Researches On Structure And Distribution Of Particles Drug Delivery System

The Dry Powder Inhalation(DPI)encapsulates drug powder and its carriers in capsules with a portable device being utilized to deliver the atomized drugs to lungs directly.While,the multiple-unit sustained-release drug delivery system(MUSR)generally refers to a preparation containing many sustained-release subunits.The micro-particulates with extended-release property are filled into hard gelatin capsules or compressed into tablets.As the DPI and the MUSR are composed of a large number of drug-containing particles,they were named particulate preparations in this study.As the depositions of inhaled particles on anticipant areas such as alveoli or focus is a necessity for coming into better therapeutic outcome.Shedding light on the deposition sites,especially at single-particle level,is a fundamental and critical issue to gain an insight into DPI preparations for an expected treatment.There are mainly two strategies to explore the deposition and spatial distribution of inhaled particles:Simulation studies in vitro and imaging methods in vivo.However,some assumptions such as the tracheas are rigid with smooth surface have to be utilized during simulating,thus the reliabilities of results from simulation in vitro need to be proofed by further scientific evidences in vivo.In an attempt to comprehend the spatial distribution of inhaled particles integrally(not only in trachea but also in bronchioles and alveoli),high resolution and whole-lung scale should be considered simultaneously.In this part of research,series of careful investigations on CL-MOFs-A488 particles were performed for its inhalable traits,firstly.Scanning electron microscopy(SEM),Dynamic light scattering analysis(DLS),and Next Generation Impactor(NGI)were utilized to characterize the morphology,hydrodynamic and aerodynamic size of CL-MOFs-A488 particles.Laser Scanning Confocal Microscopy(LSCM)and In Vivo Imaging System(IVIS)were applied to confirm the morphological and fluorescent stability of CL-MOFs-A488 particles.CCK-8 and LDH analysis were performed to detect the biocompatibility.fluorescence-Micro Optical Sectioning Tomography(f-MOST)system was utilized to gain the dual-color and lung-wide data sets of lung after passive inhalation and tissue preparation.The results showed that:CL-MOFs-A488 was homogeneous cubes.The hydrodynamic size measured by DLS was 1.932±0.17?m.Up to 79±2.8%of CL-MOFs-A488 deposited at stage 2-6.The Mass Median Aerodynamic Diameter(MMAD)of CL-MOFs-A488 was 2.912±0.085?m.The fluorescence intensity of CL-MOFs-A488 in four mediums showed a downward trend with different degree over 7 days.CL-MOFs-A488 particles were stable in vitro and biodegradable in vivo.CL-MOFs-A488 demonstrated acceptable cyto-compatibility and cellular ingestible trait as model inhaled and tracking particles.The graphic architecture gained by f-MOST system hinted out that the particles that were inhaled to lung adhered to the surface of trachea and bronchiole,which offered a greatly detail information compared to IVIS.This presented the inhaled particles spatial distribution at full volume scale with a resolution down to individual particles for the first time,providing a completely comprehension of inhaled particles localization.The metoprolol succinate sustained-release tablet is an advanced system with limited researches devoted to relating its structure to the drug release phase other than the preparation process and modulation to the release behaviors.This part of research detailed a three-dimension method to image the internal structure and detail drug release features of commercial metoprolol succinate sustained-release tablets and component individual single pellets.In this section,synchrotron radiation X-ray microcomputed tomography(SR-?CT)was utilized to obtain nondestructively in-situ structure parameters of metoprolol succinate sustained-release tablet and pellets within.The results demonstrated that:The average number of spherical pellets in a tablet was 853±12(n=3).The average volume of the pellets was 0.09±0.01 mm~3,the diameter was 0.55±0.03 mm,and the sphericity was 0.87±0.06.The pellet structures were divided into three layers of typical depot sustained release system:pellet core,drug-containing layer and outer film.The coating layer on the pellets maintained a spherical morphology whilst numerous valleys appeared on the surface during in vitro drug release process.Knowledge of these structural characteristics confirmed that the mechanism of sustained drug release was membrane controlled and consistent with the drug release profiles.Overall,the structural investigation provided knowledge of the intrinsic quality of metoprolol succinate sustained-release tablets and offers guidance for reverse engineering of MUSR.In conclusion,this research made a breakthrough in the structural exploration of pellets in metoprolol succinate sustained-release tablet and the spatial distribution of inhalable particles in vivo.