title: Oral delivery of zoledronic acid by non-covalent conjugation with lysine-deoxycholic acid: In vitro characterization and in vivo anti-osteoporotic efficacy in ovariectomized rats.
abstract: We assessed the possibility of changing the route of administration of zoledronic acid to an oral dosage form and its therapeutic efficacy in an estrogen-deficient osteoporosis rat model. To enhance oral bioavailability, we formed an ionic complex by electrostatic conjugation of zoledronic acid with lysine-linked deoxycholic acid (Lys-DOCA, an oral absorption enhancer). After forming the complex, the characteristic crystalline features of pure zoledronic acid disappeared completely in the powder X-ray diffractogram and differential scanning calorimetry thermogram, indicating that zoledronic acid existed in an amorphous form in the complex. In vitro permeabilities of zoledronic acid/Lys-DOCA (1:1) (ZD1) and zoledronic acid/Lys-DOCA (1:2) (ZD2) complex across Caco-2 cell monolayers were 2.47- and 4.74-fold higher than that of zoledronic acid, respectively. Upon intra-jejunal administration to rats, the intestinal absorption of zoledronic acid was increased significantly and the resulting oral bioavailability of the ZD2 complex was determined to be 6.76±2.59% (0.548±0.161% for zoledronic acid). Ovariectomized (OVX) rats showed 122% increased bone mineral density versus the OVX control at 12weeks after treatment with once weekly oral administration of ZD2 complex (16μg/kg of zoledronic acid). Furthermore, rats treated with ZD2 complex orally showed significant improvement in the parameters of trabecular microarchitecture and bone strength: 149% higher bone volume fraction (BV/TV), 115% higher trabecular number (Tb.N), and 56% higher mean maximum load (Fmax) than in the OVX group. The trabecular microstructure and bone mechanical properties in the oral zoledronic acid group were not significantly changed compared with the OVX control. Thus, the oral ZD2 complex inhibited osteoporosis progression effectively by promoting osteogenesis and trabecular connectivity. The oral ZD2 complex would be expected to improve patient compliance by replacing the conventional injectable form and expand the indications, to include prophylaxis for osteoporosis and bone metastases.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Ok-Cheol
authors.initials: OC
authors.lastname: Jeon
authors.affiliation: Department of Biomedical Engineering, College of Health Science, Yonsei University, Wonju, Gangwon, Republic of Korea; Yonsei-Fraunhofer IZFP Medical Device Lab., Wonju, Gangwon, Republic of Korea.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Seo
authors.affiliation: Department of Biomedical Engineering, College of Health Science, Yonsei University, Wonju, Gangwon, Republic of Korea; Yonsei-Fraunhofer IZFP Medical Device Lab., Wonju, Gangwon, Republic of Korea.
authors.forename: Han-Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea. Electronic address: yrbyun@snu.ac.kr.
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
authors.affiliation: College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, Republic of Korea. Electronic address: jwpark@mokpo.ac.kr.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Park
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D018938:Caco-2 Cells; D003840:Deoxycholic Acid / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004164:Diphosphonates / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D007408:Intestinal Absorption / Q000187:drug effects; D008239:Lysine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism; D010052:Ovariectomy; D010539:Permeability / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D003840:Deoxycholic Acid; D000077211:Zoledronic Acid; D008239:Lysine
keywords: Lysine-deoxycholic acid; Oral absorption enhancer; Oral delivery; Osteoporosis; Zoledronic acid