Programa de Pós-Graduação em Ciências Farmacêuticas
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Master Thesis Avaliação antiviral in vitro de novos sistemas de liberação com derivado naftoquinona(Universidade Federal do Rio Grande do Norte, 2025-01-31) Góes Neto, Gilson Cassiano de; Lima, Ádley Antonini Neves de; Oliveira, Veronica Da Silva; http://lattes.cnpq.br/4847921230270944; Formiga, Fábio Rocha; Silva, Marcelo de Sousa daThe outbreak of dengue fever, a disease transmitted by the DENV virus, has spread globally, causing millions of deaths worldwide. Therefore, it is necessary to develop new compounds that can act in the treatment of dengue fever. Naphthoquinones (NQs) and their derivatives have antifungal, antiparasitic and antimicrobial action, among which is the compound IVS320, a molecule with promising antimicrobial action, but with low solubility. Cyclodextrins (CDs) are used as a strategy to improve the solubility, stability and bioavailability of drugs. In this context, the development of inclusion complexes (ICs) with cyclodextrins can solve the implicit restrictions of IVS320, and in turn, increase its bioavailability and pharmacological action. Thus, the present study aims to improve the physicochemical and biological properties of naphthoquinone IVS320, through the development of inclusion complexes. In addition to evaluating the in vitro anti-DENV activity of the obtained delivery systems and analyzing the bioactive potential of the compound, the complexes obtained with γ-CD, HP-γ-CD and HP-β-CD, through the physical mixing ( MF), kneading (ML) and rotary evaporation (RT) techniques, were characterized by XRD, FTIR, DSC and TG techniques. The XRD results of the isolated IVS320 exhibited crystalline reflections with high intensity at 10°, 18°, 32° and 37°, while the diffractograms of the MF, ML and RT systems showed a reduction in the crystalline profile, suggesting the formation of complexes . The FTIR spectra of the systems bands showed characteristic of both IVS320 and the CDs employed, with modifications in the profile of some bands. In turn, the DSC showed little similarity with the endothermic and exothermic events observed in the isolated IVS320, and the IC exhibited the main occurrences in the ranges of 70-80°C, 190-200°C, up to exothermic peaks in the range of 250°C-260°C, signaling crystallization. While in the TG, well-defined stages of mass loss were observed for all complexation techniques, in which the first events of the systems occurred around 50°C to 70°C, with approximately 10% mass loss, while the second variation began between 300 and 340°C, followed by gradual mass decay up to 600°C, with the highest ∆m (approximately 80%). Regarding in vitro activity, the compound IVS320 presented quite satisfactory results, being able to inhibit the DENV virus. The results of the physicochemical characterization indicated the formation of IVS320 ICs with CDs, demonstrating that the methods employed were effective and that the systems developed are promising for enhancing the antiviral activity of IVS320. The antiviral activity against DENV-2 was evaluated and the antiviral cytotoxicity assays demonstrated that the ICs were able to protect healthy human cells against the pathogen, suggesting that the complexes are more toxic to the virus cells than to human cells.Master Thesis Complexo de inclusão entre óleo de copaíba (Copaifera multijuga Hayne ) e HPQCD: desenvolvimento e caracterização para fins anti Trypanosoma cruzi(Universidade Federal do Rio Grande do Norte, 2024-06-10) Taio, Fabrice; Lima, Adley Antonini Neves de; Martins, Rand Randall; http://lattes.cnpq.br/8062199269259772; https://orcid.org/0000-0002-3798-3915; http://lattes.cnpq.br/4061809277935577; http://lattes.cnpq.br/7432775003483542; Barbosa, Euzebio Guimarães; Damasceno, Bolivar Ponciano Goulart de LimaChagas Disease, caused by the parasite Trypanosoma cruzi and primarily transmitted by the insect known as the 'kissing bug', represents a significant public health challenge in Latin America, affecting millions of people. In addition to medical implications, the disease is inherently linked to socio-economic and environmental factors such as disordered migrations, rapid urbanization, and environmental degradation. Given this challenging context, the search for new therapeutic strategies is crucial. In this