Estudo de pré-formulação e formulação farmacêutica de uso tópico contendo Immucillin-DI4G como alternativa terapêutica para o tratamento da Leishmaniose Cutânea

Detalhes bibliográficos
Autor(a) principal: Pacheco, Fernanda Grendene
Data de Publicação: 2016
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da PUC_RS
Texto Completo: http://tede2.pucrs.br/tede2/handle/tede/6655
Resumo: Introduction: Cutaneous leishmaniasis is caused by Leishmania protozoan and transmitted through the female of Lutzomyia sandflies. The disease can manifest itself in different clinical forms: localized cutaneous leishmaniasis, disseminated cutaneous leishmaniasis, recidivans and diffuse cutaneous leishmaniasis. The North and Northeast (Brazil) are the most affected area by the disease. Pentavalent antimonials and amphotericin B have been the most used drugs for the treatment of this disease but may cause many side effects, which leads the patients to discontinue treatment. Control or progression of the disease has been related to the immune response triggered by the individual. PNP (purine nucleoside phosphorylase) is the key enzyme in the purine salvage route catalyzing the reversible phosphorolysis of purine nucleosides such as deoxyinosine or deoxyguanosine producing their respective bases and deoxyrribose-1-phosphate. The PNP inhibitors can be used for treating diseases caused by disorder mediated by T cells. Immucillin - DI4G (4th generation Immucillin ; 7-((bis(2-hydroxyiethyl)amine)methyl)-1,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one) is considered as a potent inhibitor of PNP. Objective: development of pre-formulation and formulation studies of a pharmaceutical form for topical use containing Immucillin-DI4G as drug candidate for Cutaneous Leishmaniasis treatment. Material and Methods: Characterization of the compound was performed by NMR, FTIR-ATR and HRMS. The stability of the amorphous powder was evaluated over 90 days using a HPLC method for quantification. Formulations have been developed for stability, rheological and spreadability studies over 30 and 90 days. A method for the quantification of Immucillin-DI4G in the formulation was developed and validated using the HPLC. Results and discussion: The Immucillin - DI4G (amorphous powder) was stable up to 30 days when stored at 4 °C and 25 °C. Formulation 1 (Immucillin - DI4G 1.1% Carboxyvinylpolymer gel 2%) was stable only when stored at 4 °C for a period of 60 days. Formulation 1 was considered as a non-Newtonian fluid with pseudoplastic behavior and no alterations in viscosity was observed over 90 days. On the other hand, significant changes in spreadability was observed when topical formulation was stored at 45 °C. The formulation containing additives (formulation 2) showed an improvement in stability when stored at 45 °C for a period of 30 days, but there was a significant decrease in drug content when stored at 4 °C and 25 °C. Formulations 3 (Immucillin-DI4G a 1,1% Gel-Cream) and 4 (Immucillin-DI4G 1.1% in Hydroxypropylcellulose polymer at 2%) presented significant loss in the drug content in 30 days when stored at 45 °C. The results shows that further studies should be conducted in order to analyze the possible degradation products looking for design of novel formulations.
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spelling Machado, Pablo994.698.980-87http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4757509Z3Corte, Temis Weber Furlanettohttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4782148Y4054.131.499-80http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4407955H6Pacheco, Fernanda Grendene2016-05-10T11:50:40Z2016-03-14http://tede2.pucrs.br/tede2/handle/tede/6655Introduction: Cutaneous leishmaniasis is caused by Leishmania protozoan and transmitted through the female of Lutzomyia sandflies. The disease can manifest itself in different clinical forms: localized cutaneous leishmaniasis, disseminated cutaneous leishmaniasis, recidivans and diffuse cutaneous leishmaniasis. The North and Northeast (Brazil) are the most affected area by the disease. Pentavalent antimonials and amphotericin B have been the most used drugs for the treatment of this disease but may cause many side effects, which leads the patients to discontinue treatment. Control or progression of the disease has been related to the immune response triggered by the individual. PNP (purine nucleoside phosphorylase) is the key enzyme in the purine salvage route catalyzing the reversible phosphorolysis of purine nucleosides such as deoxyinosine or deoxyguanosine producing their respective bases and deoxyrribose-1-phosphate. The PNP inhibitors can be used for treating diseases caused by disorder mediated by T cells. Immucillin - DI4G (4th generation Immucillin ; 7-((bis(2-hydroxyiethyl)amine)methyl)-1,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one) is considered as a potent inhibitor of PNP. Objective: development of pre-formulation and formulation studies of a pharmaceutical form for topical use containing Immucillin-DI4G as drug candidate for Cutaneous Leishmaniasis