Programa de Pós-Graduação em Nanotecnologia Farmacêutica
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Doctoral Thesis Nanopartículas de organogel advindas de microemulsões: uma abordagem promissora para veiculação da curcumina(Universidade Federal do Rio Grande do Norte, 2022-07-28) Oliveira, Douglas Dourado; Egito, Eryvaldo Sócrates Tabosa do; Alencar, Éverton do Nascimento; https://orcid.org/0000-0002-6148-6804; http://lattes.cnpq.br/0168495853673885; http://lattes.cnpq.br/6907806915889763; https://orcid.org/0000-0003-3445-5217; http://lattes.cnpq.br/6892254958411615; Silva Júnior, Arnobio Antônio da; https://orcid.org/0000-0002-7516-1787; http://lattes.cnpq.br/2593509584288129; Lima, Eliana Martins; Xavier Júnior, Francisco Humberto; Lopez, Renata Fonseca ViannaCurcumin 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.Doctoral Thesis Desenvolvimento de sistemas terapêuticos para leishmaniose cutânea(2019-09-26) Alexandrino Júnior, Francisco; Egito, Eryvaldo Sócrates Tabosa do; ; ; Rocha, Helvecio Vinicius Antunes; ; Pohlmann, Adriana Raffin; ; Lima, Eliana Martins; ; Frezard, Frederic Jean Georges;This study aimed to develop therapeutic alternatives containing amphotericin B (AmB) for the treatment of cutaneous leishmaniasis. Therefore, polymeric systems with distinct geometry (films and fibers) and hydrophilicity (polyvinyl alcohol) and poly(lactic acid)) were produced, and their respective kinetic release profiles were evaluated and correlated with these production parameters and thermodynamic parameters. The data indicated that the drug release was an endothermic and non-spontaneous process, with the fibers and films appropriately fitting to Peppas – Sahlin and Higuchi’s model, respectively. Among the systems evaluated, PVA hydrogels performed the best controlled release and, therefore, their properties as a potential therapeutic system was further evaluated in vitro. The results highlighted that the system was able to control the water vapor permeation, at levels compatible with the skin in its physiological state, acted as a physical barrier against microorganisms present in the environment, and simultaneously displayed efficient antifungal and antileishmania activity, without potential cytotoxicity to renal cells (VERO cell line). Meanwhile, microemulsions (ME) containing 14 %w/w of poloxamer 407 were developed, which provided to the system a thermoreversible behavior (gelation in situ at ~ 25 °C), facilitating its topical application. The poloxamer 407 attenuated the instability phenomena in the ME system during the storage period at 2 °C, without affecting the half-life of the drug. Regarding the ex vivo dermal retention of AmB, it was possible to infer that ME acted as a permeabilizing agent, enabling after 24h of exposition, an AmB dermal retention of ~ 1,37 ± 0,75 g/cm2 . However, the presence of polymer in the system reduced the diffusion rate of AmB, in such a way that no drug was detected during the in vitro assay. Although there is a required in vivo endorsement, the results obtained here demonstrate that PVA hydrogels and thermo-responsive ME are promising systems for use in combination therapy, allowing for outpatient topical treatment of cutaneous leishmaniasis.Doctoral Thesis Chemical stability of amphotericin B in lipid-based media(2017-12-14) Alencar, Éverton do Nascimento; Egito, Eryvaldo Sócrates Tabosa do; ; ; Oliveira, Elquio Eleamen; ; Ramaldes, Gilson Andrade; ; Kirsch, Lee E.; ; Verissimo, Lourena Mafra; ; Magalhães, Nereide Stela Santos;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 lipid-based nanotechnological 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. This thesis was driven on the hypothesis that AmB´s toxicity might be associated to the 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 microemulsions currently studied by our research group. For this purpose, reaction mixtures containing AmB were prepared using different solvents and cosolutes. Samples were stored under different conditions of temperature and light exposure. AmB aggregation state in the reaction mixtures was investigated by UV-Vis spectroscopy. The degradation pathway of AmB in oil was investigated. The results revealed that the use of hydrogen donator