Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFS |
Texto Completo: | http://ri.ufs.br/jspui/handle/riufs/12504 |
Resumo: | Leishmaniasis is a neglected infectious disease caused by protozoa of the genus Leishmania. The current leishmaniasis treatment is expensive, usually causes adverse effects and it is ineffective for resistant leishmania strains. Therefore, molecules derived from natural products as the monoterpene carvacrol, has been attracted interest as promising anti-leishmania agents. However, the therapeutical use of carvacrol is limited due to its low aqueous solubility, ease oxidation and volatilization. Thus, the development of nanostructured lipid carriers was proposed in the present study as a promising nanotechnology strategy to overcome these limitations and enable the use of carvacrol in leishmaniasis therapy. Firstly, it was evaluated the influence of carvacrol in the lipid matrix by Differential Scanning Calorimetry (DSC), Termogravimetry (TG), Small Angle X-ray Scattering (SAXS) and Polarized Light Microscopy (PLM). Inert and containing carvacrol NLCs were obtained by warm microemulsion method, and evaluated regarding the influence of lipid matrix and components concentration on the NLCs formation. NLCs were characterized by DSC and XRD as well. In addition, the in vitro carvacrol release from NLCs, the in vitro cytotoxicity assay, the in vitro promastigotes assay, the in vivo pharmacokinetics evaluation of free carvacrol and encapsulated were performed. Through the evaluation of influence of carvacrol on lipid matrix, it was possible to suggest that carvacrol may act also as a liquid lipid of NLCs formulation since TG, DSC, SAXS and PLM analysis that the lipid matrix became less ordered after adding carvacrol. Furthermore, DSC analysis showed that carvacrol was miscible in the tested concentration range. NLCs containing carvacrol were obtained successfully by warm microemulsion dilution method, being the NLCs formulation that presented the lowest particle size (98.42 ± 0.80 nm) and narrow size distribution (suitable for intravenous administration), the higher encapsulation efficiency, were those prepared using beeswax as solid lipid (HLB=9) and 5% of lipids and surfactant. The in vitro release of carvacrol from NLCs was fitted to Korsmeyer and Peppas, and Weibull model, demonstrating that the release mechanism is probably the Fickian diffusion type. Moreover, carvacrol encapsulation in NLCs provided a lower cytotoxicity in comparison to free carvacrol (p<0.05). However, carvacrol encapsulation in NLCs did not change its in vitro promastigotes efficacy. Finally, the in vivo pharmacokinetics of carvacrol after IV bolus administration suggests that this phenolic monoterpene undergo enterohepatic circulation and therefore presented a long half-life (t1/2) of 51.07 ± 2.80 h and low value of clearance (Cl) of 0.057 ± 0.003 L/h. In addition, C0, t1/2, mean residence time (MRT) and Vdss of encapsulated carvacrol were higher than free carvacrol (p < 0.05), favoring a higher distribution of carvacrol in the target tissues. Thus, it is possible to conclude that the developed NLCs are a promising delivery system for leishmaniasis treatment. |
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Galvão, Juliana GouveiaNunes, Rogéria de SouzaDolabella, Silvio SantanaScher, Ricardo2019-12-20T15:13:34Z2019-12-20T15:13:34Z2019-02-22GALVÃO, Juliana Gouveia. Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses. 2019. 121 f. Tese (Doutorado em Ciências Farmacêuticas) - Universidade Federal de Sergipe, São Cristóvão, SE, 2019.http://ri.ufs.br/jspui/handle/riufs/12504Leishmaniasis is a neglected infectious disease caused by protozoa of the genus Leishmania. The current leishmaniasis treatment is expensive, usually causes adverse effects and it is ineffective for resistant leishmania strains. Therefore, molecules derived from natural products as the monoterpene carvacrol, has been attracted interest as promising anti-leishmania agents. However, the therapeutical use of carvacrol is limited due to its low aqueous solubility, ease oxidation and volatilization. Thus, the development of nanostructured lipid carriers was proposed in the present study as a promising nanotechnology strategy to overcome these limitations and enable the use of carvacrol in leishmaniasis therapy. Firstly, it was evaluated the influence of carvacrol in the lipid matrix by Differential Scanning Calorimetry (DSC), Termogravimetry (TG), Small Angle X-ray Scattering (SAXS) and Polarized Light