context, this research aimed to develop and characterize inclusion complexes to improve the solubility of copaiba oil and evaluate its potential anti-Trypanosoma cruzi effect. For this purpose, copaiba oil and hydroxypropyl-G-cyclodextrin (OLC/HPGCD) were prepared by physical mixing (MF) and kneading methods (MLG). The complexes were then characterized using appropriate physicochemical methods. The results of the differential scanning calorimetry (DSC) showed endothermic peaks related to water loss, with HPGCD showing a peak at 70°C and OLC at 110°C, attributed to water molecule evaporation and volatilization, respectively. X-ray diffraction (XRD) analysis revealed crystallinity patterns characteristic of semicrystalline samples. Structural analyses by Fourier-transform infrared spectroscopy (FTIR) indicated the interaction between host and guest (OLC and HPGCD), demonstrating the potential of the developed inclusion complexes. The samples of HPGCD, MF, and MLG were analyzed with a scanning electron microscope (SEM) at various magnifications, revealing distinct morphological changes. HPGCD exhibited spherical particles, MF presented both spherical and fragmented particles, and MLG displayed irregular and porous shapes, indicating complete restructuring after processing.The anti-T. cruzi activities of HPGCD/OLC-MF and HPGCD/OLC-MLG complexes were comparable to Benznidazole at higher concentrations, although they were not effective at lower concentrations.Doctoral Thesis Desenvolvimento de complexos de inclusão multicomponentes com ácido ferúlico e obtenção de membrana para avaliação da liberação em formulações semissólidas(Universidade Federal do Rio Grande do Norte, 2020-10-30) Duarte, Fernanda Ílary Costa; Lima, Adley Antonini Neves de; Gomes, Ana Paula Barreto; ; http://lattes.cnpq.br/1689823596741892; ; http://lattes.cnpq.br/4061809277935577; ; http://lattes.cnpq.br/3035470083983748; Carvalho, André Luis Menezes; ; http://lattes.cnpq.br/6874869711888371; Converti, Attilio; ; http://lattes.cnpq.br/3423653074671287; Ferreira, Leandro de Santis; ; http://lattes.cnpq.br/6622861873027635; Marreto, Ricardo Neves; ; http://lattes.cnpq.br/6127043775208484Ferulic acid (FA) is a phytochemical constituent pat of the polyphenols group which are found mainly in rice and corn meal, with emphasis on its photoprotective and antioxidant activity. Thus, FA has been widely studied for application in photoprotective and anti-aging skin formulations. In the development of topical formulations, in vitro skin release assays present themselves as a fast, low-cost assay that enable preliminary results. The use of FA is limited by the instability of the molecule in the face of light and/or oxidation. In view of this, its stability can be improved through complexation with cyclodextrins, dispersion in polymers or inclusion in cyclodextrins followed by the association of a polymer forming a multicomponent system. Thus, the objective was to obtain a membrane model that is similar to the composition of human skin for in vitro skin release assays and development of multicomponent systems with cyclodextrins and hydrophilic polymers using ferulic acid. The membrane was obtained by impregnation of a lipid solution in synthetic membrane and characterized by Differential Exploratory Calorimetry (DSC), Atomic Force Microscopy (AFM) and Scanning Electron Microscopy (SEM). Gel and cream-gel formulations containing AF 0.5% (w/w) were evaluated for stability and in vitro release through the optimized membrane in franz diffusion cell. In the development of multicomponent complexes, studies of molecular dynamics and solubility in aqueous phase were carried out. After selection of cyclodextrin and polymer to make up the systems, they were obtained by the methods of kneading and evaporation rotary, characterized DSC and TG (thermogravimetry), X-ray diffraction (DR-X) and Fourier transform infrared spectroscopy (FTIR). In addition, they were evaluated for oxidative stability and antioxidant activity. The techniques used to characterize the obtained membrane allowed to demonstrate the occurrence of impregnation of the lipid solution. The formulations were stable when stored at 4 ºC ± 2 °C. The results of in vitro release using the optimized membrane suggest that it can be applied as an accessible and simple membrane in the in vitro release of