Akciğer Kanseri Tedavisinde Kullanılmak Üzere Nanopartikül İçeren Kuru Toz İnhalerformülasyonu Hazırlanması, Karakterizasyonu ve İn Vitro Değerlendirilmesi

Abstract

In this thesis, the aim was to develop a dry powder inhaler formulation containing gefitinib nanoparticles for the treatment of non-small cell lung cancer. Gefitinib nanoparticles, below 130 nm in size, were prepared using a high-pressure homogenization method and then coated with hyaluronic acid (HA) for active targeting to the tumor. To achieve uniform nanoparticles in the desired size, Dipalmitoylphosphatidylcholine (DPPC) present as a natural surfactant on the lung surface was used in the formulations. Carriers were added to the formulations and lyophilized to obtain inhalable particle sizes and powder characteristics. The target was to have particles with a diameter of 1-5 μm to reach the depths of the lungs as aerosolized dry powder inhalers (DPI)s. Different dry powder inhaler formulations containing various carriers were analyzed to evaluate their aerodynamic properties using the Andersen Cascade Impactor (ACI). The combination of phenylalanine-mannitol as carriers provided the best aerodynamic properties and in vitro release behavior. The water solubility of poorly soluble crystalline gefitinib was increased by forming gefitinib nanoparticles and converting them into an inhalable amorphous lyophilized powder with a wide surface area. In vitro release experiments in simulated lung fluid showed that the developed DPIs continued to release the active substance for 72 hours. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests on the Lewis Lung Carcinoma-1 (LLC1) cell line revealed that the DPI reduced the viability of cancer cells at much lower doses compared to gefitinib active pharmaceutical ingredient at 72 hours. Cellular uptake of Nile red-loaded DPI formulations in LLC1 cells was visualized using a fluorescence microscope.