title: Enteric polymer based on pH-responsive aliphatic polycarbonate functionalized with vitamin E to facilitate oral delivery of tacrolimus.
abstract: To improve the bioavailability of orally administered drugs, we synthesized a pH-sensitive polymer (poly(ethylene glycol)-poly(2-methyl-2-carboxyl-propylene carbonate)-vitamin E, mPEG-PCC-VE) attempting to integrate the advantages of enteric coating and P-glycoprotein (P-gp) inhibition. The aliphatic polycarbonate chain was functionalized with carboxyl groups and vitamin E via postpolymerization modification. Optimized by comparison and central composite design, mPEG113-PCC32-VE4 exhibited low critical micelle concentration of 1.7 × 10(-6) mg/mL and high drug loading ability for tacrolimus (21.2% ± 2.7%, w/w). The pH-responsive profile was demonstrated by pH-dependent swelling and in vitro drug release. Less than 4.0% tacrolimus was released under simulated gastric fluid after 2.5 h, whereas an immediate release was observed under simulated intestinal fluid. The mPEG113-PCC32-VE4 micelles significantly increased the absorption of P-gp substrate tacrolimus in the whole intestine. The oral bioavailability of tacrolimus micelles was 6-fold higher than that of tacrolimus solution in rats. This enteric polymer therefore has the potential to become a useful nanoscale carrier for oral delivery of drugs.
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Menglin
authors.initials: M
authors.lastname: Wang
authors.affiliation: ‡Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: §School of Medical Instrument, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Yinglei
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: §School of Medical Instrument, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: He
authors.initials: H
authors.lastname: Lian
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Luo
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Du
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Wenya
authors.initials: W
authors.lastname: Ding
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Qiu
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Liu
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Longfa
authors.initials: L
authors.lastname: Kou
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Xiangfei
authors.initials: X
authors.lastname: Han
authors.affiliation: §School of Medical Instrument, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Rongwu
authors.initials: R
authors.lastname: Xiang
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: †Department of Pharmaceutical Sciences, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D008823:Micelles; D011076:Polycarboxylate Cement / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014810:Vitamin E / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D008823:Micelles; D011076:Polycarboxylate Cement; D014810:Vitamin E; C005506:polycarbonate; D011092:Polyethylene Glycols; D016559:Tacrolimus