treatment. Material and Methods: Characterization of the compound was performed by NMR, FTIR-ATR and HRMS. The stability of the amorphous powder was evaluated over 90 days using a HPLC method for quantification. Formulations have been developed for stability, rheological and spreadability studies over 30 and 90 days. A method for the quantification of Immucillin-DI4G in the formulation was developed and validated using the HPLC. Results and discussion: The Immucillin - DI4G (amorphous powder) was stable up to 30 days when stored at 4 °C and 25 °C. Formulation 1 (Immucillin - DI4G 1.1% Carboxyvinylpolymer gel 2%) was stable only when stored at 4 °C for a period of 60 days. Formulation 1 was considered as a non-Newtonian fluid with pseudoplastic behavior and no alterations in viscosity was observed over 90 days. On the other hand, significant changes in spreadability was observed when topical formulation was stored at 45 °C. The formulation containing additives (formulation 2) showed an improvement in stability when stored at 45 °C for a period of 30 days, but there was a significant decrease in drug content when stored at 4 °C and 25 °C. Formulations 3 (Immucillin-DI4G a 1,1% Gel-Cream) and 4 (Immucillin-DI4G 1.1% in Hydroxypropylcellulose polymer at 2%) presented significant loss in the drug content in 30 days when stored at 45 °C. The results shows that further studies should be conducted in order to analyze the possible degradation products looking for design of novel formulations.Introdução: A Leishmaniose Cutânea é causada por protozoários do gênero Leishmania e transmitidas através das fêmeas dos mosquitos do gênero Lutzomyia. A Leishmaniose cutânea pode se manifestar de diferentes formas clínicas: cutânea localizada, cutânea disseminada, recidiva cútis e cutânea difusa. A região Norte e Nordeste são as mais acometidas pela doença. Os antimoniais pentavalentes e a anfotericina B são os medicamentos mais utilizados para o tratamento desta doença, porém podem causar vários efeitos adversos fazendo com que muitos pacientes abandonem o tratamento. O controle ou a progressão da doença estão diretamente relacionados com a resposta imunológica desencadeada pelo indivíduo. A PNP é a enzima chave na rota de salvamento de purinas, catalisa a fosforólise reversível de nucleosídeos purínicos como deoxinosina e deoxiguanosina formando suas respectivas bases e deoxirribose-1-fosfato. Os inibidores da PNP podem ser utilizados para tratamento de doenças causadas por desordem mediada pelas células T, através da inibição segura e seletiva da proliferação da célula T. O Immucillin-DI4G (Immucillin de 4ª geração; 7-((bis(2-hidroxietil)amino)metil)-1,5-diidro-4H-pirrolo[3,2-d]pirimidin-4-ona) é considerado como um potente inibidor da PNP. Objetivo: desenvolver estudos de pré-formulação e formulação de uma forma farmacêutica de uso tópico contendo o Immucillin-DI4G como candidato a fármaco para tratamento da Leishmaniose Cutânea. Materiais e Métodos: Foi realizada a caracterização do composto através do RMN, EMS e FTIR-ATR. A estabilidade do pó amorfo foi avaliada durante 90 dias, o doseamento foi realizado através do CLAE. Formulações foram desenvolvidas para o estudo de estabilidade, estudos reológicos e espalhabilidade durante 30 e 90 dias. Um método para o doseamento do fármaco nas formulações foi desenvolvido e validado empregando o método de CLAE. Resultados e discussão: O Immucillin-DI4G (pó amorfo) mostrou-se estável até 30 dias quando armazenado a 4 °C e 25 °C. A formulação 1(Immucillin-DI4G a 1,1% em Gel polímero Carboxivinílico a 2% ) mostrou-se estável apenas quando armazenada a 4 °C por um período de 60 dias; é considerada como um Fluído Não-Newtoniano de comportamento pseudoplástico, sem alterações na viscosidade durante 90 dias, porém com alterações significativas na espalhabilidade quando armazenada a 45 °C. A formulação que continha aditivos (formulação 2) apresentou uma melhora na estabilidade quando armazenada a 45 °C num período de 30 dias, porém apresentou queda significativa no teor do fármaco quando armazenada a 4 °C e 25 °C. As formulações 3 (Immucillin-DI4G a 1,1% em Creme-Gel) e 4 (Immucillin-DI4G a 1,1% em Gel Polímero Hidroxipropilcelulose a 2%) apresentaram perdas significativas no teor do fármaco em 30 dias quando armazenadas a 45 °C. Os resultados demonstram que novos estudos devem ser realizados para a análise de possíveis produtos de degradação, para possíveis ajustes nas formulações.Submitted by Setor de Tratamento da Informação - BC/PUCRS (tede2@pucrs.br) on 2016-05-10T11:50:40Z No. of bitstreams: 1 DIS_FERNANDA_GRENDENE_PACHECO_COMPLETO.pdf: 2728715 bytes, checksum: 93bb3d4fcee10a1e8abba33e2e0e8996 (MD5)Made available in DSpace on 2016-05-10T11:50:40Z (GMT). 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dc.title.por.fl_str_mv Estudo de pré-formulação e formulação farmacêutica de uso tópico contendo Immucillin-DI4G como alternativa terapêutica para o tratamento da Leishmaniose Cutânea
title Estudo de pré-formulação e formulação farmacêutica de uso tópico contendo Immucillin-DI4G como alternativa terapêutica para o tratamento da Leishmaniose Cutânea
