Liquid Crystalline Nanoparticles as an Ophthalmic Delivery System for Tetrandrine: Development, Characterization, and In Vitro and In Vivo Evaluation.

Rui Liu,Shuangshuang Wang,Shiming Fang,Jialu Wang,Changxiao Liu,Jingjing Chen,Xin He,Xingguo Huang

doi:10.1186/s11671-016-1471-0

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.

Highlights

Among ocular drug delivery systems, the topical application of drug solutions in eye drops is the most common and accepted method of treating ocular diseases
These systems can enhance ocular drug bioavailability by promoting transcorneal penetration, but as with traditional eye drops, the same rapid rates of drainage that result in the rapid pre-corneal loss of the drug and low bioavailability have been observed in these formulations
In summary, the present study demonstrates the potential of a TET-Liquid crystalline nanoparticles (LCNPs) drug delivery system to increase drug solubility and improve bioavailability

Summary

Introduction

Among ocular drug delivery systems, the topical application of drug solutions in eye drops is the most common and accepted method of treating ocular diseases. Solutions contained in drops typically display poor corneal penetration and have short pre-ocular retention times To overcome these shortcomings, emulsions, liposomes, nanoparticles, microspheres, nanocapsules, and micelles are being developed as new ophthalmic delivery systems [1,2,3,4,5,6]. Emulsions, liposomes, nanoparticles, microspheres, nanocapsules, and micelles are being developed as new ophthalmic delivery systems [1,2,3,4,5,6] These systems can enhance ocular drug bioavailability by promoting transcorneal penetration, but as with traditional eye drops, the same rapid rates of drainage that result in the rapid pre-corneal loss of the drug and low bioavailability have been observed in these formulations. Research of LCNPs as a drug delivery system has involved oral, percutaneous, and intravenous routes of administration [8,9,10]

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