Optimizing Andrographolide from Sambiloto Leaves (<i>Andrographis paniculata</i>) Using Cyclodextrin Metal–Organic Frameworks for Targeted Pulmonary Delivery via a Metered Dose Inhaler: A Proof-Of-Concept Study

<i>Andrographis paniculata</i> is recognized for its numerous applications in the pharmaceutical industry. The primary compound of this plant, andrographolide (AG), has demonstrated potent antibacterial properties, including against <i>K. pneumoniae</i>. However, its poor solubility limits its bioavailability. To address this, the creation of an inclusion complex (IC) using cyclodextrin (CD) and Metal-Organic Frameworks (MOFs) offers a promising solution for improving AG's solubility and bioavailability. The AG-CD-MOFs are intended to be delivered via a metered dose inhaler (MDI), allowing for direct targeting of lung tissue. This research focuses on designing AG encapsulated within CD-MOFs to boost solubility and enhance drug efficacy when delivered directly to the lungs via an MDI. Computational molecular modeling indicated that γ-CD is the most suitable host molecule for forming an inclusion complex (IC) with AG, surpassing α-CD and β-CD. The optimal AG to γ-CD ratio for the IC is 1:2 (w/w), with a particle size of 534.53 ± 49.11 nm, a PDI of 0.121 ± 0.01, an encapsulation efficiency (EE) of 89.45 ± 7.03%, and a drug loading (DL) of 26.09 ± 2.87%. The IC exhibits strong antibacterial activity comparable to AG crystal-DMSO, highlighting the importance of solubility in AG's antibacterial efficacy. Additionally, drug release studies revealed that the IC's release profile is nearly nine times greater than that of the AG crystal. In vivo studies further demonstrated the high selectivity of the MDI for lung tissue delivery compared to injection and oral administration, with drug concentrations of 7.44 ± 0.57 μg/mL, 1.52 ± 0.23 μg/mL, and 1.5 ± 0.16 μg/mL, respectively. Moreover, the MDI AG-CD-MOFs exhibited sustained-release properties, maintaining a drug concentration of 5.27 ± 0.75 μg/mL in lung tissue for up to 48 h, significantly higher than injection and oral administration, which only maintained concentrations of 1.52 ± 0.23 μg/mL and 1.50 ± 0.16 μg/mL at 8 h, respectively. The developed formulation shows high selectivity to lung tissue and shows sustained-release behavior. The formula was deemed safe based on in vitro hemolysis and irritation risk tests and did not cause inflammation in lung tissue, as confirmed by histopathology studies. Furthermore, in vivo studies are strongly recommended to validate this therapy and improve pneumonia treatment options.