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Nanoporous CD-MOF particles with uniform and inhalable size for pulmonary delivery of budesonide.
International Journal of Pharmaceutics 2019 April 12
It is essential to optimize a carrier of dry powder inhalation (DPI) for the aerodynamic deposition in vitro to achieve pulmonary delivery of drug molecules in vivo. In this study, neutralized nanoporous γ-cyclodextrin metal-organic framework (CD-MOF) crystals with cubic morphology and uniform inhalation size were developed and modified as a DPI carrier for budesonide (BUD). Cholesterol (CHO) and leucine (LEU)-poloxamer were used to modify the CD-MOF powder for the improvement of flowability and particle aerodynamic behaviour, for which the particle size distribution, Carr's index and in vitro pulmonary deposition were assessed. Compared to CD-MOF or LEU-CD-MOF-BUD, CHO-CD-MOF had a superior mass median aerodynamic diameter (4.35±0.04 μm) and inhalable performance (fine particle fraction of 30.60±0.76%), which were maintained after budesonide loading (4.47±0.30 μm, 24.95±4.33%). The crystallinity, cytotoxicity and in vivo deposition of drug loaded samples (CHO-CD-MOF-BUD) were then investigated by powder X-ray diffraction (PXRD), cell viability study, in vivo fluorescence imaging and pharmacokinetic studies in rats. The characteristic PXRD crystallinity peaks of budesonide disappeared after being loaded into CHO-CD-MOF, potentially indicating the molecular incorporation of budesonide into the pores of CD-MOF. The cell viability of A549 cell was more than 90% for CHO-CD-MOF-BUD as a result of the good biocompatibility of CD-MOF. When Rhodamine B was carried by the DPI particles, the fluorescence signal at the lung tissue was markedly improved after cholesterol modification compared with CD-MOF, whilst the bioavailability of CHO-CD-MOF-BUD in rat was equivalent with that of the commercial product of Pulmicort Turbuhaler. Therefore, the CD-MOF powders modified by cholesterol can be used as a promising inhalable carrier for pulmonary delivery of drugs with small dose.
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