title: A combined bottom-up/top-down approach to prepare a sterile injectable nanosuspension.
abstract: To prepare a uniform nanosuspension of strongly hydrophobic riboflavin laurate (RFL) allowing sterile filtration, physical modification (bottom-up) was combined with high-pressure homogenization (top-down) method. Unlike other bottom-up approaches, physical modification with surfactants (TPGS and PL-100) by lyophilization controlled crystallization and compensated for the poor wettability of RFL. On one hand, crystal growth and aggregation during freezing was restricted by a stabilizer-layer adsorbed on the drug surface by hydrophobic interaction. On the other hand, subsequent crystallization of drug in the sublimation process was limited to the interstitial spaces between solvent crystals. After lyophilization, modified drug with a smaller particle size and better wettability was obtained. When adding surfactant solution, water molecules passed between the hydrophilic groups of surface active molecules and activated the polymer chains allowing them to stretch into water. The coarse suspension was crushed into a nanosuspension (MP=162 nm) by high-pressure homogenization. For long term stability, lyophilization was applied again to solidify the nanosuspension (sorbitol as cryoprotectant). A slight crystal growth to about 600 nm was obtained to allow slow release for a sustained effect after muscular administration. Moreover, no paw-licking responses and very slight muscular inflammation demonstrated the excellent biocompatibility of this long-acting RFL injection.
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, Shanghai, PR China.
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: Xing
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, PR China. Electronic address: tanglab@126.com.
authors.forename: Yanjiao
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D003460:Crystallization; D004339:Drug Compounding; D005612:Freeze Drying; D007273:Injections, Intramuscular; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D010316:Particle Size; D011312:Pressure; D017207:Rats, Sprague-Dawley; D012256:Riboflavin / Q000008:administration & dosage* / Q000737:chemistry*; D013535:Suspensions; D013848:Thigh; D017155:Wettability
chemical_list: D013535:Suspensions; D012256:Riboflavin
keywords: Controlled crystallization; High-pressure homogenization; Nanosuspension; Physical modification; Wettability