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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5636_Библиотеки_им_академика_М_И_Перельмана
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The treatment of posterior segment eye disease remains limited by the difficulty
in achieving effective doses of drugs in target tissues in the posterior eye. In recent
years significant advances have been made in optimizing the delivery of drugs to
target tissues within the eye and in maintaining effective drug doses within those
tissues. Most pharmacologic management of ocular disease, however, continues
to utilize the topical application of solutions to the surface of the eye as drops or
ointments. Factors that can limit the usefulness of topical drug application include
the significant barrier to solute flux provided by the corneal epithelium and the rapid
and extensive precorneal loss that occurs as the result of drainage and tear fluid
turnover. Following the instillation of an eyedrop (maximum of 30 ml) into the inferior fornix of the conjunctiva, the drug mixes with the lacrimal fluid and drug contact time becomes a function of lacrimation, tear drainage, and turnover and to some
extent the composition of the precorneal tear film itself. It has been estimated that
typically less than 5% of a topically applied drug permeates the cornea and reaches
intraocular tissues. The major portion of the instilled dose is absorbed systemically
by way of the conjunctiva, through the highly vascular conjunctival stroma and
through the lid margin vessels. Significant systemic absorption also occurs when the
solution enters the nasolacrimal duct and is absorbed by the nasal and nasopharyngeal mucosa. (Lang 1995) Despite the relatively small proportion of a topically
applied drug dose that ultimately reaches anterior segment ocular tissues, topical
formulations remain effective, largely because of the very high concentrations of
drugs that are administered.
The sclera offers another potential route to obtain therapeutic vitreous and retinal
drug concentrations, using periocular injection, or by the placement of a sustainedrelease device. Delivering drugs across the permeable sclera would be safer and less
invasive than intravitreal injections or devices, yet potentially could provide a more
effective retinal dose than systemic or topical delivery.
7.2 Drug Delivery to Posterior Segment Ocular Tissues
Four general approaches may be employed to deliver drugs to the posterior segment –
topical, systemic, intraocular, and periocular (including subconjunctival, subtenons,
and retrobulbar), Fig. 7.1. Topically applied drugs may enter the eye by crossing the
conjunctiva and then diffusing through the sclera (Ahmed and Patton 1985; Ahmed
et al. 1987). Because of the barrier provided by the corneal epithelium and extensive
precorneal loss, this approach does not typically yield therapeutic drug levels in
the posterior vitreous, retina, or choroid. And, although systemic administration
can deliver drugs to the posterior eye, the large systemic doses necessary are often
associated with significant side effects. An intravitreal injection provides the most
direct approach to delivering drugs to the tissues of the posterior segment and
therapeutic tissue drug levels can be achieved. Intravitreal injections, however, have
the inherent potential side effects of retinal detachment, hemorrhage, endophthalmitis, and cataract. Repeat injections are frequently required and they are not always
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Fig. 7.1 Routes for delivering drugs to tissues of the posterior ocular segment. Drugs delivered
topically (a) must diffuse across the cornea, ciliary body, and vitreous before reaching target tissues in the posterior eye. Systemic delivery (b – not shown) has a poor dose–response profile for
the posterior segment. Also, the high systemic doses required to achieve therapeutic levels in posterior segment tissues can be associated with systemic toxicities. Intravitreal injection or implant
(c) or periocular delivery with transscleral diffusion (d) may be employed for improved delivery
of drugs to tissues in the posterior of the eye
well tolerated by the patient. Further, drugs injected directly into the vitreous are
rapidly eliminated. Intravitreal sustained-release devices have been employed to
avoid repeated injections. The best known of these devices is perhaps the Vitrasert
ganciclovir implant, used in the treatment of CMV retinitis.(Sanborn et
These and other intravitreal sustained-release systems including other implant
devices, microspheres, and liposomes are exciting new modalities of drug delivery
that offer effective treatment of visually devastating diseases. The devices, however,
do require intraocular surgery, they must be periodically replaced, and they have
potential side effects similar to those associated with intravitreal injection.
