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Item Alternativas tecnológicas para aumentar a biodisponibilidade de anti-inflamatórios: gel mucoadesivo termorreversível e aplicação de sílica mesoporosa para amorfização(Universidade Federal de Goiás, 2020-03-20) Antonino, Rayane Santa Cruz Martins de Queiroz; Nascimento, Thais Leite; http://lattes.cnpq.br/4065607913504134; Lima, Eliana Martins; http://lattes.cnpq.br/7248774319455970; Lima, Eliana Martins; Alonso, Christian Gonçalves; Gil, Eric de Souza; Silva, Luís Antônio Dantas; Brito, Wesley de AlmeidaImproving the therapeutic response of drugs is one of the major goals of pharmaceutical technology. This large area of research and development uses multidisciplinary technologies and knowledge aimed at optimizing drug delivery systems. It seeks, for example, to reduce side effects with the application of nanoparticulate systems (Chung et al., 2019), to improve the reach of drugs in the central nervous system (CNS) through new delivery and administration systems (Qureshi et al., 2019), increase the delivery and therapeutic action of drugs by promoting longer drug contact time at the site of action, such as the development of mucoadhesive formulations for the treatment of inflamed mucous membranes (Léber et al., 2019). It also seeks to increase the bioavailability of drugs with low aqueous solubility by obtaining the amorphous form of the drug either through porous adsorbent systems, such as mesoporous silicas, but also to increase the stability of the amorphous form in relation to the storage time (Zůza et al., 2019). The search for better therapeutic efficacy of drugs was the main motivation for this research, using different technologies for the development of formulations with different therapeutic objectives and targets. The first part of this research aimed to develop a mucoadhesive in situ thermoreversible gel, capturing a corticosteroid for the treatment of mucous regions with inflammation. This first part produced three scientific publications that are organized as the first two chapters of this document and an annex. The second part of the research aimed to investigate the adsorbent role of mesoporous silica in two different drugs in terms of the tendency to crystallization, aiming beyond bioavailability to increase the physical stability of the systems and the impact of the drugs on the storage of the systems. Through the development of this study, a scientific article was produced presented in the third and last chapter of this document. In summary, the research developed during the PhD period is organized in two parts, in which: Chapter 01 - This chapter has mucoadhesion as its central theme, and constitutes a review of the literature published as a chapter in the book “Sciences applied to health products”, by the publisher of the State University of Goiás in 2019, ISBN 978-85-5582- 060-1 (annex 3). Strategies for the development of new mucoadhesive pharmaceutical forms, mucus and its function in the human body, the theories that analyze mucoadhesion, the mucoadhesive formulations already available and the techniques and assays used to quantify mucoadhesion were covered in this chapter. Chapter 02 - In this chapter we describe the development and characterization in vitro / in vivo of a mucoadhesive in situ gelling formulation using poloxamer 407 (Pluronic® F 127), a thermoreversible polymer, capturing budesonide (BUD), a potent corticosteroid used for treatment of a wide range of inflammatory diseases, including those that affect mucous membranes, such as in the gastrointestinal tract. This chapter was published in 2019 as an original article in the Journal of Controlled Release, entitled Thermoreversible mucoadhesive polymer-drug dispersion for sustained local delivery of budesonide to treat inflammatory disorders of the GI tract (appendix 4). The term with the approval by the ethics committee for the use of animals is attached (annex 1). Another publication, referring to oral pharmaceutical compositions of corticosteroids that gel in situ, was the production of a patent (annex 2). Patent filed and published at the United States Patent and Trademark Office, with international application under Patent Cooperation Treaty (PCT), WO 2018/193423 A1, 2018. This patent is the result of a partnership between the University and a pharmaceutical industry, Ferring Pharmaceuticals, established for the development of mucoadhesive pharmaceutical formulations. In turn, depending on the second part, which deals with technologies aimed at optimizing bioavailability and promoting greater stability using porous adsorbent systems, we have chapter 3. Chapter 03 - In this chapter, a method has been described to determine the monolayer loading capacity (MLC) of naproxen, a weak drug to amorphize, in mesoporous silica (MS). MS can be used as a carrier to stabilize the amorphous form of a drug. In addition, the impact of monolayer, pore filling and excess, on the physical stability of this system was studied and compared to ibuprofen, a strong drug to amorphize. Finally, we investigated the impact of drug loading on storage below and above the glass transition temperature (Tg), in particular with a focus on the amorphous (in) stability of the confined drug, for both drugs. Using Theoretical Functional Density Theory (DFT) and Molecular Dynamics ab initio (AIMD), the binding energies for the monolayer suggest that the monolayer is thermodynamically more favorable than the crystalline form, while the