Desenvolvimento e avaliação do potencial citotóxico de complexos de inclusão dronedarona/ciclodextrinas
Ano de defesa: | 2017 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | , , , |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Santa Maria
Centro de Ciências da Saúde |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Ciências Farmacêuticas
|
Departamento: |
Farmacologia
|
País: |
Brasil
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/18866 |
Resumo: | Dronedarone is a new antiarrhythmic agent, analogue of amiodarone. Dronedarone was approved for the maintenance of the sinus rhythmic in adult patients with atrial fibrillation. Dronedarone show bioavailability problems due to its very low water solubility, slow dissolution rate and instability in the gastrointestinal tract. Cyclodextrins are cyclic oligosaccharides with a relatively hydrophobic central cavity and a hydrophilic surface. Because cyclodextrins can form complexes with a variety of organic molecules, they have been widely used to increase the solubility, stability and bioavailability of poorly soluble drugs. In the present study, complexes of dronedarone with β-cyclodextrin (β-CD) and 2-hydroxypropyl- β-cyclodextrin (HP-β-CD) were prepared with the aim to increase the aqueous solubility and dissolution properties of dronedarone. Solid inclusion compounds were obtained by mixing appropriate amounts of dronedarone and β-CD or HP-β-CD, in a 1:10 molar ratio. The preparation was carried out according to the lyophilization, co-lyophilization and kneading and spray-drying methods. Solubility studies were performed by phase solubility analysis. The complexes were characterized in the solid state by DSC, XRD, FTIR spectroscopy and SEM. Characterization of inclusion complexes by DSC and XRD showed that dronedarone appeared to exist in a non-crystalline form. The solubility of the complexes were evaluated and compared with pure drug. Dronedarone solubility was notably improved in simulated gastric fluid. The cytotoxicity of the inclusion complexes was evaluated by a simple method based on 3T3 embryonic mouse fibroblast monolayers culture using the reduction of 2,5-diphenyl-3,-(4,5-dimethyl-2-thiazolyl) tetrazolium bromide (MTT) as in vitro viability assay. The inclusion complexes with both cyclodextrins produced a significant reduction in cytotoxic effects compared with the free dronedarone. In order to determine the hepatotoxic potential of the free drug and inclusion complexes, the cytotoxicity was investigated using human hepatoma cell line HepG2. The assay results showed a dose response effect; higher drug concentrations induced a higher reduction in cell viability. No significant difference among the IC50 values of the free drug and inclusion complexes was observed, suggesting that inclusion complexation did not increase dronedarone hepatotoxic effect. The 3T3 Neutral Red Uptake phototoxic test was used to verify the phototoxic potential, while the in vitro photoassay using THP-1 human monocytes, with the interleukin 8 (IL-8) expression as endpoint, was used to determine the photosensitizing potential of free dronedarone and its inclusion complexes with β-CD or HP-β-CD. The free drug and inclusion complexes did not show photoirritant potential. In the photosensitizing assay, inclusion complexes prepared with β-CD by kneading following spray-drying induced lower photosensitization in comparison to free dronedarone. Finally, cyclodextrins were able to form inclusion complexes with dronedarone, and provided an improved solubility and chemical stability, reducing drug cytotoxic potential. Thus, inclusion complexes with cyclodextrins might be a promising alternative in the development of formulations with improved therapeutic efficacy. |
