betadex and andrographolide

Bacterial pneumonia is a serious disease with high mortality if no appropriate and immediate therapy is available. Andrographolide (AG) is an anti-inflammatory agent extracted from a traditional Chinese herb andrographis paniculata. Oral AG tablets and pills are clinically applied for treatment of upper respiratory tract infections. However, the low solubility and bioavailability of AG lead to high doses and long-term therapy. Here we developed an andrographolide-β-cyclodextrin inclusion complex (AG-β-CD) for inhalation therapy of Staphylococcus aureus pneumonia. AG-β-CD was identified with X-ray diffraction and FT-IR. Surprisingly, both AG-β-CD and AG showed little in vitro anti-S. aureus activity. However, pulmonary delivery of AG, AG-β-CD, or penicillin had significant anti-S. aureus pneumonia effects. Leukocytes, neutrophils, white blood cells, total proteins, TNF-α, IL-6, NF-κB p65 expression, and bacterial colonies in the bronchoalveolar lavage fluids were detected. Pulmonary delivery of AG and AG-β-CD led to bacterial inhibition and inflammation alleviation by regulating immune responses, while penicillin only killed bacteria without significant immune regulation. Moreover, the antipneumonia activity of AG-β-CD was much higher than that of AG, probably resulting from locally accelerated AG dissolution due to β-CD inclusion. The aerodynamic diameter of AG-β-CD powders was 2.03 μm, suitable for pulmonary delivery. Inhalable AG-β-CD is a promising antibacterial and anti-inflammatory medicine for the treatment of S. aureus pneumonia by regulating immune responses, and the effect is enhanced by β-CD inclusion. AG and its formulations might be potent weapons against the resistant bacterial pneumonia due to their specific mechanism in the future.

Topics: Animals; Anti-Bacterial Agents; beta-Cyclodextrins; Diterpenes; Immunohistochemistry; Interleukin-6; Leukocytes; Lung; Male; Neutrophils; NF-kappa B; Penicillins; Pneumonia; Rats; Rats, Sprague-Dawley; Spectroscopy, Fourier Transform Infrared; Staphylococcus aureus; Tumor Necrosis Factor-alpha; X-Ray Diffraction

A significant increase in solubility of andrographolide (AND), a slightly water soluble anti-inflammatory and antimicrobial drug, was achieved by inclusion with hydroxypropyl-beta-cyclodextrin (HP-beta-CD). The inclusion complex was prepared by solvent evaporation and characterized by the phase solubility method, X-ray diffractometry and differential scanning calorimetry. The solubility of AND increased linearly as a function of HP-beta-CD concentration, resulting in A(L)-type phase solubility diagram. Molecular modeling calculations were used to foresee the possible orientations of AND inside the HP-beta-CD cavity. The in vitro dissolution profile showed a significant increase in dissolving rate and percent of the inclusion complex compared with uncomplexed drug. In vivo pharmacokinetic study showed that AUC(0-infinity) was 1.6-fold higher than that of AND suspension after oral administration. These results suggest that HP-beta-CD inclusion system might be a promising formulation for the oral delivery of AND.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Biological Availability; Calorimetry, Differential Scanning; Chromatography, High Pressure Liquid; Diterpenes; Drug Carriers; Female; Kinetics; Male; Models, Molecular; Rats; Rats, Sprague-Dawley; Regression Analysis; Solubility; Solvents; Thermodynamics; X-Ray Diffraction