Doutoramento em Tecnologia Farmacêutica / PhD Degree - Pharmaceutical Technology

Thesis (M.S.)--Auburn University, 2008. / Abstract. Includes bibliographical references (p. 54-59).

There exists a demand to re-engineer pre-existing pharmaceuticals to provide improved drug delivery, new dosage forms and increased drug safety and efficacy. Furthermore, the development of novel methods and formulations allows for the patent life of pre-existing drugs to be extended, which has obvious economic benefits for pharmaceutical companies. Dense gas technology provides a means to achieve these aims and to overcome the distinct limitations of traditional technologies. A novel formulation of the antifungal drug itraconazole has been developed using gas antisolvent processes. The new itraconazole-polymer formulation displayed a significant improvement in dissolution rate achieving 89.8 % dissolution compared to 52.5 % for the commercial formulation. The results of this study demonstrate the great opportunity to use dense gases for the creation of novel drug-polymer composite formulations with improved dissolution properties. The impregnation of an active ingredient into a polymer matrix is another method that can be used to improve the dissolution of poorly water soluble drugs. Dense gas technology has been incorporated into traditional methods for the formation of porous polymer matrices decreasing process residence times. However, some issues still need to be overcome including high operating temperatures and the use of class 3 solvents. A novel dense gas process for the formation of a porous polymer hydrogel matrix has been developed to improve upon current methodologies; Dense Gas Solvent Exchange Process (DGSEP). The Dense Gas Solvent Exchange Process was used to create a porous chitosan hydrogel impregnated with a stable amorphous form of the drug griseofulvin. Furthermore, the process was extended to include a hydrophilic polymer into the matrix. The resulting formulation had a dramatically improved dissolution rate achieving complete dissolution within 70 minutes compared with the commercial formulation which achieved less than 40 %dissolution in the same time. There is great potential for DGSEP to be applied to the formation of a variety of polymer hydrogels impregnated with active ingredients and incorporating polymers and other compounds. The significance of these results is that a simple and effective processing method has been developed to produce hydrogel systems that are suitable for the development of a diverse range of drug delivery systems.

Made available in DSpace on 2014-06-11T19:33:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-11-03Bitstream added on 2014-06-13T20:45:05Z : No. of bitstreams: 1 bonfilio_r_dr_arafcf.pdf: 1872615 bytes, checksum: 95491083aa6c99821a3292b881acb065 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Universidade Estadual Paulista (UNESP) / A glimepirida é um antidiabético oral do grupo das sulfonilureias, amplamente utilizada no tratamento do diabetes tipo II. Embora existam vários métodos descritos para a determinação deste fármaco, os métodos cromatográficos demandam um considerável tempo de análise, nenhum estudo descreve um método indicador de estabilidade em comprimidos, o ensaio de dissolução preconizado pela USP 2011 não simula as condições do trato gastrintestinal e não há relatos da influência do polimorfismo sobre comprimidos de glimepirida. Com base nestas considerações, este trabalho objetiva desenvolver e validar novos métodos analíticos para quantificação da glimepirida, desenvolver um novo ensaio de dissolução, realizar estudos de estabilidade e de equivalência farmacêutica e avaliar o impacto do polimorfismo na qualidade dos comprimidos. Foi desenvolvido e validado um método espectrofotométrico por derivada de segunda ordem. Todos os parâmetros de validação foram encontrados em concordância às exigências e o método apresentou a vantagem de ser mais fácil de executar e de menor custo, em relação à cromatografia líquida de alta eficiência. O método por cromatografia líquida de alta eficiência foi desenvolvido empregando abordagem multivariada, o que permitiu a separação de glimepirida e seus produtos de degradação em cerca de nove minutos, demonstrando uma vantagem em relação aos métodos indicadores de estabilidade descritos. Todos os parâmetros de validação foram considerados satisfatórios e o método cromatográfico apresentou a vantagem de ser mais seletivo, permitindo a análise de produtos de degradação. Porém, apresenta maior custo e maior geração de resíduos em relação... / Glimepiride is an oral antidiabetic drug widely used in treatment of type 2 diabetes. Although there are several methods described for the determination of this drug, chromatographic methods require considerable time for analysis, none study describes a stability-indicating method for tablets, the dissolution test recommended by the USP 2011 does not simulate gastrointestinal tract conditions and there are no reports of the polymorphism influence of glimepiride on the properties of tablets. Based on these considerations, this work aims to develop and validate new analytical methods for quantification of glimepiride, to develop a new dissolution method, to conduct stability studies and pharmaceutical equivalence tests, and to assess the impact of polymorphism of glimepiride on the quality of tablets. A second order derivative UV spectrophotometric method for quantification of glimepiride was developed and validated. All the data meet the validation acceptance criteria and the method presented the following advantages over the chromatographic method: it does not use polluting reagents, it is simple and has low-cost. The high performance liquid chromatography method was developed using a multivariate approach, which allowed the adequate separation of glimepiride from all degradant peaks in a short analysis time (about 9 min), demonstrating an advantage over those described stability indicating methods. All validation parameters were found in accordance with the validation acceptance criteria and the chromatographic method had the advantage of being more selective, allowing the analysis of degradation products. However, it has a higher cost and waste generation in relation... (Complete abstract click electronic access below)

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references. Available also from UMI/Dissertation Abstracts International.

