Ophthalmic Formulation Containing Nilvadipine Nanoparticles Prevents Retinal Dysfunction in Rats Injected with Streptozotocin

Abstract

Retinopathy leads to irreparable vision loss via capillary closure and areas of nonperfusion. However, the current instillation systems do not allow a sufficient amount of drug required to treat retinopathy to reach the posterior segment (retina); therefore, a new formulation targeting the posterior segment is expected as therapy for retinopathy. We prepared ophthalmic formulations containing nilvadipine nanoparticles (NILnano), and demonstrated whether the instillation of NILnano can prevent retinal dysfunction in rats injected with excessive streptozotocin (STZ rats) in this study. NILnano (mean particle size, 77 nm) was prepared by wet bead mill treatment, with the inclusion of various additives (2-hydroxypropyl-β-cyclodextrin, benzalkonium chloride, d-mannitol, and methylcellulose). Retinal dysfunction was observable two weeks after rats received intraperitoneal injections of streptozotocin (100 mg/kg × 2, consecutive days, STZ rat). Changes in retinal function were evaluated by electroretinogram (ERG) and immunological methods. The retinal thickness, measured as the distance between the ganglion cell layer and the distal border of the outer nuclear layer, increased two weeks after the injection of streptozotocin, resulting in decreases in the levels of a-waves, b-waves, and oscillatory potential amplitudes in ERG of rats. The instillation of NILnano allowed the topical supplement of nilvadipine into the retina, and repeated instillation of NILnano (2 times/day) attenuated the retinal disorders led by the excessive streptozotocin. In conclusion, we found that retinal dysfunction in rats injected with streptozotocin can be prevented by the NILnano instillation. These results are useful in further studies aimed at the therapeutic treatment of retinopathy.

<p>Energy-dependent endocytosis is responsible for drug transcorneal penetration following the instillation of ophthalmic formulations containing indomethacin nanoparticles</p>

“…38 On the other hand, we previously found that nanoparticle formulations prepared by a bead mill method lead to an increase in BA, and the corneal toxicity of ophthalmic formulations containing nanoparticles is lower than that of traditional formulations (solution type). [13][14][15][16][17] In addition, we previously produced an ophthalmic formulation containing 0.5% indomethacin nanoparticles that showed high transcorneal penetration. 15 However, it is important to design ophthalmic formulations containing a higher content of drug nanoparticles in order to enhance the corneal penetration and duration.…”

“…It is known that the corneal epithelium has a barrier function in the cornea, and we previously reported that particles ,200 nm in size can penetrate the corneal tissue. [13][14][15][16][17] Therefore, we demonstrated the corneal epithelial penetration of indomethacin nanoparticles using HCE-T cell monolayers. Moreover, it is known that incubation at cold temperature (4°C) inhibits all energy-dependent uptake in cells including endocytosis, 31 which is the major route by which nanomedicines are transported across membranes.…”

“…[10][11][12] We also designed solid nanoparticles created by a breakdown mill (bead mill method), and reported on the properties of low corneal stimulation and high transcorneal penetration of formulations containing solid nanoparticles in comparison with traditional formulations (liquid formulations and ophthalmic suspensions). [13][14][15][16][17] It is expected that solid nanoparticles may increase absorption and BA, and provide a novel strategy for transcorneal DDS. However, the mechanism of nanoparticle transport through the cornea is not fully understood.…”

A Proteomic Approach for Understanding the Mechanisms of Delayed Corneal Wound Healing in Diabetic Keratopathy Using Diabetic Model Rat

“…Hematoxylin and eosin (HE) staining of the cornea in the normal and STZ rats was prepared as described previously [ 44 , 75 , 76 ]. The rats were anesthetized with sodium pentobarbital (30 mg/kg, i.p.)…”

The Intravitreal Injection of Lanosterol Nanoparticles Rescues Lens Structure Collapse at an Early Stage in Shumiya Cataract Rats

“…Then, their eyes were removed and fixed in a SUPER FIX™ rapid fixative solution. Next, 3 µm paraffin sections were prepared and stained with H&E [37].…”