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To effectively achieve the pulmonary delivery for curcumin (CN), novel inhalable mucus-penetrating nanocrystal-based microparticles (INMP) were designed. The D-Tocopherol acid polyethylene glycol 1000 succinate (TPGS) modified CN nanocrystals (CN-NS@TPGS) were prepared by high pressure homogenization and further converted into nanocrystal-based microparticles (CN-INMP@TPGS) using spray-drying. It was demonstrated that CN-NS@TPGS exhibited little interaction with the negatively charged mucin due to a strong electrostatic repulsion effect and PEG hydrophilic chain, and exhibited a much higher penetration ability across the mucus layer compared with poloxamer 407 modified CN-NS (CN-NS@P407) and tween 80 modified CN-NS (CN-NS@TW80). The aerodynamic results demonstrated that the CN-INMP with 10% TPGS acting as the stabilizer presented a high FPF value, indicating excellent deposition in the lung after inhalation administration. Additionally, in vivo bioavailability studies indicated that the AUC(0-t) of CN-INMP@TPGS (2413.18 ± 432.41 µg/L h) were 1.497- and 3.32-fold larger compared with those of CN-INMP@TW80 (1612.35 ± 261.35 µg/L h) and CN-INMP@P407 (3.103 ± 196.81 µg/L h), respectively. These results indicated that the CN-INMP@TPGS were absorbed rapidly after pulmonary administration and resulted in increased systemic absorption. Therefore, the inhalable CN-INMP could significantly improve the bioavailability of CN after inhalation administration. The developed mucus-penetrating nanocrystals-in-microparticles might be regarded as a promising formulation strategy for the pulmonary administration of poorly soluble drugs.

To Enhance Mucus Penetration and Lung Absorption of Drug by Inhalable Nanocrystals-In-Microparticles