Transscleral delivery

The intrascleral implant is a device that is implanted in the sclera it delivers the drug through the sclera to the intraocular tissues (Fig. 5). Transscleral delivery may be an effective method of achieving therapeutic concentrations of drugs in the posterior segment (24-27). The intrascleral implant that incorporated betamethasone phosphate (BP) successfully delivered the drug to the retina/choroid and vitreous (28). The concentration of BP was maintained at a level that should suppress inflammation in the retina-choroid for more than eight weeks, and did not produce any ocular toxicity. 

Ambati J, Gragoudas ES, Miller JW, et al. Transscleral delivery of bioactive protein to the choroid and retina. Invest Ophthalmol Vis Sci 2000 41 1186-1191. 

We studied the in vivo pharmacokinetics of transscleral delivery of IgG. We used an osmotic pump, the tip of which was secured flush against bare sclera in rabbits to facilitate unidirectional movement, to deliver fluorescently labeled IgG (150kDa) at rates on the order of pL/hr. Biologically relevant concentrations in the choroid and retina were attained for periods of up to four weeks with negligible systemic absorption (6). Levels in the vitreous and aqueous humors, and orbit were negligible. Although there was a spatial concentration gradient, the IgG concentration in the choroidal hemisphere distal to the footprint of the osmotic pump tip was half of that in the proximal hemisphere. The elimination of IgG from the choroid and retina followed first-order kinetics with half-lives of approximately two to three days. 

Li et al. [196] studied the sites of ion delivery in the eye during iontophoresis. Using nuclear magnetic resonance imaging (MRI) and a probe ion (Mn2+), the study compared transscleral with transcorneal iontophoresis. The results have shown that transscleral iontophoresis delivered the ion into the vitreous, whereas transcorneal iontophoresis delivered the ion into the... 

Li, S.K., E.K. Jeong, and M.S. Hastings. 2004. Magnetic resonance imaging study of current and ion delivery into the eye during transscleral and transcorneal iontophoresis. Invest Ophthalmol Vis Sci 45 1224. 

Detailed pharmacokinetic studies were performed on transscleral iontophoresis of various drugs [38-40,42,75-78]. Each drug resulted in different patterns of distribution in the vitreous. Carboplatin distribution in the vitreous after iontophoretic delivery demonstrated heightened levels in a controlled manner from 1 to 6 h after treatment [39], Foscarnet iontophoresis demonstrated a very low elimination rate, thus therapeutic levels in the vitreous were maintained for up to 60 h [78]. Methylprednisolone obtained a relatively low peak concentration 2 h after treatment [38], and gentamicin showed a peak concentration 16 h after the transscleral iontophoresis [42]. 

Geroski, D.H., and H.F. Edelhauser. 2001. Transscleral drug delivery for posterior segment disease. Adv Drug Deliv Rev 52 37. 

Subconjunctival injections of sustained-release matrix materials or microparticles have produced significant levels in the vitreous cavity. Although the kinetics of transscleral drug delivery to the retina and choroid are... 

Factors Affecting Transscleral Drug Delivery and the Related Experimental Data... 

From RantaV-P, Urtti A. Transscleral drug delivery to the posterior eye prospects of pharmacokinetic modeling. Adv Drug Deliv Rev 2006. 

There is topographic variation in the density of scleral emissaries, with the temporal sclera being most free of these vascular conduits (20). The landscape of scleral thickness is quite varied. The mean thickness of human sclera is 0.53 mm at the limbus, 0.39 mm at the equator, and 0.9-1.0mm near the optic nerve (21). However, even these figures are subject to great variation, with equatorial thickness frequently below 0.1 mm. These factors would be important considerations in the placement of a transscleral drug delivery device. With a mean total surface area of 16.3 cm2, the sclera is an inviting portal for intraocular drug delivery. 

The importance of the transscleral route in the penetration of topically administered macromolecules was demonstrated by denying corneal access by affixing a glass cylinder to the corneoscleral junction with cyanoacrylate adhesive (44). Significant intraocular levels of inulin (5 kDa) were obtained by topical administration outside the cornea in their paradigm. Neither reentry from the general circulation nor delivery by local vasculature accounted for the intraocular levels of the drug. 

Maurice was the first to report successful transscleral iontophoretic delivery of fluorescein into the rabbit vitreous humor (56). Potentially therapeutic intraocular levels of antibiotics (57 63), steroids (64), and anti-cytomegaloviral drugs (65,66), and anti-fungals (67) have been achieved via transscleral iontophoresis in animal models. 

Okabe K, Kimura H, Okabe J, et al. Effect of benzalkonium chloride on transscleral drug delivery. Invest Ophthalmol Vis Sci 2005 46 703-708. 

Kadam RS, Tyagi P, Edelhauser HP, Kompella UB. Inflnence of choroidal neovascularization and biodegradable polymeric particle size on transscleral snstained delivery of triamcinolone acetonide. International Journal of Pharmaceutics. September 15, 2012 434(l-2) 140-147. PubMed PMID 22633904. Pubmed Central PMCID 3573139. 

M.E. Myles, D.M. Neumann, and J.M. Hill, Recent progress in ocular drug delivery for posterior segment disease Emphasis on transscleral iontophoresis, Adv Drug Deliv Rev, 57, 2063-2079, 2005. 

N. Nagai, H. Kaji, H. Onami, Y. Ishikawa, M. Nishizawa, N. Osumi, T. Nakazawa, and T. Abe, A polymeric device for controlled transscleral multi-drug delivery to the posterior segment of the eye, Acta Biomater, 10,680-687,2014. 

The permeation and clearance of model ionic permeants after subconjunctival injection was assessed with NMR imaging. New Zealand white rabbit was the animal model and manganese ion (Mn ) and manganese EDTA complex (MnEDTA ) were the model permeants. The current study was divided into three parts in vitro, postmortem, and in vivo. Transscleral passive permeation experiments were conducted with excised sclera in side-by-side diffusion cells in vitro. Sub-conjunctival delivery experiments were conducted with rabbits postmortem and in vivo. The distribution and elimination of the probe permeants from the subconjunctival space after subconjunctival injections were determined by MRI. The permeability coefficients of Mn and MnEDTA across the sclera in vitro were 3.6 x 10 cm/s and 2.4 x 10 cm/s, respectively. 

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