confined amorphous form is thermodynamically less favorable. This chapter was published as an original article in the International Journal of Pharmaceutics: X, in 2019 (Annex 5).Item Biorremediação de azul de indigotina por lacase imobilizada em goma polissacarídeos purificados de Anadenanthera colubrina(Universidade Federal de Goiás, 2019-03-29) Bezerra, Alyne Gonçalves; Lopes, Flavio Marques; http://lattes.cnpq.br/1423301895802989; Santiago, Mariângela Fontes; http://lattes.cnpq.br/7143224488081563; Santos, Pierre Alexandre dos; http://lattes.cnpq.br/2491095939285293; Santos, Pierre Alexandre dos; Fiuza, Tatiana de Sousa; Bara, Maria Teresa Freitas; Garcia, Telma AlvesLacasses are capable of oxidizing various pollutants, suggesting their potential in the treatment of effluents with dyes. It was tried to produce beads with Anadenanthera colubrina gum and polysaccharides to immobilize the laccase and to use it for the bioremediation of indigotine blue dye. The extraction of polysaccharides from A. colubrina was optimized by factorial planning using as variables the pH, temperature and concentration of the gum. Pycnoporus sanguineus was used to produce laccase being the residue of the bark of Theobroma cacao as the substrate. The beads were optimized to immobilize the laccase produced by varying the concentration of the structural reagents. Immobilized laccase beads were used to bioremediate the indigotin blue dye 10 mg/L, compared to the use of the free enzyme. The optimized extraction condition of the polysaccharides were pH 5.75, temperature 30 ° C with yield of 83,01%. The laccase produced with the T. cacao residue had better enzymatic activity on day 6 of 3,000 U.mL-1. The beads optimized with the immobilized enzyme were the 16P formulation, therefore the purified polysaccharides were better used for the immobilization of the laccase in the beads. The laccase was efficient in bioremediation 94% of the dye, and the beads with immobilized enzyme bioremediated 68%.Item Aplicação de métodos inovadores na avaliação do potencial alergênico de nanomateriais(Universidade Federal de Goiás, 2019-05-30) Bezerra, Soraia Ferreira; Valadares, Marize Campos; http://lattes.cnpq.br/6157755243167018; Valadares, Marize Campos; Nascimento, Thais Leite; Cunha, Luiz Carlos; Silva, Luiz Antônio DantasIntroduction: The excessive use of fullerene (C60), titanium dioxide (TiO2) and single-wall carbon nanotubes (SWCNTs) in several areas of the industry has resulted in increased human and environmental exposures, evidencing the need for the assessment of toxicological profile of these nanomaterials (NMs). Studies have shown that the interaction of these materials in different systems, including the immune system, may cause several alterations at the cellular and tissue level, demonstrating the need to assess the allergenic potential of these NMs. Nonetheless, few data are available regarding the applicability of in vitro evaluation platforms for NMs toxicity assessment. Objective: The aim of this study was to investigate the skin sensitization potential of NMs (TiO2, SWCNTs and C60) through innovative animal-free methods with regulatory and/or scientific validation. Methods: after dispersion in aqueous solvent, the samples were characterized through the Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) techniques, while the internalization assays were carried out using the dark field microscopy technique (Cytoviva). For the assessment of skin sensitization potential, validated methodologies for regulatory/scientific purposes were used. The key-event 1 of skin sensitization adverse outcome pathway (AOP) (reactivity with skin peptides) was evaluated using the micro-Direct Peptide Reactivity Assay (micro-DPRA) technique and the key event 3 (dendritic cells activation) using the U-SENSTM assay followed by cytokine quantification through the Cytometric Bead Array method by cytometer of flux. Results: NMs were well dispersed when sonicated allowing the evaluation of the allergenicity and modulation of cytokines tests. With the PDI values SWCNTs (0.148), C60 (0.105) e TiO2 (0.548). The internalization assays demonstrated that NMs were internalized by fibroblasts, achieving the intracellular compartment. The mDPRA demonstrated that the NMs interacts potentially with skin peptides, demonstrating a significant percentage of depletion, characterizing these materials as moderate positive sensitizers according to the first key-event of sensitization. Data from the U-SENSTM assay also demonstrated an increase in CD86 marker expression with Stimulation Index (SI) higher than 150 in a concentration-dependent manner, with EC150 for SWCNTs (189.48 μg/mL), C60 (91.72 μg/mL) and TiO2 (183.05 μg/mL). Additionally, cytokine quantitation assays demonstrated a significant production increase of IL-8 by U937 monocytic cell line exposed to NMs, which is a known biomarker of dendritic cell activation. Conclusion: The results demonstrated that micro-DPRA and U-SENSTM methods are applicable for skin sensitization potential assessment of nanomaterials. Furthermore, the evaluated materials presented a positive profile for skin sensitization regarding the first and the third key-event of the Adverse Outcome Pathway of allergenicity.Item Estudo de utilização de comprimidos partidos em ambiente hospitalar: análise de prescrições e avaliação laboratorial da qualidade de comprimidos partidos(Universidade Federal de Goiás, 2018-09-21) Melo, Vivianne Vieira de; Marreto, Ricardo