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Previous issue date: 2016-03-14 / 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. / Introdu??o: A Leishmaniose Cut?nea ? causada por protozo?rios do g?nero Leishmania e transmitidas atrav?s das f?meas dos mosquitos do g?nero Lutzomyia. A Leishmaniose cut?nea pode se manifestar de diferentes formas cl?nicas: cut?nea localizada, cut?nea disseminada, recidiva c?tis e cut?nea difusa. A regi?o Norte e Nordeste s?o as mais acometidas pela doen?a. Os antimoniais pentavalentes e a anfotericina B s?o os medicamentos mais utilizados para o tratamento desta doen?a, por?m podem causar v?rios efeitos adversos fazendo com que muitos pacientes abandonem o tratamento. O controle ou a progress?o da doen?a est?o diretamente relacionados com a resposta imunol?gica desencadeada pelo indiv?duo. A PNP ? a enzima chave na rota de salvamento de purinas, catalisa a fosfor?lise revers?vel de nucleos?deos pur?nicos como deoxinosina e deoxiguanosina formando suas respectivas bases e deoxirribose-1-fosfato. Os inibidores da PNP podem ser utilizados para tratamento de doen?as causadas por desordem mediada pelas c?lulas T, atrav?s da inibi??o segura e seletiva da prolifera??o da c?lula T. O Immucillin-DI4G (Immucillin de 4? gera??o; 7-((bis(2-hidroxietil)amino)metil)-1,5-diidro-4H-pirrolo[3,2-d]pirimidin-4-ona) ? considerado como um potente inibidor da PNP. Objetivo: desenvolver estudos de pr?-formula??o e formula??o de uma forma farmac?utica de uso t?pico contendo o Immucillin-DI4G como candidato a f?rmaco para tratamento da Leishmaniose Cut?nea. Materiais e M?todos: Foi realizada a caracteriza??o do composto atrav?s do RMN, EMS e FTIR-ATR. A estabilidade do p? amorfo foi avaliada durante 90 dias, o doseamento foi realizado atrav?s do CLAE. Formula??es foram desenvolvidas para o estudo de estabilidade, estudos reol?gicos e espalhabilidade durante 30 e 90 dias. Um m?todo para o doseamento do f?rmaco nas formula??es foi desenvolvido e validado empregando o m?todo de CLAE. Resultados e discuss?o: O Immucillin-DI4G (p? amorfo) mostrou-se est?vel at? 30 dias quando armazenado a 4 ?C e 25 ?C. A formula??o 1(Immucillin-DI4G a 1,1% em Gel pol?mero Carboxivin?lico a 2% ) mostrou-se est?vel apenas quando armazenada a 4 ?C por um per?odo de 60 dias; ? considerada como um Flu?do N?o-Newtoniano de comportamento pseudopl?stico, sem altera??es na viscosidade durante 90 dias, por?m com altera??es significativas na espalhabilidade quando armazenada a 45 ?C. A formula??o que continha aditivos (formula??o 2) apresentou uma melhora na estabilidade quando armazenada a 45 ?C num per?odo de 30 dias, por?m apresentou queda significativa no teor do f?rmaco quando armazenada a 4 ?C e 25 ?C. As formula??es 3 (Immucillin-DI4G a 1,1% em Creme-Gel) e 4 (Immucillin-DI4G a 1,1% em Gel Pol?mero Hidroxipropilcelulose a 2%) apresentaram perdas significativas no teor do f?rmaco em 30 dias quando armazenadas a 45 ?C. Os resultados demonstram que novos estudos devem ser realizados para a an?lise de poss?veis produtos de degrada??o, para poss?veis ajustes nas formula??es.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/6655 |
| Date | 14 March 2016 |
| Creators | Pacheco, Fernanda Grendene |
| Contributors | Machado, Pablo, Corte, Temis Weber Furlanetto |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Biotecnologia Farmac?utica, PUCRS, Brasil, Faculdade de Farm?cia |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2304961219518893267, 600, 600, 600, -8380654636843378116, 6997636413449754996 |
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