Microscopy (PLM). Inert and containing carvacrol NLCs were obtained by warm microemulsion method, and evaluated regarding the influence of lipid matrix and components concentration on the NLCs formation. NLCs were characterized by DSC and XRD as well. In addition, the in vitro carvacrol release from NLCs, the in vitro cytotoxicity assay, the in vitro promastigotes assay, the in vivo pharmacokinetics evaluation of free carvacrol and encapsulated were performed. Through the evaluation of influence of carvacrol on lipid matrix, it was possible to suggest that carvacrol may act also as a liquid lipid of NLCs formulation since TG, DSC, SAXS and PLM analysis that the lipid matrix became less ordered after adding carvacrol. Furthermore, DSC analysis showed that carvacrol was miscible in the tested concentration range. NLCs containing carvacrol were obtained successfully by warm microemulsion dilution method, being the NLCs formulation that presented the lowest particle size (98.42 ± 0.80 nm) and narrow size distribution (suitable for intravenous administration), the higher encapsulation efficiency, were those prepared using beeswax as solid lipid (HLB=9) and 5% of lipids and surfactant. The in vitro release of carvacrol from NLCs was fitted to Korsmeyer and Peppas, and Weibull model, demonstrating that the release mechanism is probably the Fickian diffusion type. Moreover, carvacrol encapsulation in NLCs provided a lower cytotoxicity in comparison to free carvacrol (p<0.05). However, carvacrol encapsulation in NLCs did not change its in vitro promastigotes efficacy. Finally, the in vivo pharmacokinetics of carvacrol after IV bolus administration suggests that this phenolic monoterpene undergo enterohepatic circulation and therefore presented a long half-life (t1/2) of 51.07 ± 2.80 h and low value of clearance (Cl) of 0.057 ± 0.003 L/h. In addition, C0, t1/2, mean residence time (MRT) and Vdss of encapsulated carvacrol were higher than free carvacrol (p < 0.05), favoring a higher distribution of carvacrol in the target tissues. Thus, it is possible to conclude that the developed NLCs are a promising delivery system for leishmaniasis treatment.A Leishmaniose é uma doença infecciosa negligenciada causada por protozoários do gênero Leishmania. O tratamento atual da leishmaniose tem custo elevado, causa efeitos adversos e é ineficaz para cepas de leishamnia resistentes. Sendo assim, moléculas derivadas de produtos naturais como o monoterpeno carvacrol, têm atraído interesse como promissores agentes anti-leishmania. Entretanto, o carvacrol tem seu uso terapêutico limitado pela sua baixa solubilidade aquosa, facilidade de oxidação e volatilização. Dessa forma, o desenvolvimento de carreadores lipídicos nanoestruturados (CLNs) foi proposto no presente estudo como uma estratégia nanotecnológica promissora para contornar essas limitações e possibilitar seu uso na terapia de leishmanioses. Para isso, primeiramente foi avaliada a influência do carvacrol na matriz lipídica a partir da caracterização por Calorimetria Exploratória Diferencial (DSC), Termogravimetria (TG), Espalhamento de raios X a baixo ângulo (SAXS) e Microscopia de luz polarizada (MLP). Os CLNs inertes e contendo carvacrol foram preparados através do método de microemulsão a quente e avaliados quanto à influência da matriz lipídica e concentração dos componentes na sua formação. Os CLNs ainda foram caracterizados por DSC e DRX. Também foi avaliada a cinética de liberação do carvacrol a partir dos CLNs, a citotoxicidade, a viabilidade sobre formas promastigotas, e o perfil farmacocinético do carvacrol livre e encapsulado. Através da avaliação da influência do carvacrol na matriz lipídica foi possível sugerir que o carvacrol também pode atuar como lipídeo líquido dos CLNs, pois foi observado nas análises de TG, DSC, SAXS e MLP que as matrizes lipídicas se tornaram menos estruturadas ao adicionar concentrações crescentes de carvacrol. Através da análise de DSC também demonstrou que o carvacrol foi miscível nos lipídeos sólidos e na faixa de concentração testados. Os CLNs inertes e contendo carvacrol foram obtidos com sucesso através do método de diluição de microemulsão a quente sendo que os CLNs contendo carvacrol que apresentaram menor diâmetro médio (98,42 ± 0,80 nm) e estreita distribuição de tamanho (adequadas para administração intravenosa) e maior eficiência de encapsulação, foram aqueles preparados com cera de abelha (EHL=9) e concentração de 5% de lipídeos e tensoativo. A diminuição nos valores de entalpia e deslocamento do