Periocular drug delivery using subconjunctival or retrobulbar injections or placement of sustained-release devices provides another route for delivering drugs to the
posterior tissues of the eye. This approach to drug delivery is safer and less invasive
than intravitreal injection and it also offers the potential for localized, sustainedrelease drug delivery. Drug delivery by this vector would ideally be transscleral, and
it could thus take advantage of the large surface area of the sclera. The average
2
surface area of the human sclera accounts for 95% of the total surface area
17 cm
of the globe and provides a significantly larger avenue for drug diffusion to the
inside of the eye than the 1 cm2 surface area of the cornea. Also, regional differences
in scleral thickness could be utilized to further optimize transscleral drug diffusion
al. 1992)
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if sustained-release delivery devices or systems could be placed in regions where
scleral permeability was greatest. Further, an increasing body of evidence suggests
that the sclera is quite permeable to a wide range of solutes and holds significant
potential for posterior segment drug delivery.
In recent years, experiments in our laboratory have been targeted at investigating
the potential for delivering drugs across the sclera by periocular injection or by the
placement of a sustained-release device. The relatively high scleral permeability, as
compared to the cornea, could, perhaps, be used to good advantage in developing
methods for transscleral drug delivery, especially for compounds that need to be
administered to the posterior part of the eye. Additionally, the sclera provides a very
large surface area. It comprises 95% of the surface area of the human eye. (Olsen
et al. 1998) This large area not only provides a potentially large region for transscleral drug absorption, but also offers the exciting possibility for delivering neuroprotective agents, antioxidants, or angiostatic agents to specific regions of the
retina.
7.3 Scleral Structure and Drug Delivery
The structure and composition of the sclera are comparable to those of the corneal
stroma. The principal components of the scleral stroma are collagen fibers, a sparse
population of fibroblasts, proteoglycans, and a few elastic fibers. Collagen is the
major component of the sclera, comprising some 75% of the scleral dry weight,
with type I being the major collagen type. As one moves from central cornea into
the sclera, collagen fibril size and fiber organization change progressively from the
lamellar, orderly array of uniform fibers seen in the central cornea to the branched
and interwoven array of fibrils varying in diameter seen in the sclera. (Borcherding
et al. 1975) Because of the similarities in structure, it is perhaps not surprising that
the solute permeability of the sclera is, in general, quite comparable to that of corneal stroma.
The large surface area of the sclera is also advantageous to intraocular drug
delivery. In a series of experiments reported by Olsen et
thickness and surface area of human sclera was investigated in donor eyes. The
mean (± SD) scleral thickness at the limbus was determined as 0.53 ± 0.14 mm.
Near the equator of the globe, 13 mm from the limbus, the sclera was found to have
a mean thickness of 0.39 ± 0.17 mm. Scleral thickness in the equatorial region was
found to be significantly less than that at the limbus. Interestingly, five of the 55 eyes
studied had a scleral thickness of 0.1 mm or less at the equator. Using measurements
from regions 12–17 mm posterior to the limbus, which is approximately at the equator, 38% of the eyes studied had scleral thickness measurements of 0.25 mm or less.
Thickness was found to increase gradually as one moved toward the posterior.
A maximal thickness of 0.9–1.0 mm was observed near the optic nerve.
In this same series of experiments, scleral surface area was measured by dissecting the scleral tissue from donor globes and making flat preparations. For the adult
al. (1998) the regional
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human donor eyes analyzed, mean scleral surface area was measured as 16.3 ± 1.8 cm2
(N = 17).
Drug delivery through the sclera is dependent upon the thickness of the tissue
that the solute must traverse as well as the surface area available to the compound
for diffusion. The sclera is relatively thick near the limbus. It thins at the equator and
becomes significantly thicker near the optic nerve. If transscleral drug delivery
could be directed to near the equator, 12–17 mm posterior to the limbus, transscleral
flux of the applied solute could be maximized. Because of its large surface area the
tissue, thus, provides a significantly larger avenue for drug diffusion to the inside of
the eye compared to the 1 cm2 surface area of the cornea. Also, if regional differences in scleral thickness could be taken advantage of by localized delivery, for
example by regional application of sustained-release delivery systems, regional
scleral delivery could be further optimized.
7.4 Scleral Permeability: Initial Studies
Initial in vitro permeability studies, largely from our laboratory, have shown the
sclera to be permeable to a wide molecular weight range of solutes. Scleral solute
permeability is, in fact, comparable to that of the corneal stroma; and passive solute
diffusion through an aqueous pathway is the primary mechanism of drug permeation across the tissue. The sclera by virtue of its large surface area, accessibility,
and relatively high permeability may indeed provide a useful vector for delivering
drugs to tissues in the posterior of the eye.
