Scientific Evidence

Pharmaceutical products have contributed to improving the expectancy and quality of life of millions of patients and their role in our society is undisputed. However, many active pharmaceutical ingredients have been found in rivers, lakes, seas, drinking water and can cause damage to the environment and ecosystems. Environmental contamination is known to affect biodiversity and health. From a "One Health" perspective, human health is safeguarded by preserving the environment and ecosystems. Italy is at the forefront on the issue of protecting biodiversity, having included it among the fundamental principles of the Constitution. At the same time the European Commission launched the strategy to protect biodiversity by 2030. To map and limit the environmental effect of drugs, it has been proposed the topic of ecopharmacovigilance and eco-directed sustainable prescribing.

It's in this context that this work on the ready biodegradability of a drug-based on loperamide and a medical device made of complex natural matrix, Lenodiar-Pediatric®, was carried out for the first time. The products, indicated to treat diarrhoea, were found to be readily biodegradable. For Lenodiar-Pediatric® the biodegradation isn't surprising, while for the drug-based on loperamide it was due to the degradation of excipients. Indeed, the UHPLC-qToF investigation highlighted that loperamide was present at the end of the test and is therefore potentially persistent in the environment, confirming the most relevant literature.

In conclusion, therapeutic products made of natural complex matrix which efficacy and safety have been proven according to Evidence-Based Standards may play an important role in safeguarding biodiversity.

Suspect screening and untargeted analysis using UHPLC-qToF are two advanced analytical approaches now used to achieve an extensive chemical profile of samples, which are then typically confirmed through targeted analysis. These techniques can detect a large number of chemical features simultaneously and are currently being introduced into the study of contaminants of emerging concern (CECs) and into the study of the extent of human chemical exposure (the exposome). Here is described the use of these techniques to characterize chemical mixtures derived from the OECD 301F ready biodegradability test (RBT) of a chemical and natural formulation currently used to treat reflux disease and functional dyspepsia. Untargeted analysis clearly evidenced a different behavior between formulations containing only natural products with respect to that containing synthetic and non-naturally occurring substances. Suspect screening analysis improved the untargeted analysis of the omeprazole-based medicine, leading to the tentative identification of a number of omeprazole-derived transformation products, thereby enabling their preliminary quali-quantitative evaluation. Targeted analysis was then performed to confirm the preliminary data gained from the suspect screening approach. The validation of the analytical method for the quantitative determination of omeprazole and its major metabolite, omeprazole sulphide, has provided robust data to evaluate the behavior of omeprazole during the OECD 301F test. Using advanced analytical approaches, the RBT performed on the two products under investigation confirmed that omeprazole is not readily biodegradable, while the medical device made of natural substances has proven to be readily biodegradable.

Drugs are indispensable products with incontrovertible benefits to human health and lifestyle. However, due to their overuse and improper disposal, unwanted residues of Active Pharmaceutical Ingredients (APIs) have been found in different compartments of the environment and now are considered as Contaminants of Emerging Concern (CEC). Therefore, they are very likely to have a boomerang effect on human health, because they can enter into the food cycle. In the current legislation framework one of the test first used to evaluate biodegradation of APIs as well as chemical compounds is the ready biodegradability test (RBT). This test can be performed according to a series of protocols prepared by OECD (Organization for Economic Co-operation and Development) and usually is carried out on pure compounds. RBTs, largely used due to their relatively low cost, perceived standardization, straightforward implementation and interpretation, are known to have a number of well-documented limitations. In this work, following a recently reported approach, we propose to improve the evaluation of the RBT results applying advanced analytical techniques based on mass spectrometry, not only to the APIs but also to complex formulated products, as the biodegradability can potentially be affected by the formulation. We evaluated the ready biodegradability of two therapeutic products, Product A- a drug based on Metformin- and Product B- Metarecod a natural substance-based medical device - through the acquisition of the fingerprint by UHPLC-qToF of samples coming from the RBT OECD 301F. Untargeted and targeted evaluation confirmed the different behavior of the two products during the respirometry-manometric test, which showed a difficulty of the Metformin-based drug to come back in the life cycle, while Metarecod resulted ready biodegradable. The positive results of this research will hopefully be useful in the future for a better evaluation of the risk/benefit ratio of APIs extended to the environment.

UHPLC-qToF analysis is reported here as a modern and reliable spectrometric technique, for a more accurate evaluation of the biodegradation of pharmaceutical formulations that should be considered as complex mixtures of organic compounds interacting with naturally occurring microfauna. The untargeted approach evidences that natural and non-natural compounds are not equally biodegraded even when both passed the requirements of the respirometry test. In particular, we demonstrated that for mixtures containing synthetic non-naturally occurring compounds, a new cluster of derivatives can be detected and in part interpreted by a target analysis. We also demonstrated that the fate of the biodegradation of an active ingredient pure or inserted in a pharmaceutical formulation is not the same, confirming that complex chemical systems should be better analyzed using a holistic approach rather than a reductionistic one. The biodegradation of a pharmaceutical formulation could present a different fate compared to that predicted by considering the biodegradability of each component (the global result is not the sum of the parts). Considering these results, an update of the protocols currently used for the evaluation of the environmental impact of chemicals and chemical mixtures used in our daily life can be proposed, through the use of modern technologies nowadays widely diffused in analytical laboratories.