particular route of administration? The contraceptive pill is taken orally, so why not testosterone?

It was a strange turn of fate that thrust the University of Liège’s Laboratory of pharmaceutical technology and biopharmacy into the spotlight. It was the announcement of the development of a testosterone nasal spray (a ‘Female Viagra’!) by the team from Liège, aimed at improving women’s sex life, that was lucky enough to attract the attention of the media. But for the researchers, for whom Tefina (its name) only represents a small part of their activity, this experience was slightly frustrating. “Our discipline is relatively unknown; it’s rarely mentioned in the press", admits Professor Brigitte Evrard, who manages the laboratory and faced her baptism of fire in front of journalists. “And yet we carry out a lot of innovative research that is far more complex than the development of this nasal spray”(read the box). Let’s take this opportunity then to discover the discipline of pharmaceutical technology which actually has a great many ramifications. And for the red thread, what if we were to take... the development of a nasal spray?

Why not orally?

First of all, why this particular routeof administration? The contraceptive pill is taken orally, so why not testosterone? The fact is that any drug taken via the traditional oral route passes through the digestive system, where it is absorbed through the network of veins that drain the intestines and end up in the liver via the portal vein. The liver is our main detoxification centre: it metabolises all the foreign molecules that arrive in it to prepare them to be excreted either into the intestines (a sort of ‘return to sender’) or via the kidneys. This system called the ‘first-pass effect’ provides an excellent barrier against poisoning... but it is also responsible for a considerable loss in the efficacy of the majority of drugs we swallow. In the case of hormones such as testosterone, oestrogen, etc., the first-pass effect is significant.   This is especially true for the contraceptive pill, which means it has to be administered in high doses so that a sufficient amount reaches the blood stream. Oral administration, which seems the obvious choice, isn't always the most effective.

There are more interesting alternative routes – one of the key areas of research of the laboratory of Pharamaceutical Technology in Liège – that circumvent the compulsory passage through the liver. Such is the case for transdermal (patches, gels), inhalational (puffers, inhalations), rectal (suppositories), intrauterine and vaginal (hormone-based coils, vaginal rings), sublingual (because the oral mucous membrane isn’t subservient to the portal vein system), and of course transnasal routes. For instance, in the case of hormones for contraceptive purposes, using the vaginal ring that gradually releases an oestroprogestative combination allows the dose administered by the mini pill to be reduced by 20. And in the case of testosterone, where the mannish side effects - hyperpilosity, a husky voice – are highly undesirable in women, high doses must be avoided at all costs. Therefore, with a ratio of 1 to 20, oral administration is clearly not the best solution.

The chemical nature of the molecules to be administered also plays an important role in the choice of route of administration. All molecules must be made soluble in order to pass through the intestinal barrier. Molecules that aren’t soluble in water, such as testosterone, immediately pose a problem as regards oral administration. This is the second reason why our testosterone couldn’t be given orally.

“Choosing the right dosage  form for every active ingredient is no small matter”, Brigitte Evrard stresses. “In fact, it lies at the basis of Pharmaceutical Technology (Pharmacie Galénique in French): the art of administering [a drug] is as important as [the composition of] what we give. It is derived from Galen, a doctor in ancient Rome, who was the first to think about choosing the most ‘suitable’ way to administer drugs to patients to obtain the desired effect. We can consider Galen as the true father of pharmacy, just as Hippocrates is considered the father of medicine.”

Hence, the aim of pharmaceutical technology is to optimise drug administration in order to reduce its side effects, improve the bioavailability of its active ingredients and, in addition, a more down-to-earth but no less important objective, to develop robust and reproducible manufacturing procedures (without which it is impossible to guarantee the product’s consistent quality – Read the box).

ULg's laboratory regularly collaborates with the pharmaceutical industry to develop drugs, whether they be 'conventional', rapid release (such as oral lyophilisates that melt on the tongue), or – on the contrary – sustained release such as enteric tablets, which allow targeted release in the intestines to treat Crohn’s Disease for instance. But Brigitte Evrard’s team focuses mainly on the less conventional administration routes, especially pulmonary and transnasal. Which brings us back to our female Viagra...

Why the transnasal route?

Testosterone has been on the market for a long time in an intravenous form, but these are products developed for men – with the aim of treating specific hormonal deficiencies but also for certain forms of doping... - and, be that as it may, for prolonged use. On the contrary, Tefina had to have a rapid effect. The key objective was to provoke a short peak in testosterone in the female brain (and not in the genital organs, which confirms that everything happens in the head...) in order to obtain the desired effect on female libido and sensitivity to pleasure. After the oral route, exit the intravenous route.

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.

Another challenge: the nasal mucous membrane's surface of absorption is very limited, compared with that of the intestinal villi for instance. Hence, we can only administer powerful molecules via this route that are active at very low doses, i.e. micrograms, which is luckily the case for sex hormones. On the other hand, there is no question of administering one gram of paracetamol via the nose!

“Every formulation is therefore the result of a compromise between the patient’s comfort, the biopharmaceutical activity, the molecule’s stability, etc. In this case, the challenge was above all to make the molecule soluble in the right excipient, in order to obtain a sufficiently concentrated solution to achieve the therapeutic concentrations – and the desired effect – with just a few microlitres spayed into the nose”, Brigitte Evrard continues.

As for the spray itself – i.e. the device that delivers the product – this is beyond the competences of a pharmaceutical technology laboratory and falls under the scope of another domain: plastics engineering. Companies specialising in the development of drug administration systems are responsible for designing devices according to the desired angle of the spray, the fineness of the drops, etc. Services that are also useful for the development of products intended for administration through inhalation, which is, it would seem, one of the most promising areas according to Brigitte Evrard. “Currently, this route is only used for pulmonary drugs: against asthma, COPD, cystic fibrosis, etc., for topical use. But the lungs could also be used for the systemic administration of drugs because they have the benefit of having a much larger surface of absorption than the nose. Therefore, it’s a very attractive route for a formulator!” she says enthusiastically. A inhalable insulin formukation was briefly marketed a few years ago but was quickly removed from the market (for commercial reasons, apparently, and not because of the method of administration). Today, several phase II and III studies are testing molecules that can’t be administered through the conventional routes, such as peptides, proteins, genetic material, etc. A whole new chapter of pharmaceutical technology looks set to begin in the future (Read the box).