Most inhaled pharmaceutical formulations on the market are intended to exert immediate pharmacological action, even although inhaled sustained-release formulations can be needed to reduce the frequency of dosing. The purpose of this study was to investigate the pulmonary retention and pharmacokinetics of a poorly water-soluble drug after loading its nanocrystal form into inhalable mucoadhesive microparticles composed of hyaluronic acid. It was intended to prolong the pharmacological effect without compromising the dissolution rate of the poorly water-soluble drug. In this study, budesonide, a corticosteroid anti-inflammatory drug, was used as a model poorly water-soluble drug. Submicron budesonide particles were prepared by wet ball milling, and subsequently loaded into hyaluronic acid microparticles by the spray drying process. The ball-milled budesonide particles and the spray-dried microparticles were characterized using dynamic light scattering (DLS), laser diffraction, Scanning electron microscopy (SEM), X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). Selected formulations were evaluated in terms of their dissolution/release rate, aerosol performance, muco-adhesion and pharmacokinetics in rats. As shown by XRD and DSC analysis, the nanonized budesonide particles in this study were mainly in crystalline form. The dissolution/release study showed that the in vitro release of budesonide from the microparticles was not significantly sustained compared with the dissolution rate of budesonide nanocrystals (BUD-NC). However, the budesonide in the microparticles exhibited prolonged retention on the surface of porcine tracheal tube owing to the muco-adhesion ability of hyaluronic acid. After intratracheal administration to rats, the BUD-NC exhibited a similar pharmacokinetic profile to that of budesonide solution via i.v. injection. In contrast, budesonide loaded in the mucoadhesive microparticles exhibited a significantly prolonged T_max and increased bioavailability with the animal model. This study demonstrated that inhaled microparticles composed of hyaluronic acid could produce sustained budesonide pharmacological effects. This can be attributed to the mucoadhesion of the polymer that overcame the mucociliary clearance and, consequently, prolonged the retention of the active substance in the lung without necessarily reducing the in vitro dissolution rate.

尽管可能需要吸入缓释制剂以减少给药频率，但市场上大多数吸入药物制剂均旨在立即发挥药理作用。这项研究的目的是研究水溶性差的药物在将其纳米晶形式加载到由透明质酸组成的可吸入粘膜粘附性微粒中后的肺滞留性和药代动力学。目的是延长药理作用而不损害水溶性差的药物的溶解速率。在这项研究中，将布地奈德（一种皮质类固醇抗炎药）用作难溶于水的模型药物。通过湿式球磨制备亚微米布地奈德颗粒，然后通过喷雾干燥法将其装载到透明质酸微粒中。使用动态光散射（DLS），激光衍射，扫描电子显微镜（SEM），X射线粉末衍射（XRD）和差示扫描量热法（DSC）对球磨过的布地奈德颗粒和喷雾干燥的微粒进行了表征。根据其在大鼠中的溶解/释放速率，气雾剂性能，粘膜粘附和药代动力学评估了选定的制剂。如XRD和DSC分析所示，本研究中的布地奈德纳米颗粒主要为晶体形式。溶出/释放研究表明 根据其在大鼠中的溶解/释放速率，气雾剂性能，粘膜粘附性和药代动力学评估了选定的制剂。如XRD和DSC分析所示，本研究中的布地奈德纳米颗粒主要为晶体形式。溶出/释放研究表明 根据其在大鼠中的溶解/释放速率，气雾剂性能，粘膜粘附性和药代动力学评估了选定的制剂。如XRD和DSC分析所示，本研究中的布地奈德纳米颗粒主要为晶体形式。溶出/释放研究表明与布地奈德纳米晶体（BUD-NC）的溶解速率相比，布地奈德在体外从微粒中的释放没有显着维持。然而，由于透明质酸的粘膜粘附能力，微粒中的布地奈德在猪的气管管表面上显示出延长的保留。在向大鼠气管内给药后，BUD-NC通过静脉注射显示出与布地奈德溶液相似的药代动力学特征。相反，负载在粘膜粘附微粒中的布地奈德表现出显着延长的T _max。并提高了动物模型的生物利用度。这项研究表明，由透明质酸组成的吸入微粒可以产生持续的布地奈德药理作用。这可以归因于克服了粘膜纤毛清除作用的聚合物的粘膜粘附力，因此延长了活性物质在肺中的保留时间，而不必降低体外溶解速率。