Thesis (Ph. D.)--Uppsala University, 2000. / "Acta Universitatis Upsaliensis." Extra abstract sheet inserted. Includes bibliographical references (p. 42-46).

Every year more than 10 million people develop cancers globally. Ovarian cancer, specifically, results in more than 22,000 new cases and 16,000 deaths from this disease yearly, more than any other cancer of the female reproductive system. In addition, because of non-specific symptoms and poor screening techniques, most ovarian cancer cases are discovered after the disease is in an advanced state. Consequently, aggressive and effective treatment options that incur minimal toxic effects to healthy tissue are in great need. In the present research, stealth biodegradable nanoparticles were developed as vehicles for the controlled and targeted delivery of chemotherapeutic agents for the treatment of ovarian cancer. The design of this delivery system consisted of nanoparticles of biodegradable polymers of the poly(lactic-co-glycolic acid) family loaded with the chemotherapeutic agent doxorubicin or the imaging agents rhodamine 6G, indocyanine green or gadopentetic acid. Nanoparticles were modified by incorporation of functional poly(ethylene glycol) on their surface to improve the stability of the colloidal suspension, increase their circulation lifetime in vivo, and provide a site for conjugation of targeting agents specific to ovarian tissue. Various methods were evaluated for this surface modification, including the use of polymer blends, the chemical conjugation of the polymers, and the polymerization of lactide and glycolide monomers initiated by heterofunctional poly(ethylene glycol). Nanoparticles incorporating poly(ethylene glycol) presented improved characteristics compared to unmodified particles including smaller size, higher stability and slower release of the chemotherapeutic agent doxorubicin The actual drug or agent content was decreased in the case of doxorubicin and rhodamine, but increased for indocyanine green as a result of improved agent-polymer interactions. Poly(ethylene glycol)-containing nanoparticles were conjugated to monoclonal antibody mAb106-105, which is specific to the extracellular domain of human folliclestimulating hormone (FSH) receptors. These receptors are only expressed in ovarian cells in women, thus providing a system that is highly specific to ovarian tissue. The interaction and therapeutic potential of nanoparticles with or without targeting antibodies were tested on OVCAR-3, Caov-3, and MDA-MB-231 cancer cells.

Not available / text

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Orientador: Hérida Regina Nunes Salgado / Coorientador: Magali Benjamin de Araújo / Banca: Cristina Helena dos Reis Serra / Banca: Regina Vicenzi Oliveira / Banca: Marlus Chorilli / Banca: Patricia de Carvalho Mastroianni / Resumo: A glimepirida é um antidiabético oral do grupo das sulfonilureias, amplamente utilizada no tratamento do diabetes tipo II. Embora existam vários métodos descritos para a determinação deste fármaco, os métodos cromatográficos demandam um considerável tempo de análise, nenhum estudo descreve um método indicador de estabilidade em comprimidos, o ensaio de dissolução preconizado pela USP 2011 não simula as condições do trato gastrintestinal e não há relatos da influência do polimorfismo sobre comprimidos de glimepirida. Com base nestas considerações, este trabalho objetiva desenvolver e validar novos métodos analíticos para quantificação da glimepirida, desenvolver um novo ensaio de dissolução, realizar estudos de estabilidade e de equivalência farmacêutica e avaliar o impacto do polimorfismo na qualidade dos comprimidos. Foi desenvolvido e validado um método espectrofotométrico por derivada de segunda ordem. Todos os parâmetros de validação foram encontrados em concordância às exigências e o método apresentou a vantagem de ser mais fácil de executar e de menor custo, em relação à cromatografia líquida de alta eficiência. O método por cromatografia líquida de alta eficiência foi desenvolvido empregando abordagem multivariada, o que permitiu a separação de glimepirida e seus produtos de degradação em cerca de nove minutos, demonstrando uma vantagem em relação aos métodos indicadores de estabilidade descritos. Todos os parâmetros de validação foram considerados satisfatórios e o método cromatográfico apresentou a vantagem de ser mais seletivo, permitindo a análise de produtos de degradação. Porém, apresenta maior custo e maior geração de resíduos em relação... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Glimepiride is an oral antidiabetic drug widely used in treatment of type 2 diabetes. Although there are several methods described for the determination of this drug, chromatographic methods require considerable time for analysis, none study describes a stability-indicating method for tablets, the dissolution test recommended by the USP 2011 does not simulate gastrointestinal tract conditions and there are no reports of the polymorphism influence of glimepiride on the properties of tablets. Based on these considerations, this work aims to develop and validate new analytical methods for quantification of glimepiride, to develop a new dissolution method, to conduct stability studies and pharmaceutical equivalence tests, and to assess the impact of polymorphism of glimepiride on the quality of tablets. A second order derivative UV spectrophotometric method for quantification of glimepiride was developed and validated. All the data meet the validation acceptance criteria and the method presented the following advantages over the chromatographic method: it does not use polluting reagents, it is simple and has low-cost. The high performance liquid chromatography method was developed using a multivariate approach, which allowed the adequate separation of glimepiride from all degradant peaks in a short analysis time (about 9 min), demonstrating an advantage over those described stability indicating methods. All validation parameters were found in accordance with the validation acceptance criteria and the chromatographic method had the advantage of being more selective, allowing the analysis of degradation products. However, it has a higher cost and waste generation in relation... (Complete abstract click electronic access below) / Doutor