Topical pharmacokinetics of dexamethasone suspensions in the rabbit eye: Bioavailability comparison

Naageshwaran, Vatsala; Ranta, Veli‐Pekka; Toropainen, Elisa; Tuomainen, Marjo; Gum, G G; Xie, Enli; Bhoopathy, Siddhartha; Urtti, Arto; Amo, Eva M. del

doi:10.1016/j.ijpharm.2022.121515

Cited by 13 publications

(13 citation statements)

References 21 publications

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“…It can also be noticed that the difference in the amount of drug recovered for each part of the eye is negligible between the different eye movements (maximum velocity of 41 °/s) and the static model (no movement). While the current model broadly accounts for drug CL via the AH and RCS outflow, it does not account for iris-ciliary permeation, which would impact CL for molecules with different log D values (Fayyaz et al, 2020a;Naageshwaran et al, 2022). Drugs that are more lipophilic are expected to clear faster, for example, a study reported that intracameral dexamethasone (a hydrophobic drug) predominantly cleared via the iris-ciliary body as compared to aqueous outflow and corneal permeation in rabbit eyes (Naageshwaran et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…While the current model broadly accounts for drug CL via the AH and RCS outflow, it does not account for iris-ciliary permeation, which would impact CL for molecules with different log D values (Fayyaz et al, 2020a;Naageshwaran et al, 2022). Drugs that are more lipophilic are expected to clear faster, for example, a study reported that intracameral dexamethasone (a hydrophobic drug) predominantly cleared via the iris-ciliary body as compared to aqueous outflow and corneal permeation in rabbit eyes (Naageshwaran et al, 2022). A similar trend was observed with intracameral timolol, with approximately 16% of the drug eliminating via the AH outflow resulting in a half-life of 33.64 min in rabbit eyes (Fayyaz et al, 2020a).…”

Section: Discussionmentioning

confidence: 99%

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Development of an in vitro model to estimate mass transfer from the anterior cavity

Liu

Ibeanu

Brocchini

et al. 2022

Front. Drug. Deliv.

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Knowledge of drug mass transfer from the anterior chamber via the iris-lens barrier has important implications for the development of front of the eye medicines that can also deliver drugs to the vitreous cavity. Here, the design and evaluation of a novel in vitro model that estimates anterior clearance (CL) kinetics is described. To mimic some aspects of the human eye to aid with pharmaceutical modelling, the model incorporated a simulation of aqueous inflow from the ciliary inlet at the physiological flow rate, two CL elimination pathways [anterior hyaloid pathway and retina choroid sclera (RCS) pathway], human cavity dimensions and use of simulated vitreous fluid (SVF). An eye movement platform that incorporated 3 different eye movements (smooth pursuit, microsaccadic and saccadic) was tested against the control (no movement) to observe any difference in anterior kinetics profile and drug convection to the posterior cavity. Both timolol and brimonidine injected in the intracameral space were evaluated in the new in vitro prototype. An initial release study with one selected eye movement (smooth pursuit) with timolol (6.8 ± 0.4 µg, 30 μL) and brimonidine (15.3 ± 1.5 µg, 30 μL) showed half-life values of 105.3 and 97.8 min respectively in the anterior cavity (AC) space. Another study evaluated the effect of all eye movements against control with both drugs with higher doses of timolol (146.0 ± 39.1 μg, 25 μL) and brimonidine (134.5 ± 39.5 μg, 25 μL). The amounts of timolol in the back of the eye (RCS membrane and outflow) were 0.07 ± 0.05%, 1.36 ± 0.88%, 1.55 ± 1.03% and 0.98 ± 0.06% by 8 h with smooth pursuit, microsaccadic, saccadic and no movement respectively; whereas brimonidine amounts were 0.70 ± 0.21%, 0.94 ± 0.40%, 1.48 ± 1.02%, and 0.76 ± 0.33% respectively. A small amount of both drugs was seen in other compartments in the model (lens part, iris part, hyaloid membrane part and silicone cornea). These results indicate that this model can be used to determine transfer of small molecules via the iris-lens barrier to help optimise front of the eye formulations to treat tissues further back in the eye.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Development of an in vitro model to estimate mass transfer from the anterior cavity

Liu

Ibeanu

Brocchini

et al. 2022

Front. Drug. Deliv.

