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. 2020 Feb 14;12(2):155.
doi: 10.3390/pharmaceutics12020155.

Novel Sustained-Release Drug Delivery System for Dry Eye Therapy by Rebamipide Nanoparticles

Noriaki Nagai  1 , Miyu Ishii  1 , Ryotaro Seiriki  1 , Fumihiko Ogata  1 , Hiroko Otake  1 , Yosuke Nakazawa  2 , Norio Okamoto  3 , Kazutaka Kanai  4 , Naohito Kawasaki  1
Affiliations

Novel Sustained-Release Drug Delivery System for Dry Eye Therapy by Rebamipide Nanoparticles

Noriaki Nagai et al. Pharmaceutics. .

Abstract

The commercially available rebamipide ophthalmic suspension (CA-REB) was approved for clinical use in patients with dry eye; however, the residence time on the ocular surface for the traditional formulations is short, since the drug is removed from the ocular surface through the nasolacrimal duct. In this study, we designed a novel sustained-release drug delivery system (DDS) for dry eye therapy by rebamipide nanoparticles. The rebamipide solid nanoparticle-based ophthalmic formulation (REB-NPs) was prepared by a bead mill using additives (2-hydroxypropyl-β-cyclodextrin and methylcellulose) and a gel base (carbopol). The rebamipide particles formed are ellipsoid, with a particle size in the range of 40-200 nm. The rebamipide in the REB-NPs applied to eyelids was delivered into the lacrimal fluid through the meibomian glands, and sustained drug release was observed in comparison with CA-REB. Moreover, the REB-NPs increased the mucin levels in the lacrimal fluid and healed tear film breakup levels in an N-acetylcysteine-treated rabbit model. The information about this novel DDS route and creation of a nano-formulation can be used to design further studies aimed at therapy for dry eye.

Keywords: dry eye; eyelid; mucin; rebamipide; sustained delivery system.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Characterization of the particle size, shape and solubility of rebamipide solid microparticles (REB-MPs) and nanoparticle (REB-NPs)-based ophthalmic formulation. (A) REB-MPs size by laser diffraction measurement. (B) REB-NPs size by dynamic light scattering measurement. (C) AFM image of REB-NPs. (D) Drug solubility in REB-MPs and REB-NPs. n = 6. *P < 0.05, vs. REB-MPs. 99.92% of the rebamipide existed in the solid form in REB-NPs, and the mean particle size was 109.5 nm.
Figure 2
Figure 2
Stability of rebamipide solid in REB-NPs one month after preparation. (A) REB-NPs size by dynamic light scattering measurement. (B) Number of rebamipide nanoparticles in REB-NPs. (C) AFM image of REB-NPs. (D) Drug solubility in REB-MPs and REB-NPs. n = 6. The rebamipide solid in REB-NPs remained in the nano-size range, and no difference was observed in either the shape or solubility after one month.
Figure 3
Figure 3
Rebamipide release from REB-MPs and REB-NPs through 25 nm and 450 nm pore membranes. Drug release from REB-MPs and REB-NPs through (A) 25 nm and (B) 450 nm pore membranes. (C) Particle size and (D) number of rebamipide nanoparticles that passed through the 450 nm pore membrane 24 h after the application of REB-NPs. Data show the size distribution and number of nanoparticles in the reservoir chamber. n = 5–6. N.D., not detectable. *P < 0.05, vs. REB-MPs. The rebamipide solid was released as nanoparticles from REB-NPs.
Figure 4
Figure 4
Changes in rebamipide levels in the lacrimal fluid and meibum of rabbits receiving a single treatment of REB-NPs or REB-MPs. (A) Rebamipide profile and (B) AUCLF in the lacrimal fluid after the application of REB-MPs or REB-NPs. (C) Rebamipide levels in the meibum and lacrimal fluid without meibum after the application of REB-MPs or REB-NPs. Here, 20 min and 60 min after the application of REB-NPs, the lacrimal fluid without meibum was collected from the eyelid side using Schirmer tear test strips. n = 5–7. *P < 0.05, vs. REB-MPs for each group. #P < 0.05, vs. lacrimal fluid without meibum for each group. The rebamipide in the REB-NPs penetrated the eyelid, and was delivered to the lacrimal fluid through the meibomian glands.
Figure 5
Figure 5
Effect of a single application of REB-NPs on lacrimal fluid volume, mucin levels, and TBUT in rabbits. (A) Changes in lacrimal fluid volume and (B) mucin levels after the application of REB-MPs or REB-NPs. (C) Changes in TBUT in rabbits treated with or without REB-NPs. (D) Images of the ocular surface over the range of 0-30 min after eyelid opening in rabbits treated with or without REB-NPs. The bar indicates 1 mm. In Figure 5C,D, REB-NPs measurements were begun 6 h after the application of the formulation to the eyelid. n = 6. *P < 0.05, vs. REB-MPs for each group. The application of REB-NPs induced an increase in lacrimal fluid volume, mucin levels, and TBUT in the rabbit eye and led to the stabilization of the ocular surface.
Figure 6
Figure 6
Therapeutic effect of the repetitive application of REB-NPs on dry eye in the N-acetylcysteine-treated rabbit model (dry eye model). Effect of REB-NPs on (A) the lacrimal fluid volume and (B) mucin levels in the dry eye model. (C) Images of the ocular surface in the dry eye model after repetitive applications of REB-NPs. The bar indicates 1 mm. (D) Effect of REB-NPs on tear film breakup levels in the dry eye model. Rabbits were treated repetitively with REB formulations at 14:00, and the experiments were performed at 18:00. n = 5–8. *P < 0.05, vs. none for each group. #P < 0.05, vs. Vehicle for each group. In the dry eye model, the application of REB-NPs enhanced the lacrimal fluid volume, and normalized the decreased mucin levels. In addition, the tear film breakup levels decreased by the application of REB-NPs.
Figure 7
Figure 7
Drug delivery routes of rebamipide in REB-NPs, and the therapeutic mechanism for dry eye.
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