Neves; http://lattes.cnpq.br/6127043775208484; Marreto, Ricardo Neves; Dewulf, Nathalie de Souza; Argolo, Ângela Ferreira Lopes de TeiveIntroduction: The practice of tablet splitting has been widely performed and motivated for several reasons, however, partitioning may be associated with imprecision of the administered dose and loss of drug stability. Considering the potential of tablet splitting to change the effectiveness and safety of drug therapy it becomes essential to know the frequency of tablet splitting and to determine the quality of this splitting in order to provide technical recommendations on this important practice. Purpose: To analyze the using profile of tablets splitting in a hospital and to investigate their quality by laboratory tests. Methods: The frequency of tablet splitting was verified in prescriptions of Pharmacy Sector of a university hospital. Prescriptions for thirteen random days were collected between January and March 2016. The fourteen tablets most frequently prescribed to be splitting were split using commercial tablet cutter. Loss and mass variation tests, as well as the evaluation of the friability of the split halves were performed. Results: 238 tablets were splitted in the study (4.5% of total tablets prescribed), with clonazepam (25.2%) being the most frequently used, followed by warfarin (11.3%) and propranolol (7, 1%). About three quarters of the tablets were splitted by medical decision. More than 95% of the tablets were splitted in a half and to 85.1% a pharmaceutical alternative was available in Brazilian market. The laboratory tests showed loss mass mean and mean mass variation of 8.7% ± 1.8% and 11.7% ± 2.3%, respectively. The friability after the tablets splitting increased by an average of 3.3%. Discussion: The mean tablet splitting frequency was lower than those described in other studies. However, the existence of pharmaceutical alternatives in Brazilian market for most of the tablets splitting suggested that the process of standardizing medications in the hospital, as well as the knowledgment about tablet split by pharmacists and physicians needs to be improved to rationalize the tablet splitting practice in the hospital environment. In the present study, a strong association was observed between the tablet splitting and the age group, which is more frequent in elderly patients. Laboratory tests showed mean values of loss mass and mass variation similar to those described in the literature. The presence of score had positively influenced the obtaining of more homogeneous halves, and the presence of the coating gave a reduction of the mass loss. Conclusion: The set of findings reported here allowed us to observe that the tablets splitting in the hospital has been done in part unnecessarily and laboratory tests have shown that there is a potential health risk due to a reduction in the quality of the broken tablets.Item Avaliação toxicogenetica do biocida timol encapsulado em nanopartícula biogênica de sílica sobre organismos aquáticos(Universidade Federal de Goiás, 2020-04-01) Pereira, Iúri Barbosa; Oliveira, Gisele Augusto Rodrigues de; http://lattes.cnpq.br/6221735418479539; Oliveira, Gisele Augusto Rodrigues de; Taveira, Stephânia Fleury; Silva, Gloria Narjara Santos daIntroduction: Thymol (Thy) is a monoterpene with biocidal activity against fungi, bacteria, some agricultural pests and mosquito larvae, and other applications. It is repeatedly used in high concentrations, due to its low stability with respect to temperature and light and by its rapid degradation in the environment. These facts can reduce exposure for non-target organisms. The application of nanotechnology by changing the physical-chemical characteristics of Thy and a controlled release system could reduce toxicity as a biocide. Objective: This study aimed to investigate and compare the acute toxicity and genotoxicity of the non-encapsulated Thy and its association in biogenic silica nanoparticles (BSiO2#Thy) on aquatic organisms. Methods: The acute toxicity test was performed with Artemia salina (Meyer et al., 1982 and OECD 202, 2004) and zebrafish (Danio rerio) early-life stage (OECD 236, 2013). The genotoxic effects were investigated in the comet assays with cells from zebrafish larvae (Kosmehl et al., 2006; Tice, 2000). Results: For A. salina test, the acute toxicity of Thy associated in a silica nanoparticle (BSiO2#Thy - LC50-48h = 1.06 ± 0.56 mg/L) remained practically unchanged in comparison to the non-encapsulated Thy (LC50- 48h = 1.03 ± 0.23 mg/L). The unloaded BSiO2 nanoparticle also induced significant mortality, but with less toxic potential (LC50-48h = 61.83 ± 0.43 mg/L). For zebrafish assay, the BSiO2 did not cause significant lethal, sublethal or genotoxic effects, even in high concentrations; however, the BSiO2#Thy was more toxic for the embryo-larval stage of zebrafish (LC50-96h = 13.13 mg/L) when compared to the non-encapsulated Thy (LC50-96h = 25.60 mg/L). In addition, BSiO2#Thy induced the same significant sublethal effects as the non-encapsulated Thy, such as defect in absorption of the yolk sac, pericardial edema and delayed hatching at 96h of exposure. Both formulations (BSiO2#Thy and Thy) were significantly genotoxic from 6.25 mg/L. Conclusion: Therefore, it can be concluded that the encapsulation of the Thy using silica nanoparticles increased acute toxicity for the zebrafish early-life stage and did not remove the toxic potential for A. salina nauplii and genotoxic for zebrafish larvae, since both effects remain unchanged.