Topical drug delivery to the posterior segment of the eye: Thermodynamic considerations

Sripetch, Suppakan; Loftsson, Þorsteinn

doi:10.1016/j.ijpharm.2021.120332

Cited by 22 publications

(14 citation statements)

References 61 publications

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“…Passive drug diffusion into the eye is hampered by three major obstacles or barriers (Loftsson et al. 2008; Loftsson & Stefansson 2017; Sripetch & Loftsson 2021). The first obstacle is aqueous drug solubility.…”

Section: Barriers To Penetration Of Drugs Into the Eyementioning

confidence: 99%

“…Other barriers to topical drug absorption include the vascular tissues. The conjunctiva and vascular choroid result in a “first‐pass”‐like effect when drugs permeate via the non‐corneal route into the eye (Varela‐Fernandez et al., 2020; Sripetch & Loftsson 2021).…”

Section: Barriers To Penetration Of Drugs Into the Eyementioning

confidence: 99%

“…Highly lipophilic drugs, while they readily partition from the tear fluid into membranes, have low aqueous solubility and thus cannot achieve high concentrations in the tear film. The result is that neither highly water-soluble, nor highly lipid-soluble molecules can achieve high intraocular concentrations after topical application (Sripetch & Loftsson 2021). This is the fundamental dilemma that has so far prevented formulation of eye drops that effectively deliver drugs to the posterior segment.…”

Section: Barriers To Penetration Of Drugs Into the Eyementioning

confidence: 99%

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Aqueous eye drops containing drug/cyclodextrin nanoparticles deliver therapeutic drug concentrations to both anterior and posterior segment

Loftsson

Stefánsson

2021

Acta Ophthalmologica

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Using topical application to deliver therapeutic concentrations of drugs to the posterior segment of the eye remains very challenging. As a result, posterior segment diseases are usually treated by intravitreal injection or implant. While topical treatments are commonly used for anterior segment conditions, they sometimes require frequent applications. Eye drop formulations based on γ‐cyclodextrin (γCD)‐based nanoparticle aggregates were developed, which in animal models and clinical studies deliver therapeutic concentrations of drugs (dorzolamide and dexamethasone) to both anterior and posterior segments of the eye. An early study in humans showed dorzolamide/γCD eye drops could achieve comparable intraocular pressure decreases to commercial dorzolamide eye drops, but with less frequent application. Pilot studies with dexamethasone/γCD eye drops suggested that they could be effective in a range of conditions, including diabetic macular oedema, cystoid macular oedema and vitritis secondary to uveitis, postcataract surgery inflammation and postoperative treatment in trabeculectomy. Phase II studies with similar dexamethasone/γCD nanoparticle eye drops in diabetic macular oedema and postcataract surgery inflammation have recently been completed. This technology has the potential to be used with other classes of drug molecules and to replace or complement invasive treatments, providing safer, non‐invasive therapies, particularly for posterior segment conditions, that can be self‐administered as eye drops by patients.

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Section: Barriers To Penetration Of Drugs Into the Eyementioning

confidence: 99%

Section: Barriers To Penetration Of Drugs Into the Eyementioning

confidence: 99%

Section: Barriers To Penetration Of Drugs Into the Eyementioning

confidence: 99%

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Aqueous eye drops containing drug/cyclodextrin nanoparticles deliver therapeutic drug concentrations to both anterior and posterior segment

Loftsson

Stefánsson

2021

Acta Ophthalmologica

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“…Ophthalmic topical drugs are indicated for several diseases of the anterior segment of the eye; acute states such as conjunctivitis, keratitis, and iritis; or chronic conditions, for example, dry eye and glaucoma (Hopkins, 2007b). However, topical administration is currently being actively investigated to be applied in the treatment of ocular posterior segment diseases, i.e., retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), retinal vein occlusion (RVO), and optic neuropathy glaucoma disease (Adams et al, 2018;Askew et al, 2018;Joussen et al, 2019;Samanta et al, 2020;Sripetch and Loftsson, 2021). The prevalence of these vision-threatening illnesses is increasing with the aging of the population.…”

Section: Introductionmentioning

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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“…The current study aimed to evaluate the non-clinical pharmacokinetics and bio-distribution of γCD based competitive antagonists of the angiotensin II receptor irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple instillations in rabbits. These formulation are aqueous microsuspensions in which the solid particles are metastable γCD/drug complexes that readily dissolve upon media dilution resulting in sustained high drug concentrations in the tear fluid [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits

et al. 2021

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The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 (n = 31) received irbesartan 1.5% and group 2 (n = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (Cmax), time of maximal drug concentration (Tmax), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the Cmax of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a Cmax of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while Cmax was below 2 ng/g for candesartan. For multiple dosing, the observed Cmean in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and <2 ng/g, respectively. The highest plasma concentrations of both irbesartan (Cmax 5.64 ± 4.08 ng/mL) and candesartan (Cmax 4.32 ± 1.04 ng/mL) were reached 0.5 h (Tmax) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit’s eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model.

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Topical drug delivery to the posterior segment of the eye: Thermodynamic considerations

Cited by 22 publications

References 61 publications

Aqueous eye drops containing drug/cyclodextrin nanoparticles deliver therapeutic drug concentrations to both anterior and posterior segment

Aqueous eye drops containing drug/cyclodextrin nanoparticles deliver therapeutic drug concentrations to both anterior and posterior segment

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

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits

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