Improved dissolution and oral absorption by co-grinding active drug probucol and ternary stabilizers mixtures with planetary beads-milling method  

作　　者：Fang Li Linsen Li Shaoning Wang Yan Yang Jia Li Dongchun Liu Sijie Zhang Siling Wang Hui Xu 

机构地区：[1]School of Pharmacy,Shenyang Pharmaceutical University,Benxi 117004,China [2]Shenyang Medical College,Shenyang 110031,China [3]School of Pharmaceutical Engineering,Shenyang Pharmaceutical University,Benxi 117004,China [4]School of Traditional Chinese Medicine,Shenyang Pharmaceutical University,Benxi 117004,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2019年第6期649-657,共9页亚洲药物制剂科学（英文）

基　　金：financial support from the National Basic Research Program of China(973 Program,No.2009CB930300)

摘　　要：The objective of this work is to construct a nanosuspension drug delivery system of probucol,a BCS II drug,in order to improve its dissolution and oral bioavailability.The wet milling procedure using planetary beads-milling equipment was utilized to grind the raw probucol to ultrafine nanoparticle/nanocrystal aqueous suspension that was further solidified by freeze-drying process.Cellulose derivatives of different substitution groups and molecular weights,including HPMC,HPC,and MC,were evaluated as the primary stabilizer of probucol nanosuspension.Ternary stabilizers system composed of a primary stabilizer(cellulose derivative,i.e.HPC),a nonionic surfactant(Pluronic R F68),and an anionic surfactant(SDS)was employed to obtain probucol nanosuspension of finer particle size and enhanced dissolution in aqueous media.The probucol nanosuspension with good physical stability showed no obvious change of particle size even after storing over 7 d at 4°C or 25°C.The solidified probucol nanosuspension with trehalose as the cryoprotectant showed the highest dissolution rate(>60%at 2 h)compared to other cryoprotectant.The in vivo pharmacokinetic evaluation indicated about 15-folds higher AUC value of the probucol nanosuspension compared to that of coarse probucol suspension after oral administration to rats.The probucol nanosuspension prepared by wet-milling and ternary stabilizers system may find wide applications for improving the dissolution and oral absorption of water-insoluble drugs.The objective of this work is to construct a nanosuspension drug delivery system of probucol, a BCS II drug, in order to improve its dissolution and oral bioavailability. The wet milling procedure using planetary beads-milling equipment was utilized to grind the raw probucol to ultrafine nanoparticle/nanocrystal aqueous suspension that was further solidified by freeze-drying process. Cellulose derivatives of different substitution groups and molecular weights, including HPMC, HPC, and MC, were evaluated as the primary stabilizer of probucol nanosuspension. Ternary stabilizers system composed of a primary stabilizer(cellulose derivative, i.e. HPC), a nonionic surfactant(Pluronic~?F68), and an anionic surfactant(SDS) was employed to obtain probucol nanosuspension of finer particle size and enhanced dissolution in aqueous media. The probucol nanosuspension with good physical stability showed no obvious change of particle size even after storing over 7 d at 4 °C or 25 °C. The solidified probucol nanosuspension with trehalose as the cryoprotectant showed the highest dissolution rate( > 60% at 2 h) compared to other cryoprotectant. The in vivo pharmacokinetic evaluation indicated about 15-folds higher AUC value of the probucol nanosuspension compared to that of coarse probucol suspension after oral administration to rats. The probucol nanosuspension prepared by wet-milling and ternary stabilizers system may find wide applications for improving the dissolution and oral absorption of water-insoluble drugs.

关 键 词：PROBUCOL NANOSUSPENSION Ternary STABILIZERS systems PLANETARY beads-milling Bioavailability 

分 类 号：TG1[金属学及工艺—金属学]