Fette Compacting

THE KEY TO THE RECEPTOR

The effects and processing of highly potent substances

It is hoped that highly potent substances will make it possible to develop new therapies. Countless scientists are currently researching such high-potency active pharmaceutical ingredients (HPAPIs). In this interview, expert Prof. Dr. Karl G. Wagner explains the potential that these minute particles hold and the challenges faced by researchers.

Prof. Dr. Wagner, what makes an API highly potent?
Two aspects need to be considered when answering that question. One is the desired effect of a drug within the body. In this respect, a substance is considered highly potent is it is biologically effective at a dose of no more than 150 micrograms per kilo of body weight. The other aspect is operator exposure during pharmaceutical processing, which is defined in the OEL figures. In this context, APIs with a workplace concentration of 10 micrograms per cubic meter of air or less are rated as highly potent.

Which therapies are highly potent substances used for?
There are substances that are effective at extremely low doses in every therapeutic area. However, key application areas include highly toxic cytostatic drugs for cancer therapies and hormones for contraception, HRT, and numerous other uses.

What is the significance of HPAPIs for new drugs?

Due to their genesis, new API molecules are becoming more and more selective and active. This is also necessary, so that manufacturers can develop drugs that offer an advantage over the existing standard therapy, which is crucial for them to be approved.

Which fields of research are driving the development of high-dose drugs?
As the biochemical processes in the body are very well understood, we now know where most receptors – the targets for drug therapy – are located. The high-potency approach came about because we are increasingly able to design the right molecule keys for the receptors with the help of computer-aided simulations. After all, there is a key for each receptor which fits that particular lock perfectly. A picklock might work too, but this is more of a rough and ready approach which won’t operate the lock mechanism so smoothly. In the field of solids, however, we still often face the problem of low bioavailability when high-potency substances are administered orally.

What causes this low bioavailability?
Due to their high receptor affinity, most new chemical entities (NCEs) have low water solubility, which limits their absorption in the gastrointestinal tract. In this case, suitable formulation concepts need to be found. New biological entities (NBEs) suffer from another problem: our bodies are programmed to break down proteins and peptides as food. Outwitting this program is very complicated.

How can this problem be solved in solids production for biopharmaceuticals?

Personally, I think it might be possible to protect the protein by encasing it. Simply coating a tablet is not enough though. The substance needs to be made of into extremely fine particles – just a few micrometers or even nanometers. These then have to be used to generate miniparticles, which need to be encapsulated to protect them from enzymes and stomach acid. The casing also has to have an affinity with the mucous membrane in the intestine so that the particle can embed itself there in a targeted fashion and the active ingredient can penetrate the wall of the intestine. Scientists are already able to produce such particles.  The challenge lies in finding the right shell. It is particularly difficult to subsequently put the particles in a solid form that enables them to disperse again as effective individual particles following administration. A lot of research still needs to be done here in the coming years and decades.

How is knowledge shared with pharmaceutical manufacturers?

There’s still a huge gap here. In my view, it would be constructive for pharmaceutical manufacturers to set up a cross-industry initiative to statistically analyze toxicological data with safety factors, OELs, and data from occupational health investigations. This would enable researchers and users to interact much better and tackle current challenges more effectively.

Receptors on the cell membrane

Receptors on the cell membrane trigger specific reactions inside the cell. High-potency APIs are designed to fit the relevant receptor precisely and achieve the desired effect. (Photo: ©markusblanke - iStock)

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