These studies do demonstrate a clear inverse relationship between permeability
and molecular weight, with an abrupt decline in permeability at the larger molecular
weights. The data for human tissue are comparable to those reported by Maurice
and Polgar (1977) for bovine tissue, if one considers the differences in thickness
comparing the tissues of the two species. These studies do demonstrate a clear
inverse relationship between permeability and molecular weight, with an abrupt
decline in permeability at the larger molecular weights, Table
permeability studies, using essentially comparable methods, have shown the sclera
to be permeable to a wide range of solutes and that permeability is best correlated
with molecular radius (Prausnitz and Noonan 1998).
Subsequent in vitro studies in our laboratory have demonstrated that the sclera,
in vitro, remains permeable to a range of lower molecular weight solutes in the presence of a transscleral pressure as high as 60 mmHg (Prausnitz and Noonan 1998).
Solute permeability of the human sclera does not appear to be correlated with
age. In a series of experiments, the permeability to inulin (MW: 5,000) was determined in a series of donor ages (9 days to 87 years of age). For the 22 donor globes
studied. No significant correlation was found between scleral permeability to inulin
and donor age (Olsen et al. 1995).
The results of the in vitro permeability studies indicate that scleral permeability
is comparable to that of the corneal stroma (Prausnitz and Noonan 1998). As in the
7.1. A number of
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Table 7.1 Scleral permeability (K
) and molecular weight
trans
Molecular
Drug
Polymyxin B 1,800 3.90
Doxil 580 4.74 × 10
Vancomycin BODIPY 1,723 6.66 × 10
SS fluorescein-labeled oligo 7,998 7.67 × 10
Dexamthasone-fluorescein 8,414 1.64 × 10
Rhodamine 479 1.86 × 10
Penicillin G 661 1.89 × 10
Methotrexate-fluorescein 979 3.36 × 10
Doxorubicin hydrochloride 580 3.50 × 10
Nanoparticle doxorubicin 580 4.97 × 10
Fluorescein 332 5.21 × 10
Cisplatin in collagen matrix 300 8.30 × 10
Carboxyfluorescein 317 9.93 × 10
Carboplatin in fibrin sealant 371 1.37 × 10
Cisplatin in BSS 300 2.0 × 10
Carboplatin in BSS 371 2.7 × 10
Water 18 5.2 × 10
weight K
(cm/sec) Reference
trans
-7
× 10
-7
-7
-7
-6
-6
-6
-6
-6
-6
-6
-6
-6
-5
-5
-5
-5
Kau et al. 2005
Kim et al. 2009
Kau et al. 2005
Shuler et al. 2004
Cruysberg et al. 2002
Cruysberg et al. 2002
Kau et al. 2005
Gilbert et al. 2003
Kim et al. 2009
Kim et al. 2009
Cruysberg et al. 2002
Rudnick et al. 1999
Gilbert et al. 2003
Simpson et al. 2002
Gilbert et al. 2003
Simpson et al. 2002
Rudnick et al. 1999
corneal stroma, the primary route for solute transport through the sclera is by
passive diffusion through an aqueous pathway. The sclera is made up of approximately 70% water, proteoglycans and closely packed collagen fibrils. The diffusion
pathway for drugs is through the interfibrillar aqueous media of the gel-like proteoglycans. Based on the geometric and physiochemical properties of the tissue and
independent measurements of permeability reported in the literature, a predictive
model that describes solute transport across the sclera (and corneal stroma) has been
constructed (Edwards and Prausnitz 1998). Rather than postulating semi-empirical
expressions, unknown constants, and data fitting to determine parameter values, this
model is based on fiber matrix theory and values in the literature reported by independent measurement. This model is novel in that all of the parameters used to correspond to geometrical and physiochemical properties of the tissue, such as water,
collagen, GAG, noncollagenous protein, salt content, and the properties of the solutes themselves. Scleral permeability values predicted by this model show excellent
agreement with reported experimental data. The model also provides further insight
into solute flux and factors important in developing improved delivery of drugs
across the sclera. It indicates that changes in the physiochemical properties of the
sclera to have a relatively weak effect on the permeability of small solutes, such as
conventional drugs. The tissue is already quite permeable to these smaller compounds and their transscleral delivery should occur readily, without the need for
enhancement. For larger molecules, however, such as proteins, DNA, viral vectors,
and other new products of biotechnology, the model indicates that transscleral
delivery could be significantly improved by taking advantage of thinner regions of
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the tissue, by increasing scleral hydration, or by transient modification of the scleral
extracellular matrix. This approach to enhancing scleral permeability might be
achieved by chemical, electrical, or ultrasonic approaches, for example.
