Many people find it difficult to swallow medicines because of their repulsive taste – will a new method make them more human-friendly?

Researchers from the Hebrew University have developed a unique algorithm that is already predicted in the design stages of the material if it has a bitter and repulsive taste, based on its chemical structure. The algorithm, created using Machine Learning, will be able to speed up and reduce drug development processes and prevent animal experiments to assess the bitterness of the materials under development.

The research effort in drug development is concentrated in the development of effective and safe drugs so that they can cure disease with a minimum of side effects. The use of sophisticated and automated processes has led to the approval of thousands of drugs by the FDA, when in 2020 only 53 new drugs were approved. However, there is a problem that does not get an optimal solution – many drugs have a very bitter taste that makes it difficult to take them orally. Although introducing the drug into capsules usually solves the taste problem, this is a solution that is not always possible as it increases the drug and may create real difficulty in swallowing.

While many of us are able to swallow the drug despite its terrible taste or problematic size, there are populations that have great difficulty doing so, including toddlers and adults with difficulty swallowing. Studies have shown that when drugs had a very bitter taste, a decrease in responsiveness to treatment was observed in children, which posed a health hazard due to incomplete drug treatment. For example, a study published recently found that over 90% of pediatricians report many children who are unwilling to take medication because of their taste, which exposes them to health damage and lack of proper medical care. Moreover, because of the potential risks posed by the daunting taste of many drugs, the US FDA recently sought to add a flavor note to the list of side effects in child drug prescriptions to warn parents of those problematic tastes.

Today, drug companies will recognize that there is a problem of very bitter taste only in the advanced stages of development, or in the clinical trials themselves, when the drug is given to thousands of people who serve as experimenters to test its effectiveness. In case a particularly unusual taste problem is identified, companies will have to go back and change the formulation of the drugs in order to try and mask the terrible taste (which is not always possible), which will lead to further delays in releasing the drug to the market, millions of dollars in financial losses and further unwanted animal experiments. Most drug companies will prefer to market a drug even if they have already realized that it is very bitter, in the hope that we will deal with the unbearable taste.

In the research group of Prof. Masha Niv, taste researcher at the Institute of Biochemistry, Food and Nutrition in the Faculty of Agriculture, Food and the Environment of the Hebrew University, Understood the severity of the problem, and were able to develop an algorithm that predicts a strong bitterness of a molecule only on the basis of its theoretical chemical structure, even before it was created in the laboratory. The study was recently published in the paper Computational and Structural Biotechnology Journal.

Eitan Margolis, PhD student in Prof. Niv’s laboratory, Tells about the research process and the process of creating the algorithm using a machine learning method regarding intense bitterness: “We collected molecules from the databaseBitterDB Established in our lab and containing information on over 1000 bitter compounds. We incorporated information about the taste of molecules we received from our colleagues at the pharmaceutical companyGSK And in the company of natural materials AnalytiCon Discovery. We taught the computer to understand which combinations of chemical properties are most important in order for a particular substance to be perceived as having a very bitter taste and thus ‘trained’ it to quickly identify whether a particular molecule may be very bitter or not. So, basically, we created the algorithmBitterIntense . After testing the performance of the model, we saw that it is correct in more than 80% of cases, which strengthens the potential for its use for the development of taste-friendly drugs – without the need for early synthesis of the substance and testing in humans or animals. In addition, since this is a computational model, we can continue to improve its accuracy as more information about bitter molecules accumulates. ”

Contrary to previous scientific beliefs, it has been found from the results of predictions that very bitter drugs do not tend to be more toxic to the liver than less bitter drugs. However very bitter substances seemed to be more toxic to the heart due to their ability to block potassium channels. “The fact that very bitter substances have a higher potential to be toxic to the heart is particularly interesting because bitter taste receptors are also expressed in the heart. Current studies focus on the physiological functions of taste receptors expressed outside the mouth.”, Explains Prof. Niv.

And what about medicines for corona disease? Doctoral student Eitan Margolis adds that “we have seen that the prevalence of highly converted drugs among those currently in development or approval for treatment with Corona is higher than in the general drug group. “In Prof. Niv’s laboratory. However, the fact that very bitter drugs can have a beneficial physiological effect emphasizes the need not to outright disqualify those very bitter drugs based solely on their taste, but only to prepare accordingly.”.

In conclusion, the researchers believe that BitterIntense is a method that may reduce financial costs, animal experiments and shorten the time the drug arrives at the clinic. The ability to detect high bitterness in an integrative way in the process of discovery and development, will help in the development of appropriate drugs for children and geriatric patients. In addition, BitterIntense is also relevant for biotechnology companies and companies working on the development of new sweeteners (sometimes also bitter) or natural ingredients that aim to be integrated into food products.

Ethan Margolis shares a personal experience in light of the study: “After the publication of the scientific article, many young people and adults approached me through social media, and told me that they very much identify with the problem of drug bitterness. Some said that until now they have to chew drugs or eat them with dominant food. And even then it does not always work. Others shared the frustration of giving bitter pills to children who in many cases emit the pill, and then do not know whether to give the drug again or in what form and dosage. We hope that thanks to our research Innovative. “

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