Banca de DEFESA: EVERTON DO NASCIMENTO ALENCAR

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
DISCENTE : EVERTON DO NASCIMENTO ALENCAR
DATA : 14/12/2017
HORA: 15:00
LOCAL: Sala do CONSEC CCS
TÍTULO:

Chemical stability of Amphotericin B in lipid-based media

PALAVRAS-CHAVES:

Amphotericin B; Microemulsions; Drug Degradation; Oxidation; Chemical Kinetics.

PÁGINAS: 225
RESUMO:

This thesis is part of research efforts with the intent of applying chemical stability and drug degradation kinetics knowledge to lipid-based systems, as amphotericin B (AmB), usually requires a nanotechnological drug delivery system to overcome its biopharmaceutical issues. The aim of this thesis was to determine the instability pathway and degradation kinetics of AmB in oil solutions, since stability of drug in delivery systems are chemically complex to be investigated due to their multi-phased aspect. The first section of this thesis was designed to provide a background on the current efforts regarding microemulsions containing Amphotericin B on the context of the research developed by our research group, for this purpose, literature reviews were published and showed that microemulsions containing AmB are systems capable of incorporating therapeutic concentrations of AmB. Those systems show effective anti-leishmania and antifungal activities. The use of lipidic formulations decrease the toxicity of AmB. In addition, freeze-drying has been one of the methods successfully used to increase stability of emulsioned systems, since the removal of water decreases degradation of lipids and drugs associated to hydrolysis mechanisms. The second section of this thesis was driven on the hypothesis that AmB´s toxicity might be associated to drug degradation instead of what is reported by the literature, which is mainly related to the drug´s aggregation state. The experimental research herein was conducted in order to investigate the chemical
instability pathways and kinetics of AmB in oils, aiming to generate knowledge that can be useful on a larger context involving nanotechnological drug delivery systems currently studied by our research group, mainly emulsions and microemulsions. For this purpose, reaction mixtures containing AmB were done using different solvents and co-solutes. Samples were stored under different conditions of temperature and light exposure. AmB aggregation state in reaction mixtures was investigated by UV-Vis spectroscopy. The degradation pathway of AmB in oil was investigated. Use of hydrogen donator antioxidants decreased the degradation of AmB under thermal stress. AmB degradation under dark conditions was not linearly temperature dependent. Use of radical initiator increased the degradation of AmB in methanol greatly. Based on the obtained results, adsorption and aggregation did not appear to play a role in AmB degradation in oil. Under dark conditions, the most likely pathway for AmB degradation in oil was autoxidation. Whereas under light exposure, the most likely degradation pathway was light catalyzed oxidation. Empirical degradation schemes were drawn and differential equations were developed to explain AmB loss process. A kinetic model was successfully used to describe AmB loss in different solvents under dark environment. The model proved that AmB undergoes a complex degradation pathway, once a simple autocatalytic model could not describe its loss. In fact, a reversible loss probably related to hydrolysis might be involved, as demonstrated by the scheme and the kinetic model. A second model described AmB loss under light exposure successfully. AmB loss in this condition showed to be pseudo-first order. Due to complex degradation pathway, the kinetics of the different processes leading to AmB degradation
could not be distinguished. The information generated by this research will help to predict AmB instability in
microemulsions once data of AmB in aqueous phase and surfactants are associated. Additionally, further efforts on trying to generate and isolate the degradants here suggested can help on the investigation of toxicity related to degradation products.

MEMBROS DA BANCA:
Externo à Instituição - ELQUIO ELEAMEN OLIVEIRA - UEPB
Presidente - 1178187 - ERYVALDO SOCRATES TABOSA DO EGITO
Externo à Instituição - GILSON ANDRADE RAMALDES - UFMG
Externo à Instituição - LEE E. KIRSCH - UIOWA
Externo ao Programa - 2569445 - LOURENA MAFRA VERISSIMO
Externo à Instituição - Nereide Stela Santos Magalhães - UFPE