Lateral diffusion, parallel to the scleral surface, could affect drug distribution
and delivery following periocular delivery. The nonisotropic architecture of collagen lamellae and other features of the scleral microanatomy suggest that lateral diffusion may behave differently than transscleral diffusion. To investigate lateral
diffusion within the human sclera, rates of diffusion of sulforhodamine, a model of a
hydrophilic drug, were measured in strips of human donor sclera for period up to
week (Jiang et al. 2006). Measureable amounts of drug were detected at distances
1
of 5 and 10 mm from the drug delivery reservoir at 4 h and 3 days, respectively.
Calculations of lateral diffusivity showed that a point source of sulforhodamine
would require 6 weeks to diffuse throughout all the sclera in a human eye. Lateral
diffusion within the sclera is thus a slow process that localizes drug distribution to
the scale of millimeters for hours to days. Lateral diffusion over larger surface areas
could occur over longer periods of time – for example during extended release drug
delivery from an implant.
7.5 Sustained-Release Delivery In Vitro
Drug delivery across the sclera is governed, in part, by the transient diffusion of a
solute across the tissue that typically occurs over a time course of minutes, unless
some type of sustained-release formulation or device is used. By comparison,
experimental studies aimed at determining scleral permeability typically derive
scleral permeability for a particular solute from steady-state flux data. In the absence
of some type of sustained-release system, drug–sclera contact times would be too
brief to permit the attainment of steady-state flux. Consequently, the in vitro flux
measurements would be expected to overestimate transscleral drug delivery
(Prausnitz et al. 1998). Experimental measurements for carboxyfluorescein confirm
that the lag time for solute diffusion across the sclera is similar to or actually longer
than the drug–sclera contact time during conventional drug administration. The
scleral lag time for carboxyfluorescein diffusion, for example, is greater than 20 min.
This solute is comparable in size and diffusivity to many conventional drugs. This
lag time is significantly longer than the few minutes which eye drops remain on the
eye’s surface before being washed away by tear fluid. The scleral lag time for carboxyfluorescein is also similar to the residence time at the scleral surface for a drug
introduced by peribulbar injection. Consequently, flux across the sclera would not
achieve steady state for most drug delivery applications.
Although carboxyfluorescein provides a good model solute for many drugs,
other compounds will bind to the sclera to different extents and at different rates and
their scleral lag times could be significantly different. Also, larger sized solutes
including macromolecules will diffuse across the tissue much more slowly. Their
scleral lag times would be significantly greater.
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The utilization of some type of sustained-release delivery system would thus appear
to be necessary for the successful utilization of transscleral drug delivery. An ideal
sustained-release transscleral delivery system would provide controlled, long-term
drug release, specific scleral site delivery, and prolong drug–sclera contact time. Such
a system would permit improved drug flux through thinner regions of the tissue, potentially allow treatment to specific posterior segment regions of the eye, and minimize
systemic drug absorption by the conjunctival vasculature. A variety of sustainedrelease drug delivery systems currently exist and new systems are being explored.
Current technologies include a variety of sustained-release delivery systems, including various gel formulations, erodible polymers, microspheres, liposomes, and several
inserts, including miniosmotic pumps and combinations of these technologies.
Fibrin sealant, collagen matrices, and pluronic F-127 have been widely used in
medical and pharmaceutical systems (Miyazaki et
F-127 is a polyol compound that exhibits reverse thermal gelation, remaining in the
liquid state at refrigerator temperatures and gelling on warming to ambient or physiological temperatures. These compounds have been shown to have good tissue compatibility and are good candidate systems for sustained-release delivery. Drugs can
be incorporated into them and the formulation can be applied to a scleral site, on or
within the tissue, where it will quickly gel or solidify. In vitro flux studies completed in our laboratories have demonstrated that each of these systems can provide
slow, uniform sustained-release of drugs across the human sclera. Carboplatin in
fibrin sealant (Simpson et al. 2002), cisplatin (chemotherapeutic drugs used in the
treatment of retinoblastoma) incorporated into a collagen matrix, dexamethasone
(corticosteroid) in fibrin sealant and in pluronic F-127 (Lee et al. 2004), and
methotrexate (chemotherapeutic) in fibrin sealant (Cruysberg et al. 2005) were all
found to provide relatively uniform sustained delivery across the human sclera for
up to 24 h in vitro compared to delivery of these drugs in a balanced salt vehicle.