active substances. Regarding the development of multicomponent systems, through characterization techniques it was possible to understand the interactions between FA, cyclodextrins and polymers. The techniques of obtaining the multicomponent systems were adequate, with high incorporation content of the asset. The method of obtaining by kneading was highlighted, which presented considerably higher yield when compared to the method by evaporation rotary. The cyclodextrins and polymers selected had the potential to be used in multicomponent systems. Since they increased the stability of FA against high temperatures, they also assisted in the transition from crystalline to amorphous state of the drug, due to the insertion of the active inside the cavity and interaction with the polymer. For oxidative stability, it was verified that the components of the system conferred significant stability for FA. In antioxidant activity, in general, multicomponent complexes enhanced FA activity. The results suggest the formation of stable multicomponent systems, enabling optimization to the asset. Providing subsidies for the incorporation of these systems in cosmetic formulations.Master Thesis Complexos de inclusão entre a mistura binária de α, β-amirenona com ciclodextrinas para avaliação da atividade inibitória da enzima lipase in vitro(Universidade Federal do Rio Grande do Norte, 2020-10-26) Oliveira, Luana Carvalho de; Lima, Adley Antonini Neves de; Barbosa, Euzebio Guimarães; ; http://lattes.cnpq.br/3197108792266393; ; http://lattes.cnpq.br/4061809277935577; ; http://lattes.cnpq.br/5559095493145617; Araújo, Adriano Antunes de Souza; ; http://lattes.cnpq.br/6234025640524218; Silva, Marcelo de Sousa da; ; http://lattes.cnpq.br/1295430560645312Α, β-amirenone (ABAME), a triterpene derivative, as well as other derivatives of this class, has many biological activities and, in turn, potential pharmacological applicability. However, ABAME presents in its physical-chemical characteristics, low aqueous solubility, which hinders it’s oral administration and, consequently, its bioavailability, limiting its pharmacological use. In the pharmaceutical area, cyclodextrins (CD) are used as a strategy to increase the solubility, stability and bioavailability of drugs. The development of inclusion complexes (CI) with cyclodextrins makes it possible to overcome the limitations imposed by ABAME, thus enabling an increase in the solubility and protection of this prototype, an improvement in the dissolution profile and an increase in bioavailability, allowing the evaluation of the possible improvement of the pharmacological activities. In this context, the present work aimed to develop complexes for the inclusion of this triterpene with CD and to improve biological activities. The complexes obtained were systematically characterized through molecular modeling studies, analysis by FTIR, DRX, DSC, TG and SEM. Then, in vitro tests for inhibiting the lipase enzyme were performed. The physical-chemical characterization, combined with molecular modeling studies, indicated the formation of CI with CD being able to induce changes in the physical-chemical properties of ABAME. The IC showed results above 90% when compared to the reference standard (77% inhibition) in tests for enzyme lipase, showing superiority in inhibitory effects. Thus, it has been proven that CIs with ABAME are capable of potentiating the inhibitory effects of ABAME on swine pancreas enzymes. In this study, a new pharmaceutical ingredient was developed with potential improvement in the physical-chemical characteristics and in the lipo-enzymatic inhibitory activity, demonstrating to be an alternative of a new drug and a delivery system, which can be incorporated in several pharmaceutical forms.Doctoral Thesis Desenvolvimento e avaliação físico-química e mecânica de membranas de quitosana contendo sistemas multicomponentes de triancinolona acetonida(Universidade Federal do Rio Grande do Norte, 2020-07-30) Nascimento, Ednaldo Gomes do; Silva Júnior, Arnóbio Antonio da; Azevedo, Eduardo Pereira de; Kairuz, Álvaro Federico Jimenez; Aragão, Cicero Flávio Soares; Longhi, Marcela Raquel; Barbosa, Raquel de Melo; Marreto, Ricardo NevesThe physical, mental and social well-being of individuals has been the pillar of the study of science to improve the quality of life for humanity. One of