Publicação
Exploring anti-tuberculosis drugs through green solvents for effective treatment of tuberculosis
| Resumo: | Tuberculosis is an airborne infectious disease caused by Mycobacterium tuberculosis that remains to be one of the deadliest infectious diseases worldwide. Despite being considered treatable, the treatment of this disease involves a combination of different antibacterial drugs administrated for several months. This may cause serious adverse effects and lead to low treatment compliance by the patient, contributing to the ineffectiveness of the therapy and the emergence of drug resistance. The approaches used for treating tuberculosis are the same since their development, around 50 years ago. Therefore, and given the emergence and persistence of drug resistance to the various antibiotics used, it is of the utmost importance to conduct a breakthrough investigation to find alternatives able to rapidly reduce the incidence of tuberculosis, mainly in low-income countries. Considering the drawbacks of tuberculosis therapy, it is proposed in this work to explore alternative strategies to address long term therapies and poor patient compliance, which include the use of alternative solvents, such as ionic systems, therapeutic liquid mixtures, and supercritical fluid technology. In a first step, the preparation of ionic systems (organic salts) and eutectic mixtures incorporating anti-tuberculosis drugs in their structure were explored. Then, all prepared compounds were fully characterized both in terms of their physicochemical properties and their in vitro biological performance through a myriad of different procedures and techniques, such as polarized optical microscopy, differential scanning calorimetry, nuclear magnetic resonance, infrared spectroscopy, solubility, permeability (using Franz cells and transwell inserts), cytotoxicity in different cell lines, antibacterial activity, among others. Additionally, eutectic mixtures were prepared by dissolving first-line treatment anti-tuberculosis drugs and an organic salt (isoniazid di-chloride, [INH][Cl]2) in the system composed by citric acid, ethambutol, and water in a ratio of 1:1:5. In order to obtain inhalable particles for targeted site-infection delivery of these formulations, supercritical fluid technology was used to encapsulate the eutectic mixtures and formulate biocompatible particles with a suitable size for pulmonary administration. In general, the main objectives of the work were achieved, being the alternative strategies explored (ionic systems, eutectic mixtures, and supercritical fluid technology) capable to improve some essential characteristics of anti-tuberculosis drugs, in particularly, its solubility and stability. Hereupon, their potential should be further explored with different and more complex biological models. |
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| Autores principais: | Santos, Márcia Filipa Carvalho dos |
| Assunto: | Tuberculosis ionic liquids organic salts eutectic mixtures herapeutic deep eutectic systems supercritical CO2 technology |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | Tuberculosis is an airborne infectious disease caused by Mycobacterium tuberculosis that remains to be one of the deadliest infectious diseases worldwide. Despite being considered treatable, the treatment of this disease involves a combination of different antibacterial drugs administrated for several months. This may cause serious adverse effects and lead to low treatment compliance by the patient, contributing to the ineffectiveness of the therapy and the emergence of drug resistance. The approaches used for treating tuberculosis are the same since their development, around 50 years ago. Therefore, and given the emergence and persistence of drug resistance to the various antibiotics used, it is of the utmost importance to conduct a breakthrough investigation to find alternatives able to rapidly reduce the incidence of tuberculosis, mainly in low-income countries. Considering the drawbacks of tuberculosis therapy, it is proposed in this work to explore alternative strategies to address long term therapies and poor patient compliance, which include the use of alternative solvents, such as ionic systems, therapeutic liquid mixtures, and supercritical fluid technology. In a first step, the preparation of ionic systems (organic salts) and eutectic mixtures incorporating anti-tuberculosis drugs in their structure were explored. Then, all prepared compounds were fully characterized both in terms of their physicochemical properties and their in vitro biological performance through a myriad of different procedures and techniques, such as polarized optical microscopy, differential scanning calorimetry, nuclear magnetic resonance, infrared spectroscopy, solubility, permeability (using Franz cells and transwell inserts), cytotoxicity in different cell lines, antibacterial activity, among others. Additionally, eutectic mixtures were prepared by dissolving first-line treatment anti-tuberculosis drugs and an organic salt (isoniazid di-chloride, [INH][Cl]2) in the system composed by citric acid, ethambutol, and water in a ratio of 1:1:5. In order to obtain inhalable particles for targeted site-infection delivery of these formulations, supercritical fluid technology was used to encapsulate the eutectic mixtures and formulate biocompatible particles with a suitable size for pulmonary administration. In general, the main objectives of the work were achieved, being the alternative strategies explored (ionic systems, eutectic mixtures, and supercritical fluid technology) capable to improve some essential characteristics of anti-tuberculosis drugs, in particularly, its solubility and stability. Hereupon, their potential should be further explored with different and more complex biological models. |
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