Development of Sustained-Release Ophthalmic Formulation Based on Tranilast Solid Nanoparticles

Abstract

Eye drops containing Tranilast (TL), N-(3,4-dimethoxycinnamoyl) anthramilic acid, are used as an anti-allergic conjunctivitis drug in the ophthalmic field. Traditional eye drops are very patient compliant, although the bioavailability (BA) of most eye drops is low since eye drops cannot be instilled beyond the capacity of the conjunctival sac due to its limited volume. Thus, traditional eye drops have low BA and a short duration of the drug on the ocular surface, so solutions to these problems are highly anticipated. In this study, we designed a sustained-release drug-delivery system (DDS) for TL nanoparticles. TL nanoparticles were prepared by bead mill treatment, and the gel formulations containing TL nanoparticles (TL-NPs-Gel, particle size 50 nm–100 nm) were provided by carboxypolymethylene. The crystal structure of TL with and without bead mill treatment is the same, but the TL solubility in formulations containing nanoparticles was 5.3-fold higher compared with gel formulations containing TL microparticles (TL-MPs-Gel). The photo and thermal stabilities of TL-NPs-Gel are also higher than those of dissolved TL. Moreover, when TL-NPs-Gel is applied to the upper eyelid skin (outside), the TL is released as nanoparticles, and delivered to the lacrimal fluid through the meibomian glands. In addition, the TL release profile for TL-NPs-Gel was sustained over 180 min after the treatment. These findings can be used to develop a sustained-release DDS in the ophthalmic field.

An in situ Gelling System Based on Methylcellulose and Tranilast Solid Nanoparticles Enhances Ocular Residence Time and Drug Absorption Into the Cornea and Conjunctiva

“…Table 1 shows the composition of the ophthalmic TL-NPs formulations (nTL, nTL-LMC, nTL-MMC, and nTL-HMC) prepared by using the bead mill method ( Nagai and Ito, 2014 ; Nagai et al, 2014b , 2017 ; Minami et al, 2020 ). TL powder was dispersed in a purified water containing mannitol, benzalkonium chloride, and HPβCD, added into 1.5 mL tubes with 0.1 mm zirconia beads, and subjected to the Bead Smash 12 (Wakenyaku Co. Ltd, Kyoto, Japan).…”

“…A methacrylate cell equipped with a 0.22 μm-pore membrane filter was used ( Nagai et al, 2014a ; Minami et al, 2020 ). One side of the cell (donor chamber) was filled with an ophthalmic TL-NPs formulation, and the other side (reservoir chamber) was filled with saline.…”

“…A methacrylate cell equipped with a 0.22 µm-pore membrane filter was used (Nagai et al, 2014a;Minami et al, 2020). One side…”

“…In particular, nanotechnology has been expected to be applied in the ophthalmic field, and many researchers have provided novel nanomedicines and nanodevices ( Sahoo and Labhasetwar, 2003 ). We also designed solid nanoparticles coated with 2-hydroxypropyl-β-cyclodextrin (HPβCD) ( Nagai and Ito, 2014 ; Nagai et al, 2014a , 2017 ; Minami et al, 2020 ), and reported that the corneal toxicity of solid tranilast (TL) nanoparticles (TL-NPs) is lower than that of commercially available TL eye drops (TL-sol), and that nanoparticles show high drug adhesion to corneal tissue ( Nagai et al, 2014b ; Minami et al, 2020 ). These ophthalmic drug delivery systems containing solid nanoparticles are useful, although further improvements are necessary to prolong the drug residence time in the lacrimal fluid and to enhance the absorption into the ocular tissues after instillation for such systems to provide effective therapy for ocular diseases.…”

Prevention of Postprandial Hyperglycemia by Ophthalmic Nanoparticles Based on Protamine Zinc Insulin in the Rabbit

“…It has been reported that the effect of reducing the particle size in ocular DDS can result in a three-fold increase in the post-instillation concentration of a drug [ 19 ]. We have designed solid nanoparticles (NPs) containing indomethacin, tranilast, and minoxidil by using the bead mill method, which is one of the top-down approaches [ 20 , 21 , 22 ], and used them to prepare ophthalmic dispersions [ 21 , 22 ]. Moreover, we have found that particles approximately 150 nm in size result in increased ophthalmic absorption of a drug (indomethacin) via the multiple energy-dependent endocytosis system in the ocular surface [ 23 ].…”