Pulmoner Mukus Tabakasına Yönelik İlaç Taşıyıcı Sistemlerin Geliştirilmesi

Abstract

Lungs are critical organs for human body, which provide healthy respiration. During respiration, lungs are exposed to pathogens/viruses, and they are protected by the mucus layer. The presence of the mucus layer contributes to immune system with its ability to trap and clean the exogenous matter. In case of drug delivery to/through lungs, this layer acts as a strong barrier against spreading and penetration of drug formulations. Pulmonary route is considered to be advantageous for drug delivery as it provides direct access to epithelial sites, low catabolyic enzmatic activity,etc. Drug formulations applied to lungs are generally dissolved in saline, posessing high surface tension. So, spreading of these kinds of solutions on the pulmonary mucus layer are limited. Another problem is the poor penetration ability of the drug carrier systems through the mucus. These problems decrease the effectiveness of the treatment. Enhancing the diffusion of the drug carriers is an important problem, since penetration of carriers are considerably hindered by the mucus via several interactions which should be unterstood and optimized well. The aim of this study is to develop a formulation which is able to spread effectively on mucus layer. It is also aimed to provide efficient penetration of the lipid-based nanoparticles, which are transported with the spreading formulation. To our knowledge, this study is the first one that investigates the drug delivery through lungs as a whole process including spreading and penetration of lipid-based nanoparticles. At the first part of the study, spreading performances of different types of surfactants are investigated via particle tracking experiments and for the first time in the literature, it is proposed to use DTAB/AOT catanionic surfactant mixtures to maintain Marangoni-dominated spreading. Especially, the mixtures composed of xDTAB=0.8 and xDTAB=0.7 displayed synergistic interaction and provided super-spreading both on mucus and cystic-fibrosis mucus subphases. At the second part, solid lipid nanoparticles(SLN) and nanostructured lipid carriers(NLC) are synthesized and their interaction with mucus are analyzed. From the results obtained with the light scattering, zeta potential, atomic force microscope(AFM) measurements and Langmuir-Blodgett trough experiments, it is found that the particles KLN3 and NLC showed nearly zero interaction with the mucin both in the solution form and also at the mucin/air interface. At the last part of the study, penetration performances of these particles are investigated with Franz diffusion cell and rotating diffusion tubes. It is determined that 27.8% and 33.4% of KLN3 and NLC, respectively, can penetrate through the 2.65 mm-thick mucus layer, which are higher percentages than the results reported in the literature. The results obtained from the rotating diffusion tube have also verified that these particles can diffuse through the mucus layer. Moreover, the surfaces of KLN3 are modified with mucoadhesive chitosan, which is used to increase the pore size of mucin layer and thus the penetrated amount of NLCs is increased. As a conclusion, current study is the first one that investigates critical parameters for drug delivery through lungs together and the results obtained from this study are promising in terms of successful treatments.