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2019-11-08T20:01:29Z2019-11-08T20:01:29Z2017-09-06http://repositorio.ufsm.br/handle/1/18866Dronedarone is a new antiarrhythmic agent, analogue of amiodarone. Dronedarone was approved for the maintenance of the sinus rhythmic in adult patients with atrial fibrillation. Dronedarone show bioavailability problems due to its very low water solubility, slow dissolution rate and instability in the gastrointestinal tract. Cyclodextrins are cyclic oligosaccharides with a relatively hydrophobic central cavity and a hydrophilic surface. Because cyclodextrins can form complexes with a variety of organic molecules, they have been widely used to increase the solubility, stability and bioavailability of poorly soluble drugs. In the present study, complexes of dronedarone with β-cyclodextrin (β-CD) and 2-hydroxypropyl- β-cyclodextrin (HP-β-CD) were prepared with the aim to increase the aqueous solubility and dissolution properties of dronedarone. Solid inclusion compounds were obtained by mixing appropriate amounts of dronedarone and β-CD or HP-β-CD, in a 1:10 molar ratio. The preparation was carried out according to the lyophilization, co-lyophilization and kneading and spray-drying methods. Solubility studies were performed by phase solubility analysis. The complexes were characterized in the solid state by DSC, XRD, FTIR spectroscopy and SEM. Characterization of inclusion complexes by DSC and XRD showed that dronedarone appeared to exist in a non-crystalline form. The solubility of the complexes were evaluated and compared with pure drug. Dronedarone solubility was notably improved in simulated gastric fluid. The cytotoxicity of the inclusion complexes was evaluated by a simple method based on 3T3 embryonic mouse fibroblast monolayers culture using the reduction of 2,5-diphenyl-3,-(4,5-dimethyl-2-thiazolyl) tetrazolium bromide (MTT) as in vitro viability assay. The inclusion complexes with both cyclodextrins produced a significant reduction in cytotoxic effects compared with the free dronedarone. In order to determine the hepatotoxic potential of the free drug and inclusion complexes, the cytotoxicity was investigated using human hepatoma cell line HepG2. The assay results showed a dose response effect; higher drug concentrations induced a higher reduction in cell viability. No significant difference among the IC50 values of the free drug and inclusion complexes was observed, suggesting that inclusion complexation did not increase dronedarone hepatotoxic effect. The 3T3 Neutral Red Uptake phototoxic test was used to verify the phototoxic potential, while the in vitro photoassay using THP-1 human monocytes, with the interleukin 8 (IL-8) expression as endpoint, was used to determine the photosensitizing potential of free dronedarone and its inclusion complexes with β-CD or HP-β-CD. The free drug and inclusion complexes did not show photoirritant potential. In the photosensitizing assay, inclusion complexes prepared with β-CD by kneading following spray-drying induced lower photosensitization in comparison to free dronedarone. Finally, cyclodextrins were able to form inclusion complexes with dronedarone, and provided an improved solubility and chemical stability, reducing drug cytotoxic potential. Thus, inclusion complexes with cyclodextrins might be a promising alternative in the development of formulations with improved therapeutic efficacy.A dronedarona é um novo agente antiarrítmico análogo à amiodarona. Foi aprovado para a manutenção do ritmo cardíaco normal em pacientes com fibrilação atrial. A dronedarona possui baixa biodisponibilidade e é instável no trato gastrintestinal. As ciclodextrinas são oligossacarídeos cíclicos com uma cavidade central relativamente hidrofóbica e superfície hidrofílica. Por formarem complexos com uma variedade de moléculas orgânicas, as ciclodextrinas têm sido amplamente utilizadas para aumentar a solubilidade, estabilidade e biodisponibilidade de fármacos pouco solúveis em água. No presente estudo, complexos de inclusão de dronedarona com β-ciclodextrina e 2-hidroxipropil-β-ciclodextrina foram preparados com o objetivo de melhorar a solubilidade aquosa e as propriedades de dissolução da dronedarona. Os