antioxidants decreased the degradation of AmB under thermal stress. Also, the AmB degradation under dark conditions was not linearly temperature dependent. Additionally, the use of radical initiator greatly increased the degradation of AmB in methanol. Based on the obtained results, adsorption and aggregation did not appear to play an important role in the 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 the AmB loss process. A kinetic model was successfully used to describe the 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 successfully described the AmB loss under light exposure. AmB loss in this condition showed to be of pseudo-first order. Due to the complex degradation pathway, the kinetics of the different processes leading to the AmB degradation could not be distinguished. The information generated by this research will help to predict AmB instability in microemulsion systems, once the data of AmB degradation in aqueous phase and surfactants will be associated. Additionally, further efforts on trying to generate and isolate the degradants here suggested can help on the investigation of the toxicity related to degradation products.Doctoral Thesis Intérêt de la lyophilisation pour améliorer la stabilité des microémulsions charges en Amphotéricine B destinées au traitement de la leishmaniose(2017-10-20) Morais, Andreza Rochelle do Vale; Egito, Eryvaldo Socrates Tabosa do; ; ; Frezard, Fréderic Jean Georges; ; Barratt, Gillian; ; Fessi, Hatem; ; Legrand, Philippe; ; Loiseau, Philippe;A leishmaniose visceral é uma doença tropical negligenciada que pode ser fatal se não tratada. A Anfotericina B (AmB) é eficiente no tratamento desta doença, porém o seu elevado custo ou sua alta toxicidade torna necessário o desenvolvimento de novos sistemas terapêuticos para solucionar tais inconvenientes. Nesse contexto, pode-se utilizar o aquecimento da formulação micelar de AmB aquecida (A-AmB), e o desenvolvimento de uma microemulsão (ME) contendo AmB (MEAmB). Adicionalmente, é desejada a remoção da água desses sistemas microemulsionados a fim de diminuir instabilidades relacionadas à contaminação microbiológica e a hidrólise. Desta forma, o objetivo deste trabalho foi desenvolver e avaliar a atividade e toxicidade in vitro e in vivo da A-AmB e da MEAmB contra Leishamania donovani (LV9), além de otimizar um sistema microemulsionado liofilizado contendo AmB. Caracterizações da reologia, do tamanho e da morfologia da gotícula mostraram que a MEAmB apresentou tamanhos médios de 35 nm, um comportamento Newtoniano e uma morfologia esférica. A caracterização da A-AmB mostrou a formação de superagregados, que, são menos tóxicos que os outros estados de agregação. Análises in vitro, tanto para a forma amastigota axênica como para a intramacrofágica mostraram que as atividades da A-AmB e da MEAmB foram semelhantes ao do Ambisome®. Além disso, foi observado um alto índice de seletividade da A-AmB e da MEAmB comparada a formulação não aquecida. Adicionalmente, essas duas formulações, quando comparadas ao Ambisome®, mostraram elevada atividade contra cepas AmB resistentes. Essas formulações foram testadas in vivo a fim de avaliar sua atividade e toxicidade. Os resultados não apresentaram diferenças significativas entre as atividades das amostras contendo AmB, e, com relação a toxicidade, não mostraram diferenças expressivas capazes de causar uma disfunção renal ou hepática. Portanto, tanto a A-AmB como a MEAmB podem ser usados como alternativa no tratamento contra LV9, apresentando a vantagem sobre o Ambisome® devido aos menores custos de suas produções. Por conseguinte, a fim de liofilizar o sistema microemulsionado, foi realizado um planejamento experimental completo, no qual o observou-se que MEs com menores tamanhos de gotículas foram obtidos quando utilizado maltose como crioprotetor na concentração de 5 %, com congelamento a – 80 ºC e por um período de liofilização de 24 h. Além disso, foi observado que a ME contendo AmB não teve mudanças significativas quanto ao conteúdo do fármaco, quando comparado o produto antes e após o processo de liofilização. Desta forma, a ME, em sua forma liofilizada, pode manter a estabilidade do sistema perante os danos que poderiam ser causados pela quantidade de água.