Kardiyovasküler Hastalıklar İçin Sabit Doz Kombinasyonunda Ağızda Dağılan Dozaj Formlarının Geliştirilmesi ve In vitro Yöntemlerle Değerlendirilmesi

Abstract

Hypertension and dyslipidemia are important risk factors for cardiovascular diseases, which are important life-threatening health problems. Amlodipine besylate (AML) is a bitter tasting BCS class I active substance used in the treatment of hypertension. Rosuvastatin calcium (ROS) is a low-solubility BCS class II active substance used in the treatment of dyslipidemia. Within the scope of this thesis study, it is aimed to develop orally disintegrating dosage forms (ODTs and ODFs) in fixed dose combination of AML and ROS active substances. Saturation solubilities determined or AML and ROS and their combination. Cyclodextrin inclusion complex and solid dispersion of AML were prepared to mask the bitter taste of AML. Cyclodextrin inclusion complex of ROS and electrospun film formulations were prepared to increase the solubility of ROS active substance. SeDeM-ODT expert system was used in the development of ODT formulations. Based on the optimum ODT formulation offered by the system, 4 ODT formulations (PAÇ, AMLCD, ROSCD and AMLEUD) were produced and in vitro characterizations were made. The electrospinning method as preferred for ODF preparation due to its high surface area and drug loading capacity. Two different ODF formulations (ODF-1 and ODF-2) were developed, and in vitro characterization studies were performed. The HPLC method has been developed and validated for the analysis of samples. The solubilities of each active substance decreased with the presence of the other active substance. Among ODT formulations, AMLCD and AMLEUD tablets showed more than 90% dissolution in 15 minutes at pH 1.2 for AML, while they showed more than 90% dissolution in 30 minutes at pH 6.8 for ROS. In accelerated stability studies, more than 90% of the active substance content was preserved in AMLCD and AMLEUD tablets and no significant change was observed in the in vitro characterization properties. ODF-1 and ODF-2 formulations showed very rapid disintegration (approximately 1 s) and more than 90% dissolution in 5 minutes in all three media (pH1.2, pH4.5 and pH 6.8) in vitro dissolution studies. ODF-1 formulation showed higher Young's modulus value compared to ODF-2 in mechanical strength evaluations and its content uniformity and in vitro characterization properties were maintained in the long-term stability studies. Caco-2 permeability studies were conducted in order to evaluate the effects of ODT and ODF formulations, excipients used and simultaneous use of active substances on drug permeabilities. Both active substances showed high permeability in mixture and also in formulation. The findings of the thesis studies have shown that ODT and ODF formulations containing AML and ROS active substances in fixed dose combination have been successfully developed