Disertación/Tesis

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2022
Tesis
1
  • DOUGLAS DOURADO OLIVEIRA
  • MICROEMULSION-BASED ORGANOGEL NANOPARTICLES: A PROMISSING APPROACH FOR CURCUMIN DELIVERY

  • Líder : ERYVALDO SOCRATES TABOSA DO EGITO
  • MIEMBROS DE LA BANCA :
  • ERYVALDO SOCRATES TABOSA DO EGITO
  • ARNOBIO ANTONIO DA SILVA JUNIOR
  • ELIANA MARTINS LIMA
  • FRANCISCO HUMBERTO XAVIER JUNIOR
  • RENATA FONSECA VIANNA LOPEZ
  • ÉVERTON DO NASCIMENTO ALENCAR
  • Data: 28-jul-2022


  • Resumen Espectáculo
  • Curcumin is a polyphenol obtained from the rhizome of Curcuma longa, which has stood out due to its high biological potential. However, this molecule is a Class IV compound in the biopharmaceutical classification (low water solubility and low permeability), which compromises its bioavailability in a physiological environment. Additionally, this molecule is not only susceptible to intense metabolism, being rapidly eliminated, but also presents worrisome instability in the gastrointestinal pH. To circumvent limitations of class IV molecules, the use of lipid nanoparticles (NPs) has been suggested. Among these, organogel nanoparticles may be highlighted. These are reservoir systems that shows nanometric hydrophobic particles with gel characteristics. Altogether, these features allow greater stability and higher entrapment of drugs when compared to conventional lipid NPs. Due to their recent development, these NPs require improvements (size decrease and uniformity of NPs) to achieve increased permeability and bioavailability when administered orally. In this perspective, the aim of this thesis was to develop curcumin-entrapped organogel nanoparticles using microemulsions (10-100 nm) as a template system for particle size reduction and uniformity. Studies were initially developed to evaluate the solubility of curcumin in surfactants, oil and different proportions of surfactants: oil mixtures. Then, a pseudoternary phase diagram was developed by the water titration method to obtain microemulsion (ME) regions. The systems were emulsified by an ultrasound probe. An oil-in-water (O/W) formulation with low concentration of surfactants and an oil phase adequate for entrapment curcumin was selected. A ME with curcumin was produced by adding the drug to the mixture of compounds before emulsification. The MEs were characterized in terms of droplet size distribution, electrical conductivity, surface tension, rheology, morphology and thermal profile. The entrapment efficiency (EE) was determined by high performance liquid chromatography. Additionally, the stability over time of MEs and stability in simulated gastrointestinal fluid (SGIF) was assessed. Finally, the kinetics of curcumin release in SGIF was also evaluated. Posteriorly, different concentrations of low molecular weight gelators were added to the oil phase of the ME and mixed by high and low energy methods. The obtained dispersions were initially characterized by turbidimetry and hydrodynamic particle size distribution. Subsequently, the chosen samples were further characterized in terms of zeta potential, morphology, surface tension and rheology. In addition, the stability over time and in SGIF was assessed. The obtained NPs were loaded with curcumin (Curc-ME-Org-NPs). They were characterized in terms of physicochemical stability (storage and in FGIS), morphology, rheology, % EE and release kinetics. Finally, Curc-ME-Org-NPs displayed spherical shape (with the presence of a surfactant corona) with an average hydrodynamic size of 22 nm, monomodal distribution, negative surface charge, Newtonian profile and low surface tension, characteristics similar to the template ME. Curc-ME-Org-NPs showed high entrapment efficiency, physicochemical stability over time and in SGIF. Furthermore, it revealed modified release kinetics that fitted models that describe a complex release mechanism, but with the presence of diffusion. Therefore, Curc-ME-Org-NPs proved to be a potential formulation for oral administration with stability and in vitro oral bioavailability.

2019
Tesis
1
  • FRANCISCO ALEXANDRINO JÚNIOR
  • Development of therapeutic systems for cutaneous leishmaniasis

  • Líder : ERYVALDO SOCRATES TABOSA DO EGITO
  • MIEMBROS DE LA BANCA :
  • ERYVALDO SOCRATES TABOSA DO EGITO
  • HELVECIO VINICIUS ANTUNES ROCHA
  • ADRIANA RAFFIN POHLMANN
  • ELIANA MARTINS LIMA
  • FREDERIC JEAN GEORGES FREZARD
  • Data: 26-sep-2019


