title: Engineering hot-melt extruded solid dispersion for controlled release of hydrophilic drugs.
abstract: It is often challenging to precisely manipulate the release behavior of hydrophilic drugs that is believed to be crucial for a satisfactory therapeutic outcome. The aim of this work was to regulate the dissolution of hydrophilic drug from hot-melt extruded solid dispersion via rational screening of the pore-forming agents. Venlafaxine hydrochloride and Compritol® 888 ATO was selected as the model drug and carrier excipient, respectively. Hydrophilic polyethylene glycol (PEG 6000) and polyvinylpyrolidone (PVP K30) were chosen as the transient pore-forming agents. The X-ray diffraction and thermal analysis showed that both drug and carrier existed in the crystalline form. Both types of polymers could generate pores upon dissolution test and the drug release rate was proportionally correlated to the pore-forming agent content. The mathematical modelling showed that the Ritger-Peppas model gave the best fit to the release curves, which demonstrates a diffusion-dominant release mechanism. The scanning electron microscopy and mercury intrusion porosimetry analysis proved that PVP K30 could generate large pores with low porosity, but PEG 6000 produced smaller pores with relatively high porosity. The in vivo pharmacokinetics study in rat revealed that solid dispersions containing either PEG 6000 or PVP K30 (both at 2.5%, w/w) exhibited an elevated bioavailability compared to the commercial product, Effexor® XR. The current work implied that rational screening of transient pore-forming polymer in solid dispersion could be a robust approach for controlling hydrophilic drug release.
authors.affiliation: School of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University, Tianjin 300072, China.
authors.forename: Shuli
authors.initials: S
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University, Tianjin 300072, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Meng
authors.affiliation: School of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University, Tianjin 300072, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University, Tianjin 300072, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Fan
authors.affiliation: Chem-Pharm R&D Institute, Tasly Holding Group Co. Ltd., Tianjin 300402, China.
authors.forename: Guocheng
authors.initials: G
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University, Tianjin 300072, China. Electronic address: zhaoyj@tju.edu.cn.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Chem-Pharm R&D Institute, Tasly Holding Group Co. Ltd., Tianjin 300402, China. Electronic address: 18630996976@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics; D004339:Drug Compounding; D065546:Drug Liberation; D005079:Excipients / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry; D006358:Hot Temperature; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry; D011145:Polyvinyls / Q000737:chemistry; D016062:Porosity; D011759:Pyrrolidines / Q000737:chemistry; D017208:Rats, Wistar; D012995:Solubility; D013535:Suspensions; D000069470:Venlafaxine Hydrochloride / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D003692:Delayed-Action Preparations; D005079:Excipients; D005227:Fatty Acids; D011145:Polyvinyls; D011759:Pyrrolidines; D013535:Suspensions; C505150:poly(N-vinylpyrrolidine); C086409:glyceryl behenate; D011092:Polyethylene Glycols; D000069470:Venlafaxine Hydrochloride
keywords: Controlled drug release; Hot-melt extrusion; Pore-forming; Solid dispersion; Venlafaxine