Estudos de pré-formulação de preparação lipossomal contendo paclitaxel e doxorrubicina: avaliação da toxicidade aguda e liofilização.

• Ano de defesa: 2021
• Autor(a) principal: Marjorie Coimbra Roque
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; Brasil; FARMACIA - FACULDADE DE FARMACIA; Programa de Pós-Graduação em Ciências Farmacêuticas; UFMG
• Palavras-chave em Português: Liofilização; Lipossomas; Doxorrubicina; Paclitaxel; Co-encapsulação; Sinergismo; Toxicidade aguda; Câncer de mama
• Link de acesso: http://hdl.handle.net/1843/44465

Combination therapy between paclitaxel (PTX) and doxorubicin (DXR) is applied as a first-line treatment for breast cancer. The co-administration of these drugs in a synergistic proportion for treatment is facilitated with the use of nanocarriers, such as liposomes. However, despite the high response rate of solid tumors to this combination, a synergism of cardiotoxicity may limit its use. An aqueous dispersion of long-circulating fusogenic liposomes containing PTX and DXR in a synergistic molar ratio of 1:10 (LFCP-PTX/DXR) was previously developed and characterized by Roque et al. (2019). Continuing the pre-clinical studies for the pharmaceutical development of this liposomal formulation, in this doctoral thesis we carried out studies related to the investigation of acute toxicity in vivo as well as the feasibility of using freeze-drying as a process to obtain a pharmaceutical formulation in the form of powder. The results of the study indicated that the LD50 dose range (lethal dose to kill 50% of the animals) of LFCP-PTX/DXR treatment (28.9 - 34.7 mg/kg) is much greater than the found for the free PTX/DXR treatment (20.8 - 23.1 mg/kg). The administration of LFCP-PTX/DXR allowed protecting the heart of animals by not increasing the levels of CK-MB, keeping the cardiomyocytes without lesions or electrocardiographic alterations. Furthermore, the survival rate of animals treated with LFCP-PTX/DXR was three times higher than those treated with free drugs, which presents advantages for this new clinical treatment platform for breast cancer. However, there are still known disadvantages for these aqueous lipid dispersions, such as physical and chemical instabilities that limit their widespread use and often result in a reduced shelf life of the product. To overcome this obstacle, freeze drying is one of the processes that can be adopted. Choosing excipients and freeze-drying parameters to protect membrane integrity against stresses caused by freezing and dehydration is a challenge. Despite the investigation of different parameters for the execution of LFCP-PTX/DXR freeze-drying, it was verified that this method was not viable, since the drying conditions at very negative temperatures for maximum retention of PTX and DXR in the vesicles are not promising for industrial application.