Solidification of volatile D-Limonene by cyclodextrin metal-organic framework for pulmonary delivery via dry powder inhalers: In vitro and in vivo evaluation

D-Limonene (D-Lim), a volatile oil extracted from citrus fruits, has therapeutic effects on lung inflammation and cancer, whilst the deep delivery of D-Lim was challenging due to its physical instability for a long period of time. To prevent the volatilization of D-Lim and achieve efficient pulmonary delivery, herein, D-Lim was loaded into biodegradable γ-cyclodextrin metal-organic framework (γ-CD-MOF) with optimal loading efficiency achieving 13.79 ± 0.01% (molar ratio of D-Lim and γ-CD-MOF was 1.6:1), which possessed cubic shape with controllable particle size (1–5 μm). The experimental results indicated that γ-CD-MOF could improve the stability of D-Lim. A series of characterizations and molecular docking were used to reveal the interaction between D-Lim and γ-CD-MOF. The solidification of D-Lim by γ-CD-MOF played a crucial role in the exploitation of its inhalable dosage form, dry powder inhaler (DPI). Specifically, the aerosolization of D-Lim@γ-CD-MOF for inhalation was satisfactory with a fine particle fraction (FPF) of 33.12 ± 1.50% at 65 L/min of flow rate. Furthermore, in vivo study had shown a 2.23-fold increase in bioavailability of D-Lim solidified by γ-CD-MOF for inhalation compared to D-Lim for oral administration. Therefore, it is considered that γ-CD-MOF could be an excellent carrier for pulmonary drug delivery to realize solidification and lung therapeutic effects of volatile oils.