complexos de inclusão no estado sólido foram obtidos pela mistura de quantidades de β-ciclodextrina e 2-hidroxipropil-β-ciclodextrina na proporção molar de 1:10 (fármaco:ciclodextrina). Os complexos foram preparados de acordo com os métodos de liofilização, coliofilização e malaxagem seguida de secagem por aspersão. Os estudos de solubilidade foram realizados pelo método do diagrama de solubilidade de fases. Os complexos no estado sólido foram caracterizados por calorimetria exploratória diferencial, difração de raios-X de pó, espectroscopia no infravermelho com transformada de Fourier e microscopia eletrônica de varredura. A caracterização dos complexos de inclusão por calorimetria exploratória diferencial e difração de raios-X mostrou que a dronedarona aparenta estar na forma amorfa. A dissolução dos complexos foi estudada e comparada com o fármaco puro. Após a complexação, houve um aumento significativo na porcentagem dissolvida da dronedarona em fluido gástrico simulado. A citotoxicidade dos complexos de inclusão foi avaliada em cultivo de fibroblastos da linhagem 3T3 utilizando o ensaio de redução do MTT (brometo 3-(4,5-dimetil-2-tiazolil)-2,5-difenil-2il-tetrazólico). Os complexos de inclusão com ambas as ciclodextrinas apresentaram uma significativa redução dos efeitos citotóxicos da dronedarona em comparação ao fármaco livre. Com a finalidade de determinar o potencial hepatotóxico da dronedarona livre e dos complexos de inclusão, avaliou-se a citotoxicidade dos compostos em células da linhagem HepG2, células tumorais de hepatoma humano. Nesse ensaio verificou-se um efeito dose-resposta, ou seja, o aumento da concentração dos compostos gerou uma redução da viabilidade celular. Não foi observada diferença significativa entre os valores de concentração inibitória (IC50) do fármaco livre e complexos de inclusão, sugerindo que a complexação do fármaco com ciclodextrinas não aumenta seu efeito hepatotóxico. O ensaio de fototoxicidade in vitro 3T3 NRU foi utilizado para verificar o potencial fototóxico e o fotoensaio utilizando células THP-1 e IL-8 foi usado para determinar o potencial fotossensibilizante do fármaco e dos complexos de inclusão de dronedarona com β-ciclodextrina e 2-hidroxipropil-β-ciclodextrina. O fármaco livre e os complexos de inclusão não apresentaram potencial fotoirritante. No ensaio de fotossensibilização, o complexo com β-CD obtido por malaxagem e secagem por aspersão mostrou potencial fotossensibilizante inferior ao do fármaco livre. Finalmente, as ciclodextrinas foram capazes de formar complexos com a dronedarona e desse modo, proporcionaram melhoria na solubilidade aquosa e estabilidade química do fármaco, além de reduzir seu potencial citotóxico. Assim, os complexos de inclusão demonstram ser uma alternativa promissora no âmbito farmacêutico, visando a obtenção de medicamentos com propriedades terapêuticas potencializadas.porUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em Ciências FarmacêuticasUFSMBrasilFarmacologiaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessDronedaronaAntiarrítmicoCiclodextrinasComplexos de inclusãoCaracterizaçãoCitotoxicidadeDronedaroneAntiarrhythmic drugCyclodextrinsInclusion complexesCharacterizationCytotoxicityCNPQ::CIENCIAS DA SAUDE::FARMACIADesenvolvimento e avaliação do potencial citotóxico de complexos de inclusão dronedarona/ciclodextrinasDevelopment and evaluation of the potential cytotoxicity of dronedarone/cyclodextrin inclusion complexesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisRolim, Clarice Madalena Buenohttp://lattes.cnpq.br/2270654658839508Librelotto, Daniele Rubert Nogueirahttp://lattes.cnpq.br/1940490517223751Frizzo, Clarissa Piccininhttp://lattes.cnpq.br/0029279904716491Paim, Clésio Soldatelihttp://lattes.cnpq.br/0120736228044122Cruz, Letíciahttp://lattes.cnpq.br/3095970241017527Silva, Marcos Antonio Segattohttp://lattes.cnpq.br/3411646377586063http://lattes.cnpq.br/2608774643184365Marcolino, Ana Isa