Yutaka Inoue, Ayana Motoda, Takashi Tanikawa, Koichi Takao, Florencio Arce, Gerard Lee See, Yoshiyuki Ishida, Daisuke Nakata, Keiji Terao
Ursolic acid (UA), a pentacyclic triterpenoid, possesses a variety of biochemical activities, including alpha-glucosidase 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 (γ-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/γ-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 γ-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 γ-CD, CD-MOF-1, and free water. NOESY 1H-1H NMR showed cross-peaks in the protons of UA and γ-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/γ-CD and about 97.8% for UA/CD-MOF-1. In the 96-hour solubility test (distilled water), UA, 3DGM (UA/γ-CD), and 3DGM (UA/CD-MOF-1) showed solubilities of 0.28 μg/mL, 53.56 μg/mL, and 1,083.92 μg/mL, respectively. In the 30-minute solubility test (FaSSIF), UA, UA/γ-CD, and UA/CD-MOF-1 showed solubility of 0.55 μg/mL, 411.08 μg/mL, and 143.93 μg/mL, respectively. The preparation of UA/γ-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 α-glucosidase was not observed. It is a cautionary discovery that complex formation may not necessarily enhance the pharmacologic activity of drugs or novel phytochemicals. © Elsevier B.V.
Laboratory of Nutri-Pharmacotherapeutics Management, Faculty of Pharmacy and Pharmaceutical Science, Josai University, 1-1 Keyakidai, Saitama, Sakado-shi, 3500295, Japan; Laboratory of Bioanalytical Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, 1-1 Keyakidai, Saitama, Sakado-shi, 3500295, Japan; Pharmaceutical Research and Drug Development Laboratories, Department of Pharmacy, School of Health Care Professions, University of San Carlos, Cebu, 6000, Philippines; CycloChem Bio Co., Ltd., 7-4-5, Minatojima-minamimachi, Chuo-ku, Kobe, 6500047, Japan
