Hipertansiyon Tedavisinde Etkili Çözünürlük Sorunu Olan Bir Etkin Madde Üzerinde Önformülasyon Çalışmaları

Abstract

This thesis aims to improve the poor solubility of M3, a molecule that can block both L-type and T-type calcium channels, with nanocrystal technology (NKT), and to develop orally disintegrating film (ADF) formulations pullulan based. The equilibrium solubility and Caco-2 permeability study results indicated that M3 could be a Biopharmaceutical Classification System (BCS) Class 4 compound. Optimum nanocrystal formulation (nanosuspension prepared with 0.5% poloxamer 188 freeze-dried with %5 trehalose; 320.2 ± 15.3 nm, -27.4 ± 0.1 mV) was determined as a result of formulation studies using different types and ratios of stabilizers and cryoprotectants by the combination of precipitation and ultrasonication methods. The optimum nanocrystal formulation and the ADF formulation prepared by the solvent casting method were analyzed by various physicochemical studies (XRD, DSC, FT-IR, SEM) and the results showed that M3 transformed from crystalline to amorphous structure. Short-term accelerated stability studies were shown that pullulan-based ADF formulation maintain their physical stability for 4 weeks. Dissolution rate, solubility (200 times), and permeability (30 times) of M3 were improved and increased by preparing M3 nanocrystals compared to raw M3. The cell culture studies on different cancer cell lines (Caco-2, MCF-7, SK-BR-3, A549) showed that M3 and M3 nanocrystals did not have a significant cytotoxic effect.