Pedroso400300000005600dced70fb-2e68-45f2-9d89-dc395bc6c0342c395ea3-ec63-4a88-9a88-cdc3954bd9a1d365fa6c-50ba-4fa4-8348-f0d3cf54860dbf4338e5-e87c-4326-93b7-60f8f505f4660aa9106e-5e7f-4311-a8fa-300c0ce15b1aa1679205-bf50-4829-ac1f-51049be5829fa6954474-bab8-4a8f-9b00-c406950d5042reponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGCF_2017_MARCOLINO_ANA.pdfTES_PPGCF_2017_MARCOLINO_ANA.pdfTese de Doutoradoapplication/pdf3315896http://repositorio.ufsm.br/bitstream/1/18866/1/TES_PPGCF_2017_MARCOLINO_ANA.pdf8ab4cb0a958b053b65a365c2992b4df6MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Desenvolvimento e avaliação do potencial citotóxico de complexos de inclusão dronedarona/ciclodextrinas |
dc.title.alternative.eng.fl_str_mv |
Development and evaluation of the potential cytotoxicity of dronedarone/cyclodextrin inclusion complexes |
title |
Desenvolvimento e avaliação do potencial citotóxico de complexos de inclusão dronedarona/ciclodextrinas |
spellingShingle |
Desenvolvimento e avaliação do potencial citotóxico de complexos de inclusão dronedarona/ciclodextrinas Marcolino, Ana Isa Pedroso Dronedarona Antiarrítmico Ciclodextrinas Complexos de inclusão Caracterização Citotoxicidade Dronedarone Antiarrhythmic drug Cyclodextrins Inclusion complexes Characterization Cytotoxicity CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Desenvolvimento e avaliação do potencial citotóxico de complexos de inclusão dronedarona/ciclodextrinas |
title_full |
Desenvolvimento e avaliação do potencial citotóxico de complexos de inclusão dronedarona/ciclodextrinas |
title_fullStr |
Desenvolvimento e avaliação do potencial citotóxico de complexos de inclusão dronedarona/ciclodextrinas |
title_full_unstemmed |
Desenvolvimento e avaliação do potencial citotóxico de complexos de inclusão dronedarona/ciclodextrinas |
title_sort |
Desenvolvimento e avaliação do potencial citotóxico de complexos de inclusão dronedarona/ciclodextrinas |
author |
Marcolino, Ana Isa Pedroso |
author_facet |
Marcolino, Ana Isa Pedroso |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Rolim, Clarice Madalena Bueno |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/2270654658839508 |
dc.contributor.advisor-co1.fl_str_mv |
Librelotto, Daniele Rubert Nogueira |
dc.contributor.advisor-co1Lattes.fl_str_mv |
http://lattes.cnpq.br/1940490517223751 |
dc.contributor.referee1.fl_str_mv |
Frizzo, Clarissa Piccinin |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/0029279904716491 |
dc.contributor.referee2.fl_str_mv |
Paim, Clésio Soldateli |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/0120736228044122 |
dc.contributor.referee3.fl_str_mv |
Cruz, Letícia |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/3095970241017527 |
dc.contributor.referee4.fl_str_mv |
Silva, Marcos Antonio Segatto |
dc.contributor.referee4Lattes.fl_str_mv |
http://lattes.cnpq.br/3411646377586063 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/2608774643184365 |
dc.contributor.author.fl_str_mv |
Marcolino, Ana Isa Pedroso |
contributor_str_mv |
Rolim, Clarice Madalena Bueno Librelotto, Daniele Rubert Nogueira Frizzo, Clarissa Piccinin Paim, Clésio Soldateli Cruz, Letícia Silva, Marcos Antonio Segatto |
dc.subject.por.fl_str_mv |
Dronedarona Antiarrítmico Ciclodextrinas Complexos de inclusão Caracterização Citotoxicidade |
topic |
Dronedarona Antiarrítmico Ciclodextrinas Complexos de inclusão Caracterização Citotoxicidade Dronedarone Antiarrhythmic drug Cyclodextrins Inclusion complexes Characterization Cytotoxicity CNPQ::CIENCIAS DA SAUDE::FARMACIA |
dc.subject.eng.fl_str_mv |
Dronedarone Antiarrhythmic drug Cyclodextrins Inclusion complexes Characterization Cytotoxicity |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
