Preparation and in vivo evaluation of an orally available enteric-microencapsulated parathyroid hormone (1-34)-deoxycholic acid nanocomplex.
The N-terminal 34-amino-acid peptide fragment of human parathyroid hormone PTH (1-34), is used clinically to treat osteoporosis; however, it is currently administered by a once-daily subcutaneous injection, resulting in poor patient compliance. We have developed enteric microcapsules containing an ionic nanocomplex between PTH (1-34) and lysine-linked deoxycholic acid (LysDOCA) for the oral delivery of PTH (1-34). We measured the particle size of the PTH/LysDOCA complex and assessed its biological activity by determining the cAMP content in MC3T3-E1 cells. We also assessed its permeability across a Caco-2 cell monolayer and the bioavailability of the intrajejunally administered PTH/LysDOCA complex compared with PTH (1-34) in rats. In addition, the antiosteoporotic activity of the PTH/LysDOCA complex, encapsulated in an enteric carrier by coaxial ultrasonic atomization, was evaluated after it was orally administered to ovariectomized (OVX) rats. The formation of an ionic complex between PTH (1-34) and LysDOCA produced nanoparticles of diameter 33.0±3.36 nm, and the bioactivity of the complex was comparable with that of PTH (1-34). The Caco-2 cell permeability and AUClast value of the PTH/LysDOCA (1:10) nanocomplex increased by 2.87- and 16.3-fold, respectively, compared with PTH (1-34) alone. Furthermore, the OVX rats treated with oral PTH/LysDOCA-loaded enteric microcapsules showed an increase in bone mineral density (159%), bone volume fraction (175%), and trabecular number (174%) compared with those in the OVX control group. Therefore, the PTH/LysDOCA nanocomplex oral delivery system is a promising treatment modality for osteoporosis because it improves osteogenesis and trabecular connectivity.
Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju.
Seung Rim
SR
Hwang
Department of Biomedical Engineering, College of Health Science, Yonsei University, Wonju, Gangwon.
Dong-Hyun
DH
Seo
Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul.
Youngro
Y
Byun
Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, Republic of Korea.
Jin Woo
JW
Park
D000284:Administration, Oral; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage; D018938:Caco-2 Cells / Q000187:drug effects; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D008239:Lysine / Q000737:chemistry; D051379:Mice; D053761:Nanocomposites / Q000008:administration & dosage* / Q000737:chemistry; D010012:Osteogenesis / Q000187:drug effects; D010024:Osteoporosis / Q000188:drug therapy; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000737:chemistry; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D019379:Teriparatide / Q000008:administration & dosage
D050071:Bone Density Conservation Agents; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D003840:Deoxycholic Acid; D019379:Teriparatide; D008239:Lysine
coaxial ultrasonic atomization; deoxycholic acid; nanocomplex; oral delivery; osteoporosis; parathyroid hormone