Desenvolvimento e avaliação biofarmacêutica de supositórios de doxiciclina hiclato para uso veterinário
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional Manancial UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/20519 |
Resumo: | Veterinary drug therapy can be quite laborious especially when performed in the home environment. Usually the animal drug treatment is done by the oral or injectable route, but the rectal route can be an alternative. The objective of this study was to develop, characterize and evaluate the pharmacokinetics of suppositories containing doxycycline hyclate (DOXH) for veterinary use, aiming to overcome the difficulties of administration and the decrease of adverse effects resulting from administration by other routes. Hydrophilic (S-PEG and SPEG-MET) and lipophilic (S-CBT and S-CBT-BHT) suppositories containing the equivalent of 25 mg doxycycline were developed and the characterization of these formulations was performed by the tests of mean weight, content uniformity, melting point, organoleptic aspects and content. The mean weight and content uniformity (UV method, 350 nm) were evaluated according to the criteria established by the Brazilian Pharmacopoeia. For the determination of the content, a working electrolyte formed by the mixture of solutions A (25 mM sodium carbonate buffer + 5 mM EDTA pH 10.6) and B (acetonitrile) in the ratio 80 : 20, temperature of 24ºC, voltage 25 kV, capillary with 40 cm of effective length and detection at 260 nm. The method presented linearity in the range of 20 to 160 μg / mL, accuracy (DPR <2%), accuracy (recovery of 98 to 102%) and robustness assessed by factorial assay 23. The specificity of the method was confirmed by absence of interference of degradation products from the forced degradation study, as well as methacycline, a common impurity of the doxycycline synthesis process. The stability of the formulations was evaluated over a period of 30 days with the lipophilic formulations with and without antioxidants kept in the refrigerator (5 ± 2 ° C) and the hydrophilic with and without antioxidants kept at room temperature (25 ± 2 ° C). The S-CBT and S-PEG formulations were found to have decreased content during stability (approximately 1 and 12%, respectively) and these formulations were chosen for the pharmacokinetic study. For this study, rabbits weighing 3 to 4 kg were used and the dose of the suppositories was adjusted to 10 mg / kg. The in vivo behavior of doxycycline was evaluated via the IV and rectal routes, using groups with three animals for the pilot study and two other animals for determination of the pharmacokinetic model (n = 5) for each formulation. The pharmacokinetics were evaluated for a 24-hour period by an HPLC method adapted from the literature, and values of half-life close to 8 hours were obtained, Cmax between 1.5 and 2 μg / mL for suppositories, concentrations above MIC for up to 4 hours and 48 and 50% bioavailability for S-PEG and S-MTG, respectively, through noncompartmental analysis (NCA). Through the popPK study it was possible to conclude that the model that best describes the behavior of the drug is that of two compartments. The results obtained provide unpublished data on the rectal absorption of doxycycline and suggest that the formulations developed are promising for use in the veterinary clinic. |
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2021-04-09T14:50:33Z2021-04-09T14:50:33Z2018-08-17http://repositorio.ufsm.br/handle/1/20519Veterinary drug therapy can be quite laborious especially when performed in the home environment. Usually the animal drug treatment is done by the oral or injectable route, but the rectal route can be an alternative. The objective of this study was to develop, characterize and evaluate the pharmacokinetics of suppositories containing doxycycline hyclate (DOXH) for veterinary use, aiming to overcome the difficulties of administration and the decrease of adverse effects resulting from administration by other routes. Hydrophilic (S-PEG and SPEG-MET) and lipophilic (S-CBT and S-CBT-BHT) suppositories containing the equivalent of 25 mg doxycycline were developed and the characterization of these formulations was performed by the tests of mean weight, content uniformity, melting point, organoleptic aspects and content. The mean weight and content uniformity (UV method, 350 nm) were evaluated according to the criteria established by the Brazilian Pharmacopoeia. For the determination of the content, a working electrolyte formed by the mixture of solutions A (25 mM sodium carbonate buffer + 5 mM EDTA pH 10.6) and B (acetonitrile) in the ratio 80 : 20, temperature of 24ºC, voltage 25 kV, capillary with 40 cm of effective length and detection at 260 nm. The method presented linearity in the range of 20 to 160 μg / mL, accuracy (DPR <2%), accuracy (recovery of 98 to 102%) and robustness assessed by factorial assay 23. The specificity of the method was confirmed by absence of interference of degradation products from the forced degradation study, as well as methacycline, a common impurity of the doxycycline synthesis process. The stability of the formulations was evaluated over a period of 30 days with the lipophilic formulations with and without antioxidants kept in the refrigerator (5 ± 2 ° C) and the hydrophilic with and without antioxidants kept at room temperature (25 ± 2 ° C). The S-CBT and S-PEG formulations were found to have decreased content during stability (approximately 1 and 12%, respectively) and these formulations were chosen for the pharmacokinetic study. For this study, rabbits weighing 3 to 4 kg were used and the dose of the suppositories was adjusted to 10 mg / kg. The in vivo behavior of doxycycline was evaluated via the IV and rectal routes, using groups with three animals for the pilot study and two other animals for determination of the pharmacokinetic model (n = 5) for each formulation. The pharmacokinetics were evaluated for a 24-hour period by an HPLC method adapted from the literature, and values of half-life close to 8 hours were obtained, Cmax between 1.5 and 2 μg / mL for suppositories, concentrations above MIC for up to 4 hours and 48 and 50% bioavailability for S-PEG and S-MTG, respectively, through noncompartmental analysis (NCA). Through the popPK study it was possible to conclude that the model that best describes the behavior of the drug is that of two compartments. The results obtained provide unpublished data on the rectal absorption of doxycycline and suggest that the formulations developed are promising for use in the veterinary clinic.A terapia medicamentosa veterinária pode ser bastante trabalhosa principalmente quando realizada no ambiente doméstico. Normalmente o tratamento medicamentoso animal é feito pela via oral ou injetável, porém a via retal pode ser uma alternativa. O objetivo desse estudo foi desenvolver, caracterizar e avaliar a farmacocinética de supositórios contendo doxiciclina hiclato (DOXH) para uso veterinário, visando contornar as dificuldades de administração e a diminuição de efeitos adversos decorrentes da administração por outras vias. Foram desenvolvidos supositórios com base hidrofílica (S-PEG e S-PEG-MET) e lipofílica (S-MTG e S-MTG-BHT) contendo o equivalente a 25 mg de doxiciclina e a caracterização destas formulações foi realizada pelos ensaios de peso médio, uniformidade de conteúdo, ponto de fusão, aspectos organolépticos e teor. O peso médio e uniformidade de conteúdo (método UV, 350 nm) foram avaliados de acordo com os critérios estabelecidos pela Farmacopeia Brasileira. Para a determinação do teor foi desenvolvido e validado método por eletroforese capilar (EC) empregando eletrólito de trabalho formado pela mistura das soluções A (tampão carbonato de sódio 25 mM + EDTA 5 mM pH 10,6) e B (acetonitrila) na proporção 80:20, temperatura de 24ºC, voltagem 25 kV, capilar com 40 cm de comprimento efetivo e detecção em 260 nm. O método apresentou linearidade na faixa de 20 a 160 µg/mL, precisão (DPR < 2%), exatidão (recuperação de 98 a 102%) e robustez avaliada através de ensaio fatorial 23. A especificidade do método foi confirmada pela ausência de interferência de produtos de degradação oriundos do estudo de degradação forçada, assim como da metaciclina, impureza comum do processo de síntese da doxiciclina. A estabilidade das formulações foi avaliada por um período de 30 dias com as formulações lipofílicas com e sem antioxidantes mantidas em geladeira (5 ± 2 °C) e as hidrofílicas com e sem antioxidantes mantidas em temperatura ambiente (25 ± 2°C). Verificou-se que as formulações S-MTG e S-PEG apresentaram menor redução no teor durante a estabilidade (aproximadamente 1 e 12%, respectivamente) e estas formulações foram escolhidas para o estudo farmacocinético. Para este estudo, foram utilizados coelhos com peso entre 3 e 4 kg e a dose dos supositórios foi ajustada para 10 mg/kg. O comportamento in vivo da doxiciclina foi avaliado através da via IV e retal, utilizando grupos com três animais para o estudo piloto e mais dois animais para determinação do modelo farmacocinético (n=5) para cada formulação. A farmacocinética foi avaliada por um período de 24 horas, através de método por CLAE adaptado da literatura, e foram obtidos valores de meia-vida próximos a 8 horas, Cmax entre 1,5 e 2 µg/mL para os supositórios, concentrações acima da CIM por até 4 horas e biodisponibilidade de 48 e 50% para S-PEG e S-MTG, respectivamente, através da análise não compartimental (NCA). Através do estudo popPK foi possível concluir que o modelo que melhor descreve o comportamento do fármaco é o de dois compartimentos. Os resultados obtidos fornecem dados inéditos a respeito da absorção retal de doxiciclina e sugerem que as formulações desenvolvidas são promissoras para uso na clínica veterinária.