  • Resumen Espectáculo
  • This thesis is part of the group's efforts to develop therapeutic alternatives containing amphotericin B (AmB) for the treatment of leishmaniasis. Since the instability of AmB, when present in an aqueous medium, is a complex mechanism, dependent on factors such as the state of aggregation, degree of ionization (pKa) and pH of the medium, the first chapter aimed to determine the pKa values of AmB in distinct hydroalcoholic solutions through Bjerrum plot. Such an approach provided support to elaborate a mathematical model with suitable predictive and explanatory capacity. Therefore, allowing a better understanding of the mechanisms involved in the aqueous instability of AmB. The second chapter aimed to evaluate the kinetic profiles of AmB released from polymeric systems with different geometry (fibers and films) and composition (polyvinyl alcohol (PVA) and poly(lactic acid) (PLA)) and to correlate such profiles with thermodynamic parameters. The results suggest that the drug release was an endothermic and non-spontaneous process, with kinetic profiles of fibers and films consistent to the Peppas-Sahlin and Higuchi model, respectively. Since the PVA hydrogels demonstrated a better control in the AmB release, its properties as a potential therapeutic system were evaluated in vitro in the third chapter. Wherein the results revealed that the system was able to control the water vapor permeation to levels compatible with the skin in its physiological state. Additionally, it displayed effective antifungal and antileishmanial activity, without potential cytotoxicity for VERO cells. The fourth chapter reports the results obtained in the development and evaluation of AmB-loaded thermo-responsive microemulsions (ME). In which the ME enabled the AmB skin retention, and the instability phenomena of ME caused by thermodestabilization were hindered by adding poloxamer 407 into the system. Thus, the results obtained herein demonstrate that PVA hydrogels and thermo-responsive ME are potential systems to be used in the topical outpatient treatment of cutaneous leishmaniasis.

2017
Tesis
1
  • ANDREZA ROCHELLE DO VALE MORAIS
  • Freeze-drying to increase stability of Amphotericin B-loaded microemulsion for leishmaniasis treatment

  • Líder : ERYVALDO SOCRATES TABOSA DO EGITO
  • MIEMBROS DE LA BANCA :
  • ERYVALDO SOCRATES TABOSA DO EGITO
  • FRÉDERIC JEAN GEORGES FREZARD
  • GILLIAN BARRATT
  • HATEM FESSI
  • PHILIPPE LEGRAND
  • PHILIPPE LOISEAU
  • Data: 20-oct-2017


  • Resumen Espectáculo
  • Visceral leishmaniasis is a neglected tropical disease that can be fatal if left untreated. Amphotericin B (AmB) is effective in the treatment of this disease, but the conventional formulation, Fungizone® has dose-limiting toxicity while the less toxic lipid-based forms such as Ambisome® are expensive. Therefore, the need for new therapeutic systems remains. In this respect, the heating of the Fungizone® formulation (H-AmB), and the development of a microemulsion (ME) containing AmB (MEAmB) are possible solutions. In addition, it is desirable to remove water from microemulsion systems in order to reduce instability due to microbiological contamination and hydrolysis. Therefore, the objective of this work was to develop and to evaluate the activity and toxicity in vitro and in vivo of H-AmB and MEAmB against Leishmania donovani (strain LV9) and, furthermore, to optimize a lyophilized microemulsion system containing AmB. Rheological, size and morphology studies showed that MEAmB presented average droplet sizes of 35 nm, a Newtonian behavior and spherical morphology. Spectroscopic characterization of H-AmB showed the formation of superaggregates, which are less toxic than the other states of aggregation. In-vitro evaluation on both the axenic and intramacrophagic amastigote forms showed that H-AmB and MEAmB showed similar activity to Ambisome®. A high selectivity index of H-AmB and MEAmB was observed compared with unheated Fungizone®. Furthermore, both new formulations showed high activity against AmB-resistant strains compared with Ambisome®. In-vivo experiments designed to evaluate their activity and toxicity did not reveal significant differences in activity between the new and reference formulations. There were no significant differences either in indicators of renal and hepatic toxicity. Therefore, both H-AmB and MEAmB can be used as an alternative for the treatment of LV9, presenting an advantage over AmBisome® in their lower costs of production. Therefore, a complete experimental design was performed in order to optimize the lyophilisation of the microemulsion system. It was observed that microemulsions with smaller droplet sizes were obtained using maltose as a cryoprotectant at a concentration of 5%, with freezing at -80 ° C, and a lyophilization process period of 24 h. Furthermore, it was observed that ME containing AmB showed no significant changes in drug content before and after the lyophilization process. Therefore, in its lyophilized form, the ME can remain stable and avoid degradation due to the presence of water.

2
  • ÉVERTON DO NASCIMENTO ALENCAR
  • Chemical stability of Amphotericin B in lipid-based media

  • Líder : ERYVALDO SOCRATES TABOSA DO EGITO
  • MIEMBROS DE LA BANCA :
  • ELQUIO ELEAMEN OLIVEIRA
  • ERYVALDO SOCRATES TABOSA DO EGITO
  • GILSON ANDRADE RAMALDES
  • LEE E. KIRSCH
  • LOURENA MAFRA VERISSIMO
  • Nereide Stela Santos Magalhães
  • Data: 14-dic-2017


  • Resumen Espectáculo
  • 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.

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