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“…While the ocular bioavailability of water-soluble DSP after SCT injection is relatively high compared to poorly soluble DEX, drug retention time in the eye is typically less than 1 day ( 15 ). The poorly soluble DEX has been formulated into topical suspensions while it has a short half-life of less than 2 hours ( 37 ). Because of the limited intraocular absorption and rapid clearance of topical eye drops, repetitive dosing is required, compromising patient compliance and increasing likelihood of corticosteroid-related side effects ( 38 , 39 ).…”

Section: Discussionmentioning

confidence: 99%

Six-month effective treatment of corneal graft rejection

et al. 2023

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Topical corticosteroid eye drop is the mainstay for preventing and treating corneal graft rejection. While the frequent topical corticosteroid use is associated with risk of intraocular pressure (IOP) elevation and poor patient compliance that leads to graft failure and the requirement for a repeated, high-risk corneal transplantation. Here, we developed dexamethasone sodium phosphate (DSP)–loaded dicarboxyl-terminated poly(lactic acid) nanoparticle (PLA DSP-NP) formulations with relatively high drug loading (8 to 10 weight %) and 6 months of sustained intraocular DSP delivery in rats with a single dosing. PLA DSP-NP successfully reversed early signs of corneal rejection, leading to rat corneal graft survival for at least 6 months. Efficacious PLA DSP-NP doses did not affect IOP and showed no signs of ocular toxicity in rats for up to 6 months. Subconjunctival injection of DSP-NP is a promising approach for safely preventing and treating corneal graft rejection with the potential for improved patient adherence.

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“…Intracameral pharmacokinetic studies (drug injection into the anterior chamber) can provide a better understanding of topical drug kinetics and allow the calculation of the absolute aqueous humor bioavailability of topical drugs; this has been demonstrated to be typically less than 4% (Fayyaz et al, 2020b;Naageshwaran et al, 2021;Naageshwaran et al, 2022). After intracameral injection, the same kinetic pathways shown in Figure 3 are present with the obvious exclusion of pathway 1 (corneal absorption).…”

Section: Corneal Absorption Routementioning

confidence: 99%

“…After intracameral injection, the same kinetic pathways shown in Figure 3 are present with the obvious exclusion of pathway 1 (corneal absorption). Intracameral lipophilic drugs also have to undergo corneal partitioning (Naageshwaran et al, 2022;del Amo et al, 2022), while lens partitioning is less relevant (del Amo et al, 2022), for example, the AUC 0-5h cornea/ aqueous humor for acetaminophen was five times and for brimonidine seven times the corresponding AUC 0-5h lens/ aqueous humor. Interestingly, the same drugs injected in the vitreous humor (using a dose to acquire similar initial concentrations) achieved three times higher lens partitioning than after intracameral administration (del Amo et al, 2022), showing that lens access is more favorable from the vitreous than from the anterior chamber.…”

Section: Corneal Absorption Routementioning

confidence: 99%

Topical ophthalmic administration: Can a drug instilled onto the ocular surface exert an effect at the back of the eye?

Amo

2022

Front. Drug. Deliv.

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Topical ophthalmic instillation is an appealing strategy to deliver drugs to the back of the eye to treat retinal diseases such as neovascular age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, and glaucomatous optic neuropathy. It has several advantages such as being non-invasive and user-friendly, e.g., allowing self-administration. However, the main obstacle has been how to achieve therapeutic drug concentrations in the retina due to the eye’s protective mechanisms, flows, and barriers. Less than 4% of the instilled drug dose enters the anterior chamber, and much less is expected to reach the posterior segment. It is crucial to understand a drug’s topical pharmacokinetics in humans and how one can extrapolate data from rabbits to humans. In this review, the available data on the retina and vitreous drug concentrations from pharmacokinetics studies conducted in human patients and rabbits have been compiled, together with the critical physiological factors to be considered for this route of administration. Improvements in the design of preclinical studies are suggested to increase their translatability to the treatment of human patients. Finally, the current status of clinical trials with topical ophthalmic formulations intended to treat the back of the eye is depicted. At present, no topical ophthalmic formulations to treat neovascular age-related macular degeneration or other retinal neurodegenerative illnesses have reached the market.

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Topical pharmacokinetics of dexamethasone suspensions in the rabbit eye: Bioavailability comparison

Cited by 13 publications

References 21 publications

Development of an in vitro model to estimate mass transfer from the anterior cavity

Development of an in vitro model to estimate mass transfer from the anterior cavity

Six-month effective treatment of corneal graft rejection

Topical ophthalmic administration: Can a drug instilled onto the ocular surface exert an effect at the back of the eye?

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