Examination of penetration routes and distribution of ionic permeants during and after transscleral iontophoresis with magnetic resonance imaging

Molokhia, Sarah; Jeong, Eun Kee; Higuchi, William I.; Li, S. Kevin

doi:10.1016/j.ijpharm.2006.11.001

Cited by 30 publications

(30 citation statements)

References 24 publications

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“…Previous MRI studies using manganese ion (Mn 2+ ) and Mn 2+ with ethylenediaminetetraacetic acid (EDTA) chelate have revealed the ocular barriers to transscleral drug delivery and contributed to the understanding of the mechanisms of ocular iontophoresis (Li et al, 2004a,b; Molokhia et al, 2007, 2008). There were several advantages of using Mn 2+ and EDTA chelate.…”

Section: Introductionmentioning

confidence: 99%

Transscleral iontophoretic and intravitreal delivery of a macromolecule: Study of ocular distribution in vivo and postmortem with MRI

Molokhia

Jeong

Higuchi

et al. 2009

Experimental Eye Research

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The distribution and clearance of macromolecules in ocular delivery are not well understood. It has been hypothesized that iontophoresis can enhance transscleral delivery of macromolecules. The objective of this study was to investigate the ocular distribution of a macromolecule after transscleral iontophoretic delivery and intravitreal injection in vivo using nuclear magnetic resonance imaging (MRI) and to compare these results. Experiments of constant current transscleral iontophoresis of 4 mA or intravitreal injection were performed on New Zealand white rabbits in vivo. Iontophoresis experiments were also performed on rabbits postmortem. Galbumin™ (Gd-labeled albumin) was the model permeant surrogate to clinical therapeutic agents. MRI was used to monitor the distribution of the molecule in the eye after ocular iontophoresis and intravitreal injection. In addition, the conjunctiva, sclera, choroid, and retina were extracted in the transscleral iontophoresis study to determine the amounts of Galbumin™ in these tissues using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES). The results show that iontophoresis enhanced the ocular delivery of Galbumin™. The macromolecule was mainly delivered into the conjunctiva and sclera in microgram quantities and then diffused towards the posterior section in the upper hemisphere of the eye in vivo. Both in vivo and postmortem studies show that the iontophoretic delivery of Galbumin™ into the vitreous was below the detection limit. In the intravitreal injection study, the diffusion coefficient of Galbumin™ in the vitreous humor was estimated to be close to that of free aqueous diffusion.

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Section: Introductionmentioning

confidence: 99%

Transscleral iontophoretic and intravitreal delivery of a macromolecule: Study of ocular distribution in vivo and postmortem with MRI

Molokhia

Jeong

Higuchi

et al. 2009

Experimental Eye Research

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“…Later applications addressed devices for the delivery of steroid-sparing immunosuppressive agents (including monoclonal antibodies)32 and two new types of devices 33,34. The inventor team has published peer-reviewed papers on the general subject,35,36 but no clinical studies have been reported from Aciont so far.…”

Section: Resultsmentioning

confidence: 99%

International patenting in ophthalmology: An analysis of its structure and relevance for the development of drugs and diagnostics

Mucke¹

2008

OPTH

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While investigative ophthalmologists access peer-reviewed journals as part of their daily routine, and while they regularly visit scientific congresses, they rarely peruse patent documents as an information source. Among the reasons for this negligence are the incompatibility of patent search algorithms with those known from journal databases, a legalistic and frequently redundant language, and misconceptions about the nature of the patenting system. Here we present key data and analyses from the ophthalmology module of a patent database system that we are developing to address some of these problems. We show that international patent applications consistently reflect developer interest in the ocular drug and diagnostics field; that they are technically focused lead indicators of developments that frequently feature in peer-reviewed patenting only much later; and that patenting targets are well aligned with the unmet therapeutic needs of populations in industrialized countries. Most applications (74%–78% in years since 2006) are supported with experimental data, and most (on average, 80%–90%) faced at least one objection to patentability during their initial stage of examination. In contrast to the peer-reviewed scenery that is highly diverse, the corresponding patenting arena shows a pronounced focus on the United States.

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“…We used constrast medium for MR, a water-soluble drug, Gd-DTPA as a tracer to determine the pathways by which the contrast medium was distributed and eliminated during and after administration of various eye drops. Further, the use of Gd-DTPA and MR can make the generation of a drug transport gradient possible in a single animal eye and perform a quantitative study of the penetration, distribution, and elimination rates of drugs by providing accurate spatial data on the drugs [15][16][17] .…”

Section: Discussionmentioning

confidence: 99%

Corneal permeability assay of topical eye drop solutions in rabbits by MRI

Mao

Zhang

Hen

et al. 2010

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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This study examined the corneal permeability of topical eye drop solutions added with various corneal penetrating accelerators and gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) by nuclear magnetic resonance imaging (MRI). Twenty-four New Zealand rabbits were randomly divided into 3 groups according to the random digits table: Gd-DTPA group, in which the rabbits received 23.45% Gd-DTPA; hyaluronic acid group, in which 23.45% Gd-DTPA plus 0.2% hyaluronic acid was administered; azone group, in which 23.45% Gd-DTPA with 0.2% azone was given. Fifty microliters of the eye drops was instilled into the conjunctive sac every 5 min, for a total of 6 applications in each group. Contrast medium signals in the cornea, anterior chamber, posterior chamber, and vitreous body were scanned successively by MRI. The morphology and cell density of the corneal endothelium were examined before and 24 h after the treatment. The results showed that the residence time of Gd-DTPA in the conjunctival sac in the hyaluronic acid and azone groups was longer than that in the Gd-DTPA group. The signals in the anterior chamber of the Gd-DTPA and hyaluronic acid groups were increased slightly, and those in the azone group strengthened sharply. The signal intensity continuously rose over 80 min before reaching plateau. The strengthening rate of signals in the anterior chamber was 19.63% in the Gd-DTPA group, 53.42% in the sodium hyaluronate group, and 226.94% in the azone group. No signal was detected in the posterior chamber or vitreous body in all the 3 groups. Corneal morphology and cell density did not show any significant changes after the treatment in all the 3 groups. It was concluded that azone can significantly improve the corneal permeability of drugs that are similar to Gd-DTPA in molecular weight and molecular size, and MRI is a noninvasive technique that can dynamically detect eye drop metabolism in real time.

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Examination of penetration routes and distribution of ionic permeants during and after transscleral iontophoresis with magnetic resonance imaging

Cited by 30 publications

References 24 publications

Transscleral iontophoretic and intravitreal delivery of a macromolecule: Study of ocular distribution in vivo and postmortem with MRI

Transscleral iontophoretic and intravitreal delivery of a macromolecule: Study of ocular distribution in vivo and postmortem with MRI

International patenting in ophthalmology: An analysis of its structure and relevance for the development of drugs and diagnostics

Corneal permeability assay of topical eye drop solutions in rabbits by MRI

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