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em Ciências FarmacêuticasUFSMBrasilAnálises Clínicas e ToxicológicasAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessSupositóriosTetraciclinasFarmacocinéticaTratamento veterinárioSuppositoriesTetracyclinesPharmacokineticsVeterinary treatmentCNPQ::CIENCIAS DA SAUDE::FARMACIADesenvolvimento e avaliação biofarmacêutica de supositórios de doxiciclina hiclato para uso veterinárioDevelopment and biopharmaceutical evaluation of doxycycline hyclate suppositories for veterinary useinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisAdams, Andréa Inês Hornhttp://lattes.cnpq.br/6872246935204149Zimmermann , Estevan SonegoSilva, Fabiana Ernestina Barcellos daFröehlich, Pedro EduardoSilva, Cristiane de Bona daCruz, Letíciahttp://lattes.cnpq.br/6202071752025168Christ, Ana Paula40030000000560060060060060060060060092cc080e-6b24-4a6b-9b3b-299e65552d5f2f8e3546-3963-4df4-bca2-9f8bbfca2a347849f678-d02b-40b7-b92e-934bb61d5ed93d85cf2a-364b-41ad-9eae-fcd202b4db4b37685e98-74d9-4d5f-86ff-28ccc13edc4442fc71ea-4e18-491b-ae18-1dbf419b4b0443d8d4de-4af1-4265-9b7d-885614e01622reponame:Repositório Institucional Manancial UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGCF_2018_CHRIST_ANA.pdfTES_PPGCF_2018_CHRIST_ANA.pdfTeseapplication/pdf1314477http://repositorio.ufsm.br/bitstream/1/20519/1/TES_PPGCF_2018_CHRIST_ANA.pdf2b81e590eeb22912ad564d376ba52282MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Desenvolvimento e avaliação biofarmacêutica de supositórios de doxiciclina hiclato para uso veterinário |
dc.title.alternative.eng.fl_str_mv |
Development and biopharmaceutical evaluation of doxycycline hyclate suppositories for veterinary use |
title |
Desenvolvimento e avaliação biofarmacêutica de supositórios de doxiciclina hiclato para uso veterinário |
spellingShingle |
Desenvolvimento e avaliação biofarmacêutica de supositórios de doxiciclina hiclato para uso veterinário Christ, Ana Paula Supositórios Tetraciclinas Farmacocinética Tratamento veterinário Suppositories Tetracyclines Pharmacokinetics Veterinary treatment CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Desenvolvimento e avaliação biofarmacêutica de supositórios de doxiciclina hiclato para uso veterinário |
title_full |
Desenvolvimento e avaliação biofarmacêutica de supositórios de doxiciclina hiclato para uso veterinário |
title_fullStr |
Desenvolvimento e avaliação biofarmacêutica de supositórios de doxiciclina hiclato para uso veterinário |
title_full_unstemmed |
Desenvolvimento e avaliação biofarmacêutica de supositórios de doxiciclina hiclato para uso veterinário |
title_sort |
Desenvolvimento e avaliação biofarmacêutica de supositórios de doxiciclina hiclato para uso veterinário |
author |
Christ, Ana Paula |
author_facet |
Christ, Ana Paula |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Adams, Andréa Inês Horn |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/6872246935204149 |
dc.contributor.advisor-co1.fl_str_mv |
Zimmermann , Estevan Sonego |
dc.contributor.referee1.fl_str_mv |
Silva, Fabiana Ernestina Barcellos da |
dc.contributor.referee2.fl_str_mv |
Fröehlich, Pedro Eduardo |
dc.contributor.referee3.fl_str_mv |
Silva, Cristiane de Bona da |
dc.contributor.referee4.fl_str_mv |
Cruz, Letícia |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/6202071752025168 |
dc.contributor.author.fl_str_mv |
Christ, Ana Paula |
contributor_str_mv |
Adams, Andréa Inês Horn Zimmermann , Estevan Sonego Silva, Fabiana Ernestina Barcellos da Fröehlich, Pedro Eduardo Silva, Cristiane de Bona da Cruz, Letícia |
dc.subject.por.fl_str_mv |
Supositórios Tetraciclinas Farmacocinética Tratamento veterinário |
topic |
Supositórios Tetraciclinas Farmacocinética Tratamento veterinário Suppositories Tetracyclines Pharmacokinetics Veterinary treatment CNPQ::CIENCIAS DA SAUDE::FARMACIA |
dc.subject.eng.fl_str_mv |
Suppositories Tetracyclines Pharmacokinetics Veterinary treatment |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
