title: Development of chitosan nanoparticles as drug delivery system for a prototype capsid inhibitor.
abstract: Oral delivery of biopharmaceutics drug disposition classification system (BDDCS) Class II or IV drugs with poor aqueous solubility and poor enzymatic and/or metabolic stability is very challenging. Bay41-4109, a member of the heteroaryldihydropyrimidine (HAP) family, inhibits HBV replication by destabilizing capsid assembly. It pertains to class II of the BDDCS which has a practically insoluble solubility which is 38 μg/mL (LYSA) and the oral delivery resulted in low bioavailability. The purpose of the current research work was to develop and evaluate Bay41-4109 loaded chitosan nanoparticles to increase the solubility and bioavailability for treatment of HBV. The Bay41-4109 nanoparticles were prepared by gelation of chitosan with tripolyphosphate (TPP) through ionic cross-linking. A three-factor three-level central composite design (CCD) was introduced to perform the experiments. A quadratic polynomial model was generated to predict and evaluate the independent variables with respect to the dependent variables. Bay41-4109 was encapsulated in the chitosan nanoparticles were demonstrated by PLM, FTIR, DSC, XRD and TEM etc. The in vivo results suggest that Bay41-4109 nanoparticles have better bioavailability and would be a promising approach for oral delivery of Bay41-4109 for the treatment of HBV.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China; Roche Pharma Research & Early Development, Roche Innovation Center, 720 CaiLun Road, Building 5, Shanghai 201203, China; Department of Pharmaceutics, School of Pharmacy, Shanghai Institute of Pharmaceutical Industry, 1320 West Beijing Road, Shanghai 200040, China.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Xue
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center, 720 CaiLun Road, Building 5, Shanghai 201203, China.
authors.forename: Steven
authors.initials: S
authors.lastname: Hu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Xutao
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Sai
authors.initials: S
authors.lastname: An
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center, 720 CaiLun Road, Building 5, Shanghai 201203, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shanghai Institute of Pharmaceutical Industry, 1320 West Beijing Road, Shanghai 200040, China. Electronic address: houhm@nperc.com.cn.
authors.forename: Huimin
authors.initials: H
authors.lastname: Hou
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: jiangchen@shmu.edu.cn.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002213:Capsid / Q000187:drug effects; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D048271:Chitosan / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D051379:Mice; D053758:Nanoparticles; D011122:Polyphosphates / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: C464059:BAY 41-4109; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D011122:Polyphosphates; D011725:Pyridines; D011743:Pyrimidines; D048271:Chitosan; C005692:triphosphoric acid
keywords: Bay41-4109; Cationic nanoparticles; Central composite factorial design; Chitosan; Drug encapsulation; Hepatitis B virus (HBV)