pico de fusão para menores temperaturas no DSC e uma diminuição de intensidade dos picos principais de difração no DRX dos CLNs em comparação com o lipídeo sólido e tensoativo, indicam a formação de uma desordem na estrutura lipídica, característica da formação dos CLNs. O perfil de liberação do carvacrol a partir dos CLNs foi ajustado ao modelo de Korsmeyer e Peppas, e Weibull e demonstrou que o mecanismo de liberação é possivelmente do tipo difusão Fickiana. Além disso, o encapsulamento do carvacrol em CLNs proporcionou uma menor citotoxicidade em relação ao carvacrol livre (p < 0,05). Entretanto a encapsulação do carvacrol em CLNs não modificou a viabilidade sobre formas promastigotas do parasita. Por fim, o perfil farmacocinético in vivo do carvacrol após administração IV em bolus sugere que este monoterpeno fenólico passa por circulação enterohepática e por isso apresentou um longo tempo de meia-vida de eliminação (t1/2) de 51,07 ± 2,80 h e baixo valor de clearance (Cl) de 0,057 ± 0,003 L/h. Também foi possível observar que a C0, o t1/2 , tempo de residência médio (MRT) e volume de distribuição do carvacrol encapsulado foram maiores do que o carvacrol livre (p < 0,05), o que favorece uma maior distribuição do carvacrol nos tecidos alvo. Sendo assim é possível concluir que os CLNs desenvolvidos são um promissor sistema de liberação do carvacrol para o tratamento de leishmanioses.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESSão Cristóvão, SEporLeishmaniaMonoterpenosProdutos naturaisNanomedicinaLipídiosLipídeos sólidosMonoterpeno fenólicoTratamento intravenosoSolid lipidsPhenolic monoterpeneNatural productsNanomedicineIntravenous treatmentCIENCIAS BIOLOGICAS::FARMACOLOGIADesenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmaniosesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisPós-Graduação em Ciências FarmacêuticasUniversidade Federal de Sergipereponame:Repositório Institucional da UFSinstname:Universidade Federal de Sergipe (UFS)instacron:UFSinfo:eu-repo/semantics/openAccessTEXTJULIANA_GOUVEIA_GALVAO.pdf.txtJULIANA_GOUVEIA_GALVAO.pdf.txtExtracted texttext/plain238268https://ri.ufs.br/jspui/bitstream/riufs/12504/3/JULIANA_GOUVEIA_GALVAO.pdf.txt6710ba76be7ed332171fe10bc99401d9MD53THUMBNAILJULIANA_GOUVEIA_GALVAO.pdf.jpgJULIANA_GOUVEIA_GALVAO.pdf.jpgGenerated Thumbnailimage/jpeg1257https://ri.ufs.br/jspui/bitstream/riufs/12504/4/JULIANA_GOUVEIA_GALVAO.pdf.jpg15d20ff2c24fe7cd7a1f2deb7fcb33ffMD54LICENSElicense.txtlicense.txttext/plain; charset=utf-81475https://ri.ufs.br/jspui/bitstream/riufs/12504/1/license.txt098cbbf65c2c15e1fb2e49c5d306a44cMD51ORIGINALJULIANA_GOUVEIA_GALVAO.pdfJULIANA_GOUVEIA_GALVAO.pdfapplication/pdf4331000https://ri.ufs.br/jspui/bitstream/riufs/12504/2/JULIANA_GOUVEIA_GALVAO.pdf19213e2e7cee554c927b2d4d34529c4fMD52riufs/125042019-12-20 12:13:35.022oai:ufs.br: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Repositório InstitucionalPUBhttps://ri.ufs.br/oai/requestrepositorio@academico.ufs.bropendoar:2019-12-20T15:13:35Repositório Institucional da UFS - Universidade Federal de Sergipe (UFS)false |
dc.title.pt_BR.fl_str_mv |
Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses |
title |
Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses |
spellingShingle |
Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses Galvão, Juliana Gouveia Leishmania Monoterpenos Produtos naturais Nanomedicina Lipídios Lipídeos sólidos Monoterpeno fenólico Tratamento intravenoso Solid lipids Phenolic monoterpene Natural products Nanomedicine Intravenous treatment CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses |
title_full |
Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses |
title_fullStr |
Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses |
title_full_unstemmed |
Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses |
title_sort |
Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses |
author |
Galvão, Juliana Gouveia |
author_facet |
Galvão, Juliana Gouveia |
author_role |
author |
dc.contributor.author.fl_str_mv |
Galvão, Juliana Gouveia |
dc.contributor.advisor1.fl_str_mv |
Nunes, Rogéria de Souza |
dc.contributor.advisor-co1.fl_str_mv |
Dolabella, Silvio Santana Scher, Ricardo |
contributor_str_mv |
Nunes, Rogéria de Souza Dolabella, Silvio Santana Scher, Ricardo |
dc.subject.por.fl_str_mv |
Leishmania Monoterpenos Produtos naturais Nanomedicina Lipídios Lipídeos sólidos Monoterpeno fenólico Tratamento intravenoso |
topic |
