Partitioning and Spatial Distribution of Drugs in Ocular Surface Tissues

Balla, Anusha; Auriola, Seppo; Grey, Angus C.; Demarais, Nicholas J.; Valtari, Annika; Heikkinen, Emma M.; Toropainen, Elisa; Urtti, Arto; Vellonen, Kati‐Sisko; Ruponen, Marika

doi:10.3390/pharmaceutics13050658

Cited by 13 publications

(4 citation statements)

References 53 publications

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“…Typically, drug absorption from the ocular surface after eye drop instillation involves distribution phenomena on the ocular surface, which reportedly correlates with the drug log D 7.4 values. 33) Accordingly, undissolved drug particles are unlikely to be absorbed by the ocular surface via passive transport. Although the direct absorption of suspended drugs into the cornea remains unclear, the absorption into the skin, which has a similar mechanism of drug absorption as the cornea, has been reported.…”

Section: Discussionmentioning

confidence: 99%

Enhancing Corneal Drug Penetration Using Penetratin for Ophthalmic Suspensions

Morofuji,

Kudo,

Honda

et al. 2024

Biological & Pharmaceutical Bulletin

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Eye drops, including solutions and suspensions, are essential dosage forms to treat ophthalmic diseases, with poorly water-soluble drugs typically formulated as ophthalmic suspensions. In addition to low bioavailability, suspensions exhibit limited efficacy, safety, and usability due to the presence of drug particles. Improving bioavailability can reduce the drug concentrations and the risk of problems associated with suspended drug particles. However, practical penetration enhancers capable of improving bioavailability remain elusive. Herein, we focused on penetratin (PNT), a cell-penetrating peptide (CPP) that promotes active cellular transport related to macromolecule uptake, such as micropinocytosis. According to the in vitro corneal uptake study using a reconstructed human corneal epithelial tissue model, LabCyte CORNEA-MODEL24, PNT enhanced the uptake of Fluoresbrite ® YG carboxylate polystyrene microspheres without covalent binding. In an ex vivo porcine eye model, the addition of 10 µM PNT to rebamipide ophthalmic suspension markedly improved the corneal uptake of rebamipide; however, the addition of 100 µM PNT was ineffective due to potentially increased particle size by aggregation. This article provides basic information on the application of PNT as a penetration enhancer in ophthalmic suspensions, including the in vitro and ex vivo studies mentioned above, as well as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay and storage stability at different pH values.

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Section: Discussionmentioning

confidence: 99%

Enhancing Corneal Drug Penetration Using Penetratin for Ophthalmic Suspensions

Morofuji,

Kudo,

Honda

et al. 2024

Biological & Pharmaceutical Bulletin

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“…S2e). The surface area of the conjunctiva is 17 times bigger than that of the cornea and the permeability can be as high as 29 times that of the cornea, and thus Tm can enoughly affect the sclera through the conjunctiva-sclera pathway [ 31 ]. From the above results, we considered that the effect of the drug on the cornea is limited.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a novel ER-stress induced myopia model in mice

Kang,

Ikeda,

Yang

et al. 2023

Eye and Vis

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Background Recent studies have indicated a strong correlation between endoplasmic reticulum (ER) stress and myopia and that eyedrops containing the ER stress inducer tunicamycin (Tm) can induce myopic changes in C57BL/6 J mice. Therefore, this study aimed to create a new myopia model using Tm eyedrops and to explore the mechanism of ER stress-mediated myopia development. Methods Three-week-old C57BL/6 J mice were treated with different concentrations (0, 25, 50, and 100 μg/mL) and/or number of applications (zero, one, three, and seven) of Tm eyedrops. Refraction and axial length (AL) were measured before and one week after Tm treatment. Scleral collagen alterations were evaluated under polarised light after picrosirius red staining. ER stress-related indicators, such as the expression of collagen I and cleaved collagen were detected using Western blotting. Results Compared with the control group, mice administered eyedrops with 50 μg/mL Tm only once showed the greatest myopic shifts in refraction and AL elongation and reduced scleral expression of collagen I. Picrosirius red staining showed a lower percentage of bundled collagen in the Tm group. Expression of ER-stress indicators increased in the Tm groups. Furthermore, optimised administration of Tm induced matrix metalloproteinase-2 (MMP2) expression in the sclera, which plays a major role in collagen degradation. Conclusions We have demonstrated that ER stress in the sclera is involved in myopia progression. Tm eyedrops induced myopic changes, loosening of the scleral collagen and decreased expression of collagen I. This process may be associated with ER stress in the sclera, which upregulates the expression of MMP2 leading to collagen degradation.

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“…The eyes were stored overnight in a keratinocyte serum-free medium (Gibco, Life Technologies Corporation, Grand Island, NY, USA) at +4 °C. The cornea was excised using an incision along the limbus, as described earlier [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

A Novel Ferroptosis Inhibitor UAMC-3203, a Potential Treatment for Corneal Epithelial Wound

et al. 2022

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Corneal wound, associated with pain, impaired vision, and even blindness, is the most common ocular injury. In this study, we investigated the effect of a novel ferroptosis inhibitor, UAMC-3203 (10 nM–50 µM), in corneal epithelial wound healing in vitro in human corneal epithelial (HCE) cells and ex vivo using alkali-induced corneal wounded mice eye model. We evaluated in vivo acute tolerability of the compound by visual inspection, optical coherence tomography (OCT), and stereomicroscope imaging in rats after its application (100 µM drug solution in phosphate buffer pH 7.4) twice a day for 5 days. In addition, we studied the partitioning of UAMC-3203 in corneal epithelium and corneal stroma using excised porcine cornea. Our study demonstrated that UAMC-3203 had a positive corneal epithelial wound healing effect at the optimal concentration of 10 nM (IC50 value for ferroptosis) in vitro and at 10 µM in the ex vivo study. UAMC-3203 solution (100 µM) was well tolerated after topical administration with no signs of toxicity and inflammation in rats. Ex-vivo distribution study revealed significantly higher concentration (~12–38-fold) and partition coefficient (Kp) (~52 times) in corneal epithelium than corneal stroma. The UAMC-3203 solution (100 µM) was stable for up to 30 days at 4 °C, 37 °C, and room temperature. Overall, UAMC-3203 provides a new prospect for safe and effective therapy for corneal wounds.

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Partitioning and Spatial Distribution of Drugs in Ocular Surface Tissues

Cited by 13 publications

References 53 publications

Enhancing Corneal Drug Penetration Using Penetratin for Ophthalmic Suspensions

Enhancing Corneal Drug Penetration Using Penetratin for Ophthalmic Suspensions

Establishment of a novel ER-stress induced myopia model in mice

A Novel Ferroptosis Inhibitor UAMC-3203, a Potential Treatment for Corneal Epithelial Wound

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