the key indicators for this well-being is oral health. However, almost half of the world's population is affected by diseases in the oral cavity, causing lesions in its mucosa, such as recurrent aphthous stomatitis. Triamcinolone acetonide is a corticosteroid that is used to treat these oral ulcerations. Nevertheless, it is usually used as ointments and creams, which requires a repeated applications and limited residence time of drug in the oral cavity. Hydrophilic polymeric films have great potential to solve these adversities. Among the polymers, chitosan has been used due to their important therapeutic properties, such as antimicrobial, antiulcerative, and healing actions. However, triamcinolone acetonide is a drug with low solubility in water, which limits its incorporation into hydrophilic films. The aim of this study was developing chitosan membranes containing triamcinolone acetonide. For this, multicomponent systems with drug, cyclodextrins, and triethanolamine were tested to make possible the preparation of membranes able to supply sustained release of drug. The chitosan membranes were prepared by the solvent evaporation method, in which the entrapment of drug was performed through the prior dispersion of this drug in solutions containing hydroxypropyl beta-cyclodextrin or beta-cyclodextrin (binary systems) or even containing triethanolamine (ternary system). The membranes were characterized by atomic force microscopy (AFM), scanning electron microscopy (SEM-FEG), infrared spectroscopy with Fourier transform (FTIR), swelling assays, measurements of surface pH, X-ray diffraction (XRD), tensile assay, and thermal analysis (DSC and TG/DTG). The quantitative analysis of the drug released from the membranes was performed by highefficiency liquid chromatography (UHPLC). All proposed systems presented physicalchemical characteristics with some singularities. Nevertheless, the ternary system containing triethanolamine stood out with the best properties. The in vitro release performance assay of triamcinolone acetonide was performed in Franz-type diffusion cells, and the mathematical treatment of the data revealed better fit by Bhaskar and parabolic diffusion models, which corroborates a two-phase drug release controlled by diffusion. The presence of triethanolamine in the chitosan membrane (ternary system) was able to modify and modulate the release of triamcinolone acetonide. This system proved to be an efficient and promising device for the release of low solubility drugs in topical administration such as triamcinolone acetonide and its potential use in the oral cavity.Doctoral Thesis Complexos de inclusão do óleo de Euterpe oleracea Mart. em (B-) ou (HP-B-) ciclodextrinas e ação antioxidante, antiinflamatória e modulatória antibacteriana(Universidade Federal do Rio Grande do Norte, 2020-06-19) Magalhães, Thalita Sévia Soares de Almeida; Lima, Adley Antonini Neves de; ; ; Damasceno, Bolivar Ponciano Goulart de Lima; ; Formiga, Fábio Rocha; ; Soares Sobrinho, José Lamartine; ; Moura, Túlio Flávio Accioly de Lima e;Euterpe oleracea Mart. (OEO), known as açaí oil, is commonly used by the food and cosmetics industry. The OEO presents important biological activities, however its use by the pharmaceutical industry is limited due to its physicochemical properties. Inclusion complexes have been used to increase solubility, stability and biological activities of vegetable oils. Therefore, the objective of this study was to obtain inclusion complexes with OEO in βcyclodextrin (OEO-β-CD) and hydroxypropyl-β-cyclodextrin (OEO-HP-β-CD), perform the physicochemical characterization of each product and test their antimicrobial, antioxidant and anti-inflammatory activity. The chemical characterization of the OEO was carried out by gas chromatography coupled to a flame ionization detector (CG-FID) and the interaction energy between oleic acid and cyclodextrins was determined. The complexes obtained through kneading (KND) and slurry (SL) were characterized by FTIR, MEV, DR-X, TG/DTG and DSC. The antibacterial activity expressed in Minimum Inhibitory Concentration (MIC) and the modulatory activity against drugs were evaluated against Staphylococcus aureus (ATCC 25932), Enterococcus faecales (ATCC 29212), Pseudomonas aeruginosa (ATCC 27853) and Escherichia coli (ATCC 25922), was evaluated (in vitro) and anti-inflammatory (models of paw edema and air sac) in Swiss mice. CG-FID presented oleic acid (47.58%) as the main constituent of the oil. Inclusion complexes with β-CD and HP-β-CD demonstrated encapsulation efficiency, with a better interaction energy between oleic acid and β-CD (-41.28 ± 0.57 kJ/mol). The results of the physical-chemical characterization showed complexation between OEO and both cyclodextrins and proposed preparation methods, without great variations. However, OEO-β-CD (KND) exhibited smaller mass loss and energy variation in ranges of 30-130ºC, related to the loss of water during their preparation, suggesting better complexation efficiency. MICs revealed that complexes improved OEO activity, especially OEO-β-CD (SL), against all the bacterial strains used. The modulatory response of OEO, OEO-β-CD (MX), OEO-β-CD (SL) and OEO-HP-β-CD (SL) showed a synergistic effect to ampicillin against E. coli, although they maintained biological activity of the other antibiotics. The OH- radical scavenging activity demonstrated synergism between CD and OEO with the use of OEO-HP-β-CD (MX), showing an increase of 437% in oil activity, while both complexes prepared by SL demonstrated enhancement of the reducing power activity by 208%. The treatment with OEO-β-CD (MX) reduced the paw edema by 200% and 112% of MPO activity. In an air bag model, this treatment showed a reduction in leukocyte, MPO and IL-1β indices, while glutathione and IL-10 were increased, demonstrating an enhancement of the anti-inflammatory effect of OEO. The pharmacological responses displayed by the complexes are highly relevant, since it supports studies for the development of new pharmaceutical formulations, as well as new dose-response and safety tests.Master Thesis Obtenção de sistemas binários com β-ciclodextrina e derivado 2-aminotiofeno para avaliação da atividade antiproliferativa e da toxicidade(Universidade Federal do Rio Grande do Norte, 2020-06-23) Ferreira, Elayne Barros; Lima, Adley Antonini Neves de; ; ; Rezende, Adriana Augusto de; ; Damasceno, Bolivar Ponciano Goulart de Lima;2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (6CN), a 2-aminothiophene derivative, has potential pharmacological applicability. However, its physical-chemical characteristics of 6CN impairs its clinical use. This work aimed to develop binary systems between 6CN and β-cyclodextrin (βCD) in order to improve the antiproliferative activity of 6CN in vitro, as well as to reduce its acute and subchronic toxicity in vivo. Molecular modeling and phase solubility studies were performed. The 6CN-βCD binary systems were prepared by physical mixture (PM), kneading (KND) and rotaevaporation (ROTA). After the physical and chemical characterization of binary systems, assays of antiproliferative activity in vitro were performed on normal fibroblast cell lines (3T3), hepatic adenocarcinoma (HepG2) and renal carcinoma (786-0) cells lines. Finally, acute and subchronic toxicity was evaluated in vivo, using only the best system, to assess biochemical, hematological and histopathological parameters. The characterization results show evident changes in the physicochemical properties of 6CN after the formation of the binary systems with βCD.Phase solubility studies indicated that βCD forms stable 1:1 complexes with 6CN, corroborating with the molecular modeling data. The 6CN-βCD binary systems at concentrations of 10 to 50µM, in the MTT assay, showed antiproliferative effects of 20–80% after 48h of exposure to 786-0 and HepG2 cancer cell lines, potentiating the antiproliferative activity of 6CN. In vivo acute and subchronic toxicity tests were conducted with ROTA, in which this binary system reduced the toxicity of 6CN, since there was no mortality for animals treated with this system. The biochemical and hematological findings did not show statistically significant changes indicative of toxicity for animals treated with ROTA. In the histopathological analysis of acute toxicity, hydropic degeneration was observed in the liver of animals treated with only 6CN. Therefore, the association between 6CN and βCD is a useful and promising strategy to improve the physical and chemical characteristics of 6CN. Which May be used in a future safe and effective anticancer therapeutic formulation, since the binary systems increased the cytostatic effect and reduced the toxicity of 6CN.