title: Liquid Crystalline Nanoparticles as an Ophthalmic Delivery System for Tetrandrine: Development, Characterization, and In Vitro and In Vivo Evaluation.
abstract: The purpose of this study was to develop novel liquid crystalline nanoparticles (LCNPs) that display improved pre-ocular residence time and ocular bioavailability and that can be used as an ophthalmic delivery system for tetrandrine (TET). The delivery system consisted of three primary components, including glyceryl monoolein, poloxamer 407, and water, and two secondary components, including Gelucire 44/14 and amphipathic octadecyl-quaternized carboxymethyl chitosan. The amount of TET, the amount of glyceryl monoolein, and the ratio of poloxamer 407 to glyceryl monoolein were selected as the factors that were used to optimize the dependent variables, which included encapsulation efficiency and drug loading. A three-factor, five-level central composite design was constructed to optimize the formulation. TET-loaded LCNPs (TET-LCNPs) were characterized to determine their particle size, zeta potential, entrapment efficiency, drug loading capacity, particle morphology, inner crystalline structure, and in vitro drug release profile. Corneal permeation in excised rabbit corneas was evaluated. Pre-ocular retention was determined using a noninvasive fluorescence imaging system. Finally, pharmacokinetic study in the aqueous humor was performed by microdialysis technique. The optimal formulation had a mean particle size of 170.0 ± 13.34 nm, a homogeneous distribution with polydispersity index of 0.166 ± 0.02, a positive surface charge with a zeta potential of 29.3 ± 1.25 mV, a high entrapment efficiency of 95.46 ± 4.13 %, and a drug loading rate of 1.63 ± 0.07 %. Transmission electron microscopy showed spherical particles that had smooth surfaces. Small-angle X-ray scattering profiles revealed an inverted hexagonal phase. The in vitro release assays showed a sustained drug release profile. A corneal permeation study showed that the apparent permeability coefficient of the optimal formulation was 2.03-fold higher than that of the TET solution. Pre-ocular retention capacity study indicated that the retention of LCNPs was significantly longer than that of the solution (p < 0.01). In addition, a pharmacokinetic study of rabbit aqueous humors demonstrated that the TET-LCNPs showed 2.65-fold higher ocular bioavailability than that of TET solution. In conclusion, a LCNP system could be a promising method for increasing the ocular bioavailability of TET by enhancing its retention time and permeation into the cornea.
authors.affiliation: School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 312 Anshanwest Road, Nankai District, Tianjin, 300193, China.|Tianjin State Key Laboratory of Modern Chinese Medicine, 312 Anshanwest Road, Nankai District, Tianjin, 300193, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 312 Anshanwest Road, Nankai District, Tianjin, 300193, China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, 312 Anshanwest Road, Nankai District, Tianjin, 300193, China.
authors.forename: Shiming
authors.initials: S
authors.lastname: Fang
authors.affiliation: School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 312 Anshanwest Road, Nankai District, Tianjin, 300193, China.
authors.forename: Jialu
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 312 Anshanwest Road, Nankai District, Tianjin, 300193, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 312 Anshanwest Road, Nankai District, Tianjin, 300193, China.
authors.forename: Xingguo
authors.initials: X
authors.lastname: Huang
authors.affiliation: School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 312 Anshanwest Road, Nankai District, Tianjin, 300193, China. hexintn@163.com.|Tianjin State Key Laboratory of Modern Chinese Medicine, 312 Anshanwest Road, Nankai District, Tianjin, 300193, China. hexintn@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.affiliation: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, 308 Anshanwest Road, Nankai District, Tianjin, 300193, China.
authors.forename: Changxiao
authors.initials: C
authors.lastname: Liu
keywords: Bioavailability; Central composite design; Corneal permeability; Glyceryl monoolein; Liquid crystalline nanoparticles; Microdialysis; Ophthalmic delivery; Pharmacokinetics; Pre-ocular retention; Tetrandrine