Leishmania Monoterpenos Produtos naturais Nanomedicina Lipídios Lipídeos sólidos Monoterpeno fenólico Tratamento intravenoso Solid lipids Phenolic monoterpene Natural products Nanomedicine Intravenous treatment CIENCIAS BIOLOGICAS::FARMACOLOGIA |
dc.subject.eng.fl_str_mv |
Solid lipids Phenolic monoterpene Natural products Nanomedicine Intravenous treatment |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Leishmaniasis is a neglected infectious disease caused by protozoa of the genus Leishmania. The current leishmaniasis treatment is expensive, usually causes adverse effects and it is ineffective for resistant leishmania strains. Therefore, molecules derived from natural products as the monoterpene carvacrol, has been attracted interest as promising anti-leishmania agents. However, the therapeutical use of carvacrol is limited due to its low aqueous solubility, ease oxidation and volatilization. Thus, the development of nanostructured lipid carriers was proposed in the present study as a promising nanotechnology strategy to overcome these limitations and enable the use of carvacrol in leishmaniasis therapy. Firstly, it was evaluated the influence of carvacrol in the lipid matrix by Differential Scanning Calorimetry (DSC), Termogravimetry (TG), Small Angle X-ray Scattering (SAXS) and Polarized Light Microscopy (PLM). Inert and containing carvacrol NLCs were obtained by warm microemulsion method, and evaluated regarding the influence of lipid matrix and components concentration on the NLCs formation. NLCs were characterized by DSC and XRD as well. In addition, the in vitro carvacrol release from NLCs, the in vitro cytotoxicity assay, the in vitro promastigotes assay, the in vivo pharmacokinetics evaluation of free carvacrol and encapsulated were performed. Through the evaluation of influence of carvacrol on lipid matrix, it was possible to suggest that carvacrol may act also as a liquid lipid of NLCs formulation since TG, DSC, SAXS and PLM analysis that the lipid matrix became less ordered after adding carvacrol. Furthermore, DSC analysis showed that carvacrol was miscible in the tested concentration range. NLCs containing carvacrol were obtained successfully by warm microemulsion dilution method, being the NLCs formulation that presented the lowest particle size (98.42 ± 0.80 nm) and narrow size distribution (suitable for intravenous administration), the higher encapsulation efficiency, were those prepared using beeswax as solid lipid (HLB=9) and 5% of lipids and surfactant. The in vitro release of carvacrol from NLCs was fitted to Korsmeyer and Peppas, and Weibull model, demonstrating that the release mechanism is probably the Fickian diffusion type. Moreover, carvacrol encapsulation in NLCs provided a lower cytotoxicity in comparison to free carvacrol (p<0.05). However, carvacrol encapsulation in NLCs did not change its in vitro promastigotes efficacy. Finally, the in vivo pharmacokinetics of carvacrol after IV bolus administration suggests that this phenolic monoterpene undergo enterohepatic circulation and therefore presented a long half-life (t1/2) of 51.07 ± 2.80 h and low value of clearance (Cl) of 0.057 ± 0.003 L/h. In addition, C0, t1/2, mean residence time (MRT) and Vdss of encapsulated carvacrol were higher than free carvacrol (p < 0.05), favoring a higher distribution of carvacrol in the target tissues. Thus, it is possible to conclude that the developed NLCs are a promising delivery system for leishmaniasis treatment. |
publishDate |
2019 |
dc.date.accessioned.fl_str_mv |
2019-12-20T15:13:34Z |
dc.date.available.fl_str_mv |
2019-12-20T15:13:34Z |
dc.date.issued.fl_str_mv |
2019-02-22 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
GALVÃO, Juliana Gouveia. Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses. 2019. 121 f. Tese (Doutorado em Ciências Farmacêuticas) - Universidade Federal de Sergipe, São Cristóvão, SE, 2019. |
dc.identifier.uri.fl_str_mv |
http://ri.ufs.br/jspui/handle/riufs/12504 |
identifier_str_mv |
GALVÃO, Juliana Gouveia. Desenvolvimento de carreadores lipídicos nanoestruturados para o encapsulamento de carvacrol : uma formulação promissora para o tratamento de leishmanioses. 2019. 121 f. Tese (Doutorado em Ciências Farmacêuticas) - Universidade Federal de Sergipe, São Cristóvão, SE, 2019. |
url |
http://ri.ufs.br/jspui/handle/riufs/12504 |
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openAccess |
dc.publisher.program.fl_str_mv |
Pós-Graduação em Ciências Farmacêuticas |
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Universidade Federal de Sergipe |
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