Inclusion complexes of Ursolic acid with Cyclodextrin-based metal-organic Framework-1 enhance its solubility

Ursolic acid (UA), a pentacyclic triterpenoid, possesses a variety of biochemical activities, including alphaglucosidase inhibitory activity, but its poor solubility has limited its clinical application. In this study, UA was prepared as a three-dimensional ground mixture (3DGM) with gamma cyclodextrin (gamma-CD) and cyclodextrin metal organic frameworks 1 (CD-MOF-1) and the resulting formulations were evaluated for their physical properties, solubility, and anti-diabetic effect. The solubility phase diagram shows that 3DGM (UA/gamma-CD and UA/ CD-MOF-1) formed soluble complexes at a 1:1 molar ratio. Powder X-ray diffraction results showed that the characteristic diffraction peaks of UA and gamma-CD and CD-MOF-1 disappeared, confirmed by a halo pattern. In differential scanning calorimetry, the melting point peak derived from the UA disappeared. In NIR, peak shifts were observed for CH groups from UA and OH groups from gamma-CD, CD-MOF-1, and free water. NOESY 1H-1H NMR showed cross-peaks in the protons of UA and gamma-CD (H-3, H-5, H-6) and CD-MOF-1 (H-5, H-6). The dissolution rate of UA in distilled water in 5 min was about 0.35% for UA intact, but about 3.92% for UA/gamma-CD and about 97.8% for UA/CD-MOF-1. In the 96-hour solubility test (distilled water), UA, 3DGM (UA/gamma-CD), and 3DGM (UA/CDMOF-1) showed solubilities of 0.28 mu g/mL, 53.56 mu g/mL, and 1,083.92 mu g/mL, respectively. In the 30-minute solubility test (FaSSIF), UA, UA/gamma-CD, and UA/CD-MOF-1 showed solubility of 0.55 mu g/mL, 411.08 mu g/mL, and 143.93 mu g/mL, respectively. The preparation of UA/gamma-CD and UA/CD-MOF-1 inclusion complexes may diversify the formulation application of UA. However, the compatibility of CDs and CD-MOF with host drugs to enhance its pharmacologic activity against alpha-glucosidase was not observed. It is a cautionary discovery that complex formation may not necessarily enhance the pharmacologic activity of drugs or novel phytochemicals.