spellingShingle Estudo de pré-formulação e formulação farmacêutica de uso tópico contendo Immucillin-DI4G como alternativa terapêutica para o tratamento da Leishmaniose Cutânea
Pacheco, Fernanda Grendene
LEISHMANIOSE
QUÍMICA FARMACÊUTICA
FARMÁCIA
CIENCIAS DA SAUDE::FARMACIA
title_short Estudo de pré-formulação e formulação farmacêutica de uso tópico contendo Immucillin-DI4G como alternativa terapêutica para o tratamento da Leishmaniose Cutânea
title_full Estudo de pré-formulação e formulação farmacêutica de uso tópico contendo Immucillin-DI4G como alternativa terapêutica para o tratamento da Leishmaniose Cutânea
title_fullStr Estudo de pré-formulação e formulação farmacêutica de uso tópico contendo Immucillin-DI4G como alternativa terapêutica para o tratamento da Leishmaniose Cutânea
title_full_unstemmed Estudo de pré-formulação e formulação farmacêutica de uso tópico contendo Immucillin-DI4G como alternativa terapêutica para o tratamento da Leishmaniose Cutânea
title_sort Estudo de pré-formulação e formulação farmacêutica de uso tópico contendo Immucillin-DI4G como alternativa terapêutica para o tratamento da Leishmaniose Cutânea
author Pacheco, Fernanda Grendene
author_facet Pacheco, Fernanda Grendene
author_role author
dc.contributor.advisor1.fl_str_mv Machado, Pablo
dc.contributor.advisor1ID.fl_str_mv 994.698.980-87
dc.contributor.advisor1Lattes.fl_str_mv http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4757509Z3
dc.contributor.advisor-co1.fl_str_mv Corte, Temis Weber Furlanetto
dc.contributor.advisor-co1Lattes.fl_str_mv http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4782148Y4
dc.contributor.authorID.fl_str_mv 054.131.499-80
dc.contributor.authorLattes.fl_str_mv http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4407955H6
dc.contributor.author.fl_str_mv Pacheco, Fernanda Grendene
contributor_str_mv Machado, Pablo
Corte, Temis Weber Furlanetto
dc.subject.por.fl_str_mv LEISHMANIOSE
QUÍMICA FARMACÊUTICA
FARMÁCIA
topic LEISHMANIOSE
QUÍMICA FARMACÊUTICA
FARMÁCIA
CIENCIAS DA SAUDE::FARMACIA
dc.subject.cnpq.fl_str_mv CIENCIAS DA SAUDE::FARMACIA
description Introduction: Cutaneous leishmaniasis is caused by Leishmania protozoan and transmitted through the female of Lutzomyia sandflies. The disease can manifest itself in different clinical forms: localized cutaneous leishmaniasis, disseminated cutaneous leishmaniasis, recidivans and diffuse cutaneous leishmaniasis. The North and Northeast (Brazil) are the most affected area by the disease. Pentavalent antimonials and amphotericin B have been the most used drugs for the treatment of this disease but may cause many side effects, which leads the patients to discontinue treatment. Control or progression of the disease has been related to the immune response triggered by the individual. PNP (purine nucleoside phosphorylase) is the key enzyme in the purine salvage route catalyzing the reversible phosphorolysis of purine nucleosides such as deoxyinosine or deoxyguanosine producing their respective bases and deoxyrribose-1-phosphate. The PNP inhibitors can be used for treating diseases caused by disorder mediated by T cells. Immucillin - DI4G (4th generation Immucillin ; 7-((bis(2-hydroxyiethyl)amine)methyl)-1,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one) is considered as a potent inhibitor of PNP. Objective: development of pre-formulation and formulation studies of a pharmaceutical form for topical use containing Immucillin-DI4G as drug candidate for Cutaneous Leishmaniasis treatment. Material and Methods: Characterization of the compound was performed by NMR, FTIR-ATR and HRMS. The stability of the amorphous powder was evaluated over 90 days using a HPLC method for quantification. Formulations have been developed for stability, rheological and spreadability studies over 30 and 90 days. A method for the quantification of Immucillin-DI4G in the formulation was developed and validated using the HPLC. Results and discussion: The Immucillin - DI4G (amorphous powder) was stable up to 30 days when stored at 4 °C and 25 °C. Formulation 1 (Immucillin - DI4G 1.1% Carboxyvinylpolymer gel 2%) was stable only when stored at 4 °C for a period of 60 days. Formulation 1 was considered as a non-Newtonian fluid with pseudoplastic behavior and no alterations in viscosity was observed over 90 days. On the other hand, significant changes in spreadability was observed when topical formulation was stored at 45 °C. The formulation containing additives (formulation 2) showed an improvement in stability when stored at 45 °C for a period of 30 days, but there was a significant decrease in drug content when stored at 4 °C and 25 °C. Formulations 3 (Immucillin-DI4G a 1,1% Gel-Cream) and 4 (Immucillin-DI4G 1.1% in Hydroxypropylcellulose polymer at 2%) presented significant loss in the drug content in 30 days when stored at 45 °C. The results shows that further studies should be conducted in order to analyze the possible degradation products looking for design of novel formulations.
publishDate 2016
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