Dronedarone is a new antiarrhythmic agent, analogue of amiodarone. Dronedarone was approved for the maintenance of the sinus rhythmic in adult patients with atrial fibrillation. Dronedarone show bioavailability problems due to its very low water solubility, slow dissolution rate and instability in the gastrointestinal tract. Cyclodextrins are cyclic oligosaccharides with a relatively hydrophobic central cavity and a hydrophilic surface. Because cyclodextrins can form complexes with a variety of organic molecules, they have been widely used to increase the solubility, stability and bioavailability of poorly soluble drugs. In the present study, complexes of dronedarone with β-cyclodextrin (β-CD) and 2-hydroxypropyl- β-cyclodextrin (HP-β-CD) were prepared with the aim to increase the aqueous solubility and dissolution properties of dronedarone. Solid inclusion compounds were obtained by mixing appropriate amounts of dronedarone and β-CD or HP-β-CD, in a 1:10 molar ratio. The preparation was carried out according to the lyophilization, co-lyophilization and kneading and spray-drying methods. Solubility studies were performed by phase solubility analysis. The complexes were characterized in the solid state by DSC, XRD, FTIR spectroscopy and SEM. Characterization of inclusion complexes by DSC and XRD showed that dronedarone appeared to exist in a non-crystalline form. The solubility of the complexes were evaluated and compared with pure drug. Dronedarone solubility was notably improved in simulated gastric fluid. The cytotoxicity of the inclusion complexes was evaluated by a simple method based on 3T3 embryonic mouse fibroblast monolayers culture using the reduction of 2,5-diphenyl-3,-(4,5-dimethyl-2-thiazolyl) tetrazolium bromide (MTT) as in vitro viability assay. The inclusion complexes with both cyclodextrins produced a significant reduction in cytotoxic effects compared with the free dronedarone. In order to determine the hepatotoxic potential of the free drug and inclusion complexes, the cytotoxicity was investigated using human hepatoma cell line HepG2. The assay results showed a dose response effect; higher drug concentrations induced a higher reduction in cell viability. No significant difference among the IC50 values of the free drug and inclusion complexes was observed, suggesting that inclusion complexation did not increase dronedarone hepatotoxic effect. The 3T3 Neutral Red Uptake phototoxic test was used to verify the phototoxic potential, while the in vitro photoassay using THP-1 human monocytes, with the interleukin 8 (IL-8) expression as endpoint, was used to determine the photosensitizing potential of free dronedarone and its inclusion complexes with β-CD or HP-β-CD. The free drug and inclusion complexes did not show photoirritant potential. In the photosensitizing assay, inclusion complexes prepared with β-CD by kneading following spray-drying induced lower photosensitization in comparison to free dronedarone. Finally, cyclodextrins were able to form inclusion complexes with dronedarone, and provided an improved solubility and chemical stability, reducing drug cytotoxic potential. Thus, inclusion complexes with cyclodextrins might be a promising alternative in the development of formulations with improved therapeutic efficacy. |
publishDate |
2017 |
dc.date.issued.fl_str_mv |
2017-09-06 |
dc.date.accessioned.fl_str_mv |
2019-11-08T20:01:29Z |
dc.date.available.fl_str_mv |
2019-11-08T20:01:29Z |
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.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/18866 |
url |
http://repositorio.ufsm.br/handle/1/18866 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
400300000005 |
dc.relation.confidence.fl_str_mv |
600 |
dc.relation.authority.fl_str_mv |
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dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Ciências Farmacêuticas |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Farmacologia |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
bitstream.url.fl_str_mv |
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bitstream.checksum.fl_str_mv |
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bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
|
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1794524456521039872 |