Veterinary drug therapy can be quite laborious especially when performed in the home environment. Usually the animal drug treatment is done by the oral or injectable route, but the rectal route can be an alternative. The objective of this study was to develop, characterize and evaluate the pharmacokinetics of suppositories containing doxycycline hyclate (DOXH) for veterinary use, aiming to overcome the difficulties of administration and the decrease of adverse effects resulting from administration by other routes. Hydrophilic (S-PEG and SPEG-MET) and lipophilic (S-CBT and S-CBT-BHT) suppositories containing the equivalent of 25 mg doxycycline were developed and the characterization of these formulations was performed by the tests of mean weight, content uniformity, melting point, organoleptic aspects and content. The mean weight and content uniformity (UV method, 350 nm) were evaluated according to the criteria established by the Brazilian Pharmacopoeia. For the determination of the content, a working electrolyte formed by the mixture of solutions A (25 mM sodium carbonate buffer + 5 mM EDTA pH 10.6) and B (acetonitrile) in the ratio 80 : 20, temperature of 24ºC, voltage 25 kV, capillary with 40 cm of effective length and detection at 260 nm. The method presented linearity in the range of 20 to 160 μg / mL, accuracy (DPR <2%), accuracy (recovery of 98 to 102%) and robustness assessed by factorial assay 23. The specificity of the method was confirmed by absence of interference of degradation products from the forced degradation study, as well as methacycline, a common impurity of the doxycycline synthesis process. The stability of the formulations was evaluated over a period of 30 days with the lipophilic formulations with and without antioxidants kept in the refrigerator (5 ± 2 ° C) and the hydrophilic with and without antioxidants kept at room temperature (25 ± 2 ° C). The S-CBT and S-PEG formulations were found to have decreased content during stability (approximately 1 and 12%, respectively) and these formulations were chosen for the pharmacokinetic study. For this study, rabbits weighing 3 to 4 kg were used and the dose of the suppositories was adjusted to 10 mg / kg. The in vivo behavior of doxycycline was evaluated via the IV and rectal routes, using groups with three animals for the pilot study and two other animals for determination of the pharmacokinetic model (n = 5) for each formulation. The pharmacokinetics were evaluated for a 24-hour period by an HPLC method adapted from the literature, and values of half-life close to 8 hours were obtained, Cmax between 1.5 and 2 μg / mL for suppositories, concentrations above MIC for up to 4 hours and 48 and 50% bioavailability for S-PEG and S-MTG, respectively, through noncompartmental analysis (NCA). Through the popPK study it was possible to conclude that the model that best describes the behavior of the drug is that of two compartments. The results obtained provide unpublished data on the rectal absorption of doxycycline and suggest that the formulations developed are promising for use in the veterinary clinic. |
publishDate |
2018 |
dc.date.issued.fl_str_mv |
2018-08-17 |
dc.date.accessioned.fl_str_mv |
2021-04-09T14:50:33Z |
dc.date.available.fl_str_mv |
2021-04-09T14:50:33Z |
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/1/20519 |
url |
http://repositorio.ufsm.br/handle/1/20519 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
400300000005 |
dc.relation.confidence.fl_str_mv |
600 600 600 600 600 600 600 600 |
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 |
Análises Clínicas e Toxicológicas |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional Manancial 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 |
Repositório Institucional Manancial UFSM |
collection |
Repositório Institucional Manancial UFSM |
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http://repositorio.ufsm.br/bitstream/1/20519/1/TES_PPGCF_2018_CHRIST_ANA.pdf http://repositorio.ufsm.br/bitstream/1/20519/2/license_rdf http://repositorio.ufsm.br/bitstream/1/20519/3/license.txt http://repositorio.ufsm.br/bitstream/1/20519/4/TES_PPGCF_2018_CHRIST_ANA.pdf.txt http://repositorio.ufsm.br/bitstream/1/20519/5/TES_PPGCF_2018_CHRIST_ANA.pdf.jpg |
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bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Repositório Institucional Manancial UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
ouvidoria@ufsm.br |
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1808854722268889088 |