Physicochemical Determinants of Drug Diffusion Across the Conjunctiva, Sclera, and Cornea

Ahmed, Imran; Gokhale, Rajeev; Shah, Mandar V.; Patton, Thomas F.

doi:10.1002/jps.2600760802

Cited by 175 publications

(80 citation statements)

References 16 publications

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“…4,5 Several authors have shown that the sclera is more permeable to hydrophilic molecules than lipophilic ones. [40][41][42] Inomata studied the transscleral diffusion of radio-or dye-labelled albumin, and a 40 kDa red dextran following injection into the suprachoroidal space of rabbits. Both substances were detected in the extra-ocular tissues.…”

Section: Introductionmentioning

confidence: 99%

Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion

Srikantha

Mourad

Suhling

et al. 2012

Experimental Eye Research

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Purpose: To study the influence of molecular shape, conformability, net surface charge and tissue interaction on transscleral diffusion.Methods: Unfixed, porcine sclera was clamped in an Ussing chamber. Fluorophore labelled, neutral, albumin, dextran, or ficoll were placed in one hemi-chamber and the rate of transscleral diffusion was measured over 24 hours using a spectrophotometer. Experiments were repeated using dextrans and ficoll with positive, or negative, net surface charges.Fluorescence recovery after photobleaching (FRAP) was undertaken to compare transscleral diffusion with diffusion through a solution.All molecules were 70 kDa.Results: Using FRAP, mean ± SD diffusion coefficient (D) was highest for albumin, followed by ficoll, then dextran (p = 0.0005). Positive dextrans diffused fastest, followed by negative, then neutral dextrans (p = 0.0005). Neutral ficoll diffused the fastest, followed by positive then negative ficoll (p = 0.0008). For the neutral molecules, transscleral D was highest for albumin, followed by dextran, then ficoll (p < 0.0001). D was highest for negative ficoll, followed by neutral, then positive ficoll (p < 0.0001). By contrast, D was highest for positive dextran, followed by neutral, then negative dextran (p = 0.0021).Conclusions: Diffusion in free solution does not predict transscleral diffusion and the molecular-tissue interaction is important. Molecular size, shape, and charge may all markedly influence transscleral diffusion, as may conformability to a lesser degree, but all need to be considered when selecting or designing drugs for transscleral delivery.Drugs directed against vascular endothelial growth factor (VEGF) have proven efficacy in some of the most common retinal diseases. The ANCHOR and MARINA studies demonstrated efficacy in wet age-related macular degeneration (AMD), 1,2 and studies such as CRUISE, BRAVO 3,4 and several from the DRCnet Group have shown favourable results in retinal vein occlusion and diabetic macular oedema. Whilst the data in these studies have led to improved clinical care, the need for regular intravitreal injections represents a burdensome regimen of treatment. A less invasive mode of delivery would have potential advantages in terms of reduced cost, discomfort, and complication rate.Systemic administration is impeded by the blood-aqueous and blood-retinal-barriers. High drug concentrations may be required to overcome these barriers to diffusion, with the attendant risk of systemic side effects. 5 A topical route would have obvious advantages. Delivery to the retina is however difficult for several reasons, such as lacrimation, low corneal permeability to large molecules, counter directional intraocular convection, and importantly the long diffusional distance. 53 Blood flow in the conjunctiva, episclera and choroid can also reduce drug concentration. 33,50 Notwithstanding these potential difficulties, transscleral delivery has a number of potential advantages. 6,7,8,9 The sclera has a large and accessible surface area, and a high d...

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Section: Introductionmentioning

confidence: 99%

Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion

Srikantha

Mourad

Suhling

et al. 2012

Experimental Eye Research

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“…In addition, they must be lipid soluble to penetrate the lipophilic corneal epithelium, pass through the corneal stroma and the lipophilic endothelium, and enter the aqueous humor (25). In short, an effective formulation in an aqueous eyedrop solution needs to be hydrophilic and hydrophobic.…”

Section: Discussionmentioning

confidence: 99%

Development and Clinical Evaluation of Clotrimazole–β-Cyclodextrin Eyedrops for the Treatment of Fungal Keratitis

Rasool

Salmo

2012

AAPS PharmSciTech

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Abstract. Fungal keratitis is a serious corneal disease that may result in loss of vision. There are limited treatment options available in Iraqi eye hospitals which might be the main reason behind the poor prognosis of many cases. The purpose of this study was to prepare and pharmaceutically evaluate clotrimazole-β-cyclodextrin (CTZ-β-CD) eyedrops then clinically assess its therapeutic efficacy on fungal keratitis compared with extemporaneous amphotericin B eyedrops (0.5% w/v). A CTZ-β-CD ophthalmic solution was prepared and evaluated by various physicochemical, microbiological, and biological tests. The prepared formula was stable in 0.05 M phosphate buffer pH 7.0 at 40±2°C and 75±5% RH for a period of 6 months. Light has no significant effect on the formula's stability. The CTZ-β-CD eyedrops efficiently complied with the isotonicity, sterility, and antimicrobiological preservative effectiveness tests. Results of the clinical study revealed that 20 (80%) patients showed a favorable response to the CTZ-β-CD eyedrops, while 16 patients (64%) exhibited a favorable response to amphotericin B (P>0.05). The mean course of treatment was significantly (P<0.05) less in the CTZ treatment group than in the amphotericin group (21.5±5.2 vs. 28.3±6.4 days, respectively). The CTZ formulation was significantly (P<0.05) more effective in the management of severe cases and also against Candida sp. than amphotericin B. There was no significant difference (P<0.05) between both therapies against filamentous fungi. The CTZ-β-CD formulation can be used alternatively to other ophthalmic antimycotic treatment options in developing countries where stability, cost, or efficacy is a limiting factor.

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“…Its surface area is greater in order of magnitude than the cornea and it is 2-30 times more permeable depending on the drug. 8 One of the major disadvantages of the topical ophthalmic water solutions and suspensions is the rapid and extensive precorneal loss caused by drainage and high tear fluid turnover. The contact time of the drug with ocular tissues is relatively short (∼1 minute) because of the permanent production of lacrimal fluid (0.5-2.2 µl/min).…”

Section: Discussionmentioning

confidence: 99%

A comparative bioavailability study of three conventional eye drops versus a single lyophilisate

Lux

Maier²,

Dinslage³

et al. 2003

British Journal of Ophthalmology

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Physicochemical Determinants of Drug Diffusion Across the Conjunctiva, Sclera, and Cornea

Cited by 175 publications

References 16 publications

Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion

Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion

Development and Clinical Evaluation of Clotrimazole–β-Cyclodextrin Eyedrops for the Treatment of Fungal Keratitis

A comparative bioavailability study of three conventional eye drops versus a single lyophilisate

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