title: Preliminary evaluation of a novel oral delivery system for rhPTH1-34: in vitro and in vivo.
abstract: rhPTH1-34 is clinically used for osteoporosis treatment. However, this peptide drug has no oral bioavailability because of proteolysis and low membrane permeability in gastrointestinal gut. This study explored the possibility of absorption enhancement for rhPTH1-34 through the oral delivery of the microemulsion. The microemulsion (85:15, oil/water) consisting of Labrasol, Crodamol GTCC, Solutol HS 15, d-α-tocopheryl acetate (6:2:1:1, w/w) and saline water was developed and characterized, including particle size, morphology, drug loading efficiency and permeability, stability and pharmacokinetics. The microemulsion showed high drug loading efficiency (83%) and permeability, and significantly higher resistance to proteolysis in vitro study. The relative oral bioavailability was 5.4% and 12.0% when delivered to gastric and ileum. Besides, osteoporosis rats were induced and treated with oral rhPTH1-34 microemulsion (0.05 mg/kg), injection (0.01 mg/kg) and vehicle, respectively, for 8 weeks. The proximal tibia bone mineral content and density in oral rats (0.188 ± 0.008 g, 0.283 ± 0.014 g/cm(2)) was significantly increased compared to the control rats (0.169 ± 0.006 g, 0.266 ± 0.011 g/cm(2)), reaching to the sham rats. And the proximal tibia microstructure of oral rats was improved greatly, approaching sham level too. These findings revealed that oral microemulsion may represent an effective oral delivery system for rhPTH1-34.
authors: State Key Laboratory of Bio-membrane and Biotechnology, School of Life Science, Tsinghua University, Beijing 100084, China.
authors: Liting
authors: L
authors: Guo
authors: Erli
authors: E
authors: Ma
authors: Haiwei
authors: H
authors: Zhao
authors: Yingfang
authors: Y
authors: Long
authors: Changxue
authors: C
authors: Zheng
authors: Mingxing
authors: M
authors: Duan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000737:chemistry; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D004655:Emulsions; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption; D008297:Male; D036103:Nanotechnology; D010024:Osteoporosis / Q000188:drug therapy / Q000473:pathology; D010052:Ovariectomy; D010316:Particle Size; D010447:Peptide Hydrolases / Q000378:metabolism; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D019379:Teriparatide / Q000008:administration & dosage* / Q000737:chemistry; D013977:Tibia / Q000187:drug effects / Q000473:pathology
chemical_list: D050071:Bone Density Conservation Agents; D004337:Drug Carriers; D004655:Emulsions; D011994:Recombinant Proteins; D019379:Teriparatide; D010447:Peptide Hydrolases