Desenvolvimento e caracterização de filmes de desintegração oral contendo dinitrato de isossorbida
Data
2021-07-06
Autores
Silva, Larissa Léa 
Orientadores
Rodrigues, Leticia Norma Carpentieri
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
O dinitrato de isossorbida (DNIS) é um insumo farmacêutico ativo vasodilatador, indicado para o tratamento profilático da dor isquêmica cardíaca associada à insuficiência coronariana e na crise da angina peitoral. O DNIS é intensamente metabolizado por meio do efeito de primeira passagem hepática, o que torna sua biodisponibilidade variável. Os filmes de desintegração oral sofrem rápida dispersão quando em contato com a saliva, o que resulta no aumento da biodisponibilidade, reduzindo a exposição das substâncias à degradação no trato gastrintestinal e ao metabolismo de primeira passagem hepática. Além disso, a fácil administração dos filmes de desintegração oral favorece a adesão do paciente ao tratamento. O objetivo deste trabalho foi desenvolver e caracterizar filmes de desintegração oral contendo dinitrato de isossorbida, utilizando hidroxipropilmetilcelulose (HPMC) como polímero formador de filme e hidroxipropil--ciclodextrina (HPCD) como agente solubilizante, através do método de evaporação de solvente. Os filmes foram preparados por meio de planejamento fatorial completo (32) empregando os fatores concentração de polímero (HPMC E6 1,5, 2,0, 2,5%) e natureza do plastificante (glicerina, propilenoglicol, sorbitol); e caracterizados quanto as suas propriedades físicas, físico-quimicas, mecânicas e colorimétricas. Foram comparados os perfis de dissolução entre os comprimidos sublingual de DNIS (medicamento utilizado como referência) e os filmes de desintegração oral. As curvas de difração de raios-X mostraram amorfização do DNIS/lactose (25/75, p/p) sendo sugerido a formação de complexos de inclusão multicomponentes [(DNIS:HPCD)-HPMC]. A quantidade de polímero formador de filme e a natureza do plastificante tiveram papel crítico nas propriedades mecânicas dos filmes. Maior transparência foi observada para os filmes orais preparados com o plastificante propilenoglicol. À exceção do filme F4, os perfis de dissolução médios dos filmes de desintegração oral e do medicamento de referência mostraram-se equivalentes. Os valores de eficiência de dissolução (ED) obtidos entre os filmes (F1-9) foram superiores àquele observado para o medicamento de referência (88,36±0,01%), sugerindo aumento da solubilidade do DNIS pelo complexo [(DNIS:HPCD)-HPMC]. Com base na avaliação dos efeitos obtidos a partir da caracterização dos filmes, foi possível selecionar a melhor formulação de acordo com a função desejabilidade (f_D) (0f_D 1), usando os fatores nos seus valores ótimos. O valor máximo para a função desejabilidade global (f_D) foi de 0,8522, correspondente a 2,0% de HPMC E6 e o emprego de propilenoglicol como plastificante
Isosorbide dinitrate (ISDN) is a vasodilator active pharmaceutical ingredient, indicated for the prophylactic treatment of ischemic heart pain associated with coronary heart failure, and in the crisis of angina pectoris. The ISDN is intensively metabolized through first-pass effect, which makes their bioavailability variable. Orally disintegrating films disperse rapidly when in contact with saliva, which results in increased bioavailability, reducing the exposure of the substances to degradation in the gastrointestinal tract and the first-pass hepatic effect. Furthermore, the easy administration of the orally disintegrating films, improves patient compliance to treatment. The aim of this work was to develop and characterize orally disintegrating films containing isosorbide dinitrate, using hydroxypropylmethylcellulose (HPMC) as film-forming polymer and hydroxypropyl--cyclodextrin (HPCD) as solubilizing agent, by the solvent casting method. The films were prepared by full factorial design (32), which the factors were - concentration of polymer (HPMC E6, 1.5, 2.0, 2.5%) and nature of plasticizer (glycerin, or propylene glycol, or sorbitol); and they were characterized as to their physical, physicochemical, mechanical, and colorimetric properties. The dissolution profiles of sublingual tablets of isosorbide dinitrate (reference medicine) were compared with the dissolution profiles of oral disintegrating films. X-ray diffraction curves showed amorphization of ISDN being suggested the formation of multicomponent inclusion complexes [(ISDN:HPCD)-HPMC]. The amount of film-forming polymer (HPMC) and the nature of plasticizer played a critical role in the mechanical properties of the films. Higher transparency was observed for films prepared with the plasticizer propylene glycol. Except for film F4, the dissolution profiles of the films were similar (𝑓2) to the reference product. The dissolution efficiency values of the films (F1 to F9) were higher than that observed for the reference product (88.360.01%), suggesting increased solubility of ISDN by complexes [(ISDN:HPCD)-HPMC]. Based on the evaluation of the effects obtained from the characterization of the films, it was possible to select the best formulation according to the desirability function (𝑓𝐷), using the factors at their optimal values. The maximum value for the overall desirability function (0𝑓𝐷1) was 0.8522, corresponding to 2.0% HPMC E6 and the use of propylene glycol as plasticizer.
Isosorbide dinitrate (ISDN) is a vasodilator active pharmaceutical ingredient, indicated for the prophylactic treatment of ischemic heart pain associated with coronary heart failure, and in the crisis of angina pectoris. The ISDN is intensively metabolized through first-pass effect, which makes their bioavailability variable. Orally disintegrating films disperse rapidly when in contact with saliva, which results in increased bioavailability, reducing the exposure of the substances to degradation in the gastrointestinal tract and the first-pass hepatic effect. Furthermore, the easy administration of the orally disintegrating films, improves patient compliance to treatment. The aim of this work was to develop and characterize orally disintegrating films containing isosorbide dinitrate, using hydroxypropylmethylcellulose (HPMC) as film-forming polymer and hydroxypropyl--cyclodextrin (HPCD) as solubilizing agent, by the solvent casting method. The films were prepared by full factorial design (32), which the factors were - concentration of polymer (HPMC E6, 1.5, 2.0, 2.5%) and nature of plasticizer (glycerin, or propylene glycol, or sorbitol); and they were characterized as to their physical, physicochemical, mechanical, and colorimetric properties. The dissolution profiles of sublingual tablets of isosorbide dinitrate (reference medicine) were compared with the dissolution profiles of oral disintegrating films. X-ray diffraction curves showed amorphization of ISDN being suggested the formation of multicomponent inclusion complexes [(ISDN:HPCD)-HPMC]. The amount of film-forming polymer (HPMC) and the nature of plasticizer played a critical role in the mechanical properties of the films. Higher transparency was observed for films prepared with the plasticizer propylene glycol. Except for film F4, the dissolution profiles of the films were similar (𝑓2) to the reference product. The dissolution efficiency values of the films (F1 to F9) were higher than that observed for the reference product (88.360.01%), suggesting increased solubility of ISDN by complexes [(ISDN:HPCD)-HPMC]. Based on the evaluation of the effects obtained from the characterization of the films, it was possible to select the best formulation according to the desirability function (𝑓𝐷), using the factors at their optimal values. The maximum value for the overall desirability function (0𝑓𝐷1) was 0.8522, corresponding to 2.0% HPMC E6 and the use of propylene glycol as plasticizer.