Síntesis y caracterización de líquidos iónicos y evaluación de su aplicabilidad en nuevas formulaciones farmacéuticas

Résumé

Ionic liquids (ILs) have been attracting interest towards the study of their applicability in different fields, especially due to their great tunability. The possibility of properly designing ILs to display different functionalities can be a promising strategy to optimise their applicability and to solve a variety of challenges in the pharmaceutical area. The poor water solubility has been pointed out as one of the most common difficulties and, therefore, a major concern for the pharmaceutical industry since the low solubility can compromise the bioavailability, therapeutic efficacy and incorporation of drugs into delivery systems. In light of this, this thesis addresses how different cationanion ILs combinations can influence the ability of ILs to improve the solubility and loading of poorly water-soluble compounds with pharmacological interest, while considering their safety and assessing if the use of ILs allows the maintenance of the biological effects of those compounds. In this context, firstly, eight ILs were synthesised by combining different cations (cholinium or imidazolium) and anions (bromide or amino acids). Considering their potential applicability as solubility enhancers for topical delivery, the cytotoxicity of the synthetised ILs in HaCaT cells and the impact of their different cation-anion combinations on the solubility of four poorly water-soluble phenolic compounds (p-coumaric, ferulic and caffeic acids and rutin) were evaluated. The anion, the cation head group and the length of the cation side chain influenced the toxicity of ILs. On the other hand, in terms of drug solubility, it seemed to be the anions that had the highest impact on this property, with all the amino acid-based ILs increasing the solubility of the studied compounds. The ability of choline amino acid-based ILs to enable a higher drug loading, in topical formulations, and their influence on the potential toxicity to MDA-MB-231 cells as well as the radical scavenging activity of rutin and ferulic acid were subsequently studied. The ferulic acid and rutin exposure did not cause cytotoxic effects on breast cancer cells. Choline amino acid-based ILs, at non-toxic concentrations, considerably improved the drug loading into the developed O/W emulsions combined with ILs, without influencing the radical scavenging activity of the studied compounds, the cell viability or the stability of the developed formulations. Then, since no cytotoxic effects were observed in MDA-MB-231 cells, the cytotoxicity of p-coumaric, caffeic and ferulic acids was studied in 786-O cells. The treatment with caffeic and p-coumaric acids induced, at higher concentrations, a significant decrease in the cell viability. The potential cytotoxic effects of rutin in 786-O cells, while considering its safety in Vero normal kidney cells, were also evaluated. The rutin caused a concentration-dependent decrease of cell viability in both cell lines, however, a more significant effect was observed in renal cancer cells. These promising results led to further explore the influence of rutin, individually or when combined, with choline amino acid-based ILs on cell viability and cell cycle progression of renal cells, as well as the applicability of these ILs to improve the delivery of rutin. The rutin’s treatment caused a significant increase in the sub-G1 population of 786-O cells. The two choline amino acid-based ILs did not affect the effects of rutin and, at non-toxic concentrations, allowed to enhance the rutin’s drug solubility and loading into IL-nanosystems, without affecting the stability and performance of the prepared delivery systems. This study emphasised the importance of properly designing ILs for a particular application. Adjusting the properties of ILs, through different cation-anion combinations, can influence their cytotoxicity and ability to improve drug solubility. These are two factors extremely important when it is intended to use ILs as solubility enhancers at nontoxic concentrations. In addition, this work revealed that rutin could be potentially used in human renal cancer. Moreover, the combination of rutin with the ILs showed to be crucial by allowing to improve the solubility and incorporation of this compound into delivery systems without having an impact on its effectiveness. Overall, the ILs proved to be a versatile and valuable tool for the pharmaceutical area since they can improve the applicability of poorly-water soluble compounds with pharmacological interest.