title: Soluplus(®) based 9-nitrocamptothecin solid dispersion for peroral administration: preparation, characterization, in vitro and in vivo evaluation.
abstract: Our study aimed to develop an amorphous 9-nitrocamptothecin solid dispersion (9-NC-SD) using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus(®)) for improving its oral bioavailability and antitumor efficacy in vivo. Freeze-dried 9-NC-SD with an optimized drug/polymer ratio at 1:15 (w/w) was characterized by powder X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy. The amorphous form of 9-NC was obtained by freeze-drying and the aqueous solubility of 9-NC was increased to 1.42 mg/mL. Upon dilution, 9-NC-SD was proven to form micellar structures with an average size distribution around 58 nm ± 5 nm (PDI=0.107 ± 0.016). Moreover, 9-NC-SD showed significantly increased intracellular uptake efficiency in Caco-2 cells compared to free 9-NC. Furthermore, the AUC0-8h of 9-NC-SD following oral administration showed a 2.68-fold increase in the lactone form of 9-NC compared to that of free 9-NC in Sprague-Dawley rats. The 9-NC-SD did not show obvious inflammatory responses and gastrointestinal toxicity following oral administration as demonstrated by the histological analysis of the rat intestinal sections. Thus, 9-NC-SD represents a promising approach for improving the solubility and oral bioavailability of drugs with poor solubility.
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University, Chengdu, China.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Lian
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University, Chengdu, China.
authors.forename: Jianxia
authors.initials: J
authors.lastname: Dong
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University, Chengdu, China.
authors.forename: Jinjie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University, Chengdu, China.
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University, Chengdu, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University, Chengdu, China. Electronic address: yfu4@scu.edu.cn.
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University, Chengdu, China. Electronic address: gongtaoy@126.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D001692:Biological Transport; D018938:Caco-2 Cells; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D018929:Cell Culture Techniques; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D004705:Endocytosis; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008297:Male; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D012510:Sarcoma 180 / Q000188:drug therapy; D013499:Surface Properties
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011145:Polyvinyls; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D011092:Polyethylene Glycols; C079905:rubitecan; D002166:Camptothecin
keywords: 9-Nitrocamptothecin; Antitumor effect; Oral bioavailability; Solid dispersion; Soluplus(®)