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

Ok Cheol Jeon, Dong Hyun Seo, Hansung Kim, Youngro Byun, Jin Woo Park

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 12 weeks after treatment with once weekly oral administration of ZD2 complex (16 μg/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.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalEuropean Journal of Pharmaceutical Sciences
Volume82
DOIs
Publication statusPublished - 2016 Jan 20

Fingerprint

zoledronic acid
Deoxycholic Acid
Lysine
Osteoporosis
Biological Availability
In Vitro Techniques
Desoxycorticosterone Acetate

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

@article{3b0f3a065c1d48518ae53d0ebe7b1304,
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 12 weeks after treatment with once weekly oral administration of ZD2 complex (16 μg/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.",
author = "Jeon, {Ok Cheol} and Seo, {Dong Hyun} and Hansung Kim and Youngro Byun and Park, {Jin Woo}",
year = "2016",
month = "1",
day = "20",
doi = "10.1016/j.ejps.2015.11.004",
language = "English",
volume = "82",
pages = "1--10",
journal = "European Journal of Pharmaceutical Sciences",
issn = "0928-0987",
publisher = "Elsevier",

}

TY - JOUR

T1 - Oral delivery of zoledronic acid by non-covalent conjugation with lysine-deoxycholic acid

T2 - In vitro characterization and in vivo anti-osteoporotic efficacy in ovariectomized rats

AU - Jeon, Ok Cheol

AU - Seo, Dong Hyun

AU - Kim, Hansung

AU - Byun, Youngro

AU - Park, Jin Woo

PY - 2016/1/20

Y1 - 2016/1/20

N2 - 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 12 weeks after treatment with once weekly oral administration of ZD2 complex (16 μg/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.

AB - 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 12 weeks after treatment with once weekly oral administration of ZD2 complex (16 μg/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.

UR - http://www.scopus.com/inward/record.url?scp=84946827293&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84946827293&partnerID=8YFLogxK

U2 - 10.1016/j.ejps.2015.11.004

DO - 10.1016/j.ejps.2015.11.004

M3 - Article

VL - 82

SP - 1

EP - 10

JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

SN - 0928-0987

ER -