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Drug release metadynamics simulations with natural micro- and nanostructured excipients

Periodic Reporting for period 1 - METADRUG (Drug release metadynamics simulations with natural micro- and nanostructured excipients)

Reporting period: 2021-01-01 to 2022-12-31

Development of new drug delivery systems for drugs as relevant as praziquantel (for schistosomiasis disease), without increasing the final cost of the treatment, are current challenges of the pharmaceutical industry to contribute to global health. The use of efficient and novel methodologies or techniques based on computational chemistry able to predict the release kinetics of the drugs in low-cost natural inorganic carriers, like clay minerals, could be of great help to improve the biopharmaceutical profile of the drugs. This would mean a huge saving in the costs of the investigation, allowing a fast screening of the performance of a great number of drug-clay systems and reducing the time with respect to in vitro experimental tests. Therefore, our goal in this project was to apply the state-of-the-art methodologies (enhanced sampling methods) to establish a solid and accurate enough computational strategy for drug release simulations from clays and apply it to the systems of relevance according to the World Health Organization. With the work carried out in this project, we have developed a viable computational strategy using as a model praziquantel and montmorillonite clay as drug and excipient, respectively, that can be applied in other drug release simulations. By applying this strategy, we obtain the drug release time, rate, and diffusion coefficient, as well as the mechanism of the drug release from the excipient. These studies open a new field of research aimed at improving the design and development of new drugs in a faster and more efficient way.
Work carried out in the METADRUG project was organized in 6 Work Packages that included several tasks. Work Package 1 aimed at managing and coordinating the action. Work Package 2 sought the training and career development of the researcher. Work Package 3 established a computational strategy for drug delivery simulations. The praziquantel-montmorillonite system, with previous experimentally determined drug release kinetics, was used to develop the computational strategy and evaluate and optimize its accuracy. Subsequently, Work Package 4 implemented the computational strategy developed in the previous work package. We automatized as much as possible all the computational steps required for the simulations building up a computational strategy which shall be useful for future studies in the field. Work Package 5 succeeded in applying the established strategy to unknown systems. We also applied the computational approach to drug-clay systems with unknown release kinetics and with potential applications for the treatment of other relevant diseases. For this, we studied the desorption of fluoxetine and mirtazapine (antidepressant drugs) from montmorillonite clay. We also investigated the praziquantel release from halloysite (nanotubular clay). The diffusion coefficients and unbinding kinetics of these drugs from distinct clays as natural excipients were obtained to determine and predict how the drug release profile will be in the human organism after its administration. Lastly, Work Package 6 focused on dissemination/exploitation and communication/outreach activities. In this Work Package, oral communications were given at prestigious conferences and meetings to show the findings and conclusions obtained (scientific meeting in Germany in 2021, XV Congress SEFIG in 2021 in Spain, 12th WATOC in 2022 in Canada, 8th Galenus International Workshop in 2022 in Spain, and scientific meeting in Spain in 2022). Moreover, a manuscript was published in an international journal of recognized prestige and open access in compliance with H2020 policy ( Other two manuscripts are in preparation. The social networks of the researcher were updated to disseminate the results to the scientific and general public ( and The researcher is currently Guest Editor of a Special Issue entitled "Inorganic Biomaterials for Drug Delivery”.
The project's impact is related to the development of new drugs, specifically, in the design drug–excipient complexes that can lead to optimal drug release kinetics. Computational chemistry and specifically enhanced sampling molecular dynamics methods can play a key role in this context, by minimizing the need for expensive experiments and reducing cost and time. With this project, we showed that recent advances in enhanced sampling methodologies can be brought to fruition in this area. We demonstrated the potential of these methodologies by simulating the drug release kinetics of the complex praziquantel–montmorillonite in water. Praziquantel finds promising applications in the treatment of schistosomiasis, but its biopharmaceutical profile needs to be improved, and a cheap material such as montmorillonite clay would be a very convenient excipient. We simulated the drug release both from the surface and interlayer space and found that the diffusion of the praziquantel inside the interlayer space is the process that limits the rate of drug release. This suggests several strategies to modulate the release time. For instance, one could search for ways of controlling the penetration length inside the clay. Attempts could also be made at regulating the interlayer distance, by means of appropriate spacers, or by using other clays with different interlayer spacing. The application of the developed strategy has been applied to other systems (praziquantel-halloysite, fluoxetine-montmorillonite, and mirtazapine-montmorillonite). The last studies with fluoxetine and mirtazapine shall contribute to improve the treatment of depression.