A novel coated coil developed for use in interventional cardiology was also studied as a potential sustained-release system. (Cruysberg et al. 2002) The coils were
made of a stainless steel wire that was coated with hydrophilic biocompatible polymers that serve as a temporary depot for controlled local drug delivery. For the
in
vitro flux studies, the coating was loaded with the fluorescent dye rhodamine.
Upon immersion into an aqueous environment, the polymers allow the rhodamine
to diffuse from the coating. Although the coils were found to provide release of
rhodamine that subsequently did diffuse across the human sclera, the release kinetics of the coils were found not to significantly sustain the delivery of rhodamine.
Flux and delivery of rhodamine across the sclera were found to be not significantly
different comparing delivery by the coils or by rhodamine in solution.
al. 1984; Yu et al. 1996). Pluronic
7.6 In Vivo Studies
The in vitro permeability and release studies have provided much useful empirical
data on the permeability of the sclera to a wide range of solutes and have also
been useful in investigating how transscleral permeability and delivery might be
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optimized through the use of sustained-release delivery systems. With a basic
understanding of the permeability characteristics of the sclera to a range of solutes provided by in vitro studies, the application of these data must ultimately be
extended to the real world delivery of drugs and solutes to the posterior tissues of
the eye in vivo.
Retinoblastoma is the most common primary intraocular malignancy of childhood. While focal treatment is effective for smaller single tumors, systemic or
local chemotherapy with vincristin, etoposide and carboplatin has become the
treatment of choice for larger tumors and vitreous seeds. Because of significant
adverse effects associated with systemic treatment, localized periocular delivery
of carboplatin might be an option that could maintain local treatment while avoiding the adverse events that accompany systemic administration of the drug. In a
series of experiments (Simpson et
al. 2002), Dutch Belted rabbits were injected
subconjunctivally with carboplatin in either fibrin sealant or in a balanced salt
solution. Eyes were enucleated at various times following injection through
2 weeks, and levels of carboplatin were measured in various ocular tissues. The
results of these studies demonstrated that fibrin sealant provided a more controlled
and localized release of carboplatin, and provided sustained delivery of carboplatin to ocular tissues for up to 2 weeks. Compared to intravitreal injection, subconjunctival administration of 25.1 mg/ml in rabbits was observed to be well tolerated
with no retinal toxicity as determined by electroretinogram (Pardue et al. 2004).
Using a transgenic murine retinoblastoma model, subconjunctival carboplatin in
fibrin sealant was shown to be effective in inducing complete or near-complete
intraocular tumor regression in 10 of 11 eyes with no histological evidence of
toxicity (Van Quill et al. 2005). In an additional study, the effects of subconjunctival topotecan (TPT) in fibrin sealant were tested in a transgenic murine retinoblastoma model (Tsui et al. 2008). For these experiments the therapeutic effects of
a single subconjunctival injection of TPT in fibrin sealant was used. Treatment
resulted in a bilateral reduction of tumor burden without a significant difference
between treated and untreated eyes. These results suggest that drug was delivered
to both eyes predominantly through the hematogenous route. Periocular administration resulted in low systemic plasma drug levels, suggesting that this approach
could provide therapeutic benefits comparable to those of intravenous administration while reducing potential systemic toxicities. Taken together, the results of
these studies suggest that chemotherapy drugs including carboplatin, cisplatin,
and topotecan in fibrin sealant delivered subconjunctivally provide sustainedrelease delivery in
vivo and could have clinical use in the treatment of intraocular
retinoblastoma.
Traditional methods of evaluating ocular pharmacokinetics are invasive and
involve either on-time sampling of the aqueous/vitreous in humans during intraocular surgery or euthanizing animals a various time points, followed by enucleation,
dissection, and isolation of the intraocular tissues (including vitreous, iris/ciliary
body, lens, neuroretina, RPE, choroid). Ocular fluorophotometry is a noninvasive
technique that does not require anesthesia; does not disturb ocular structures; and
determines the concentration of fluorescein-labeled compound in the aqueous, vitreous, and retina on a real-time basis at different time points. In albino rabbits, the
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technique also permits measurement of fluorescein in the contralateral choroidal
circulation as an excellent real-time measure of the concentration in the systemic
circulation.
Sodium fluorescein (NaF) has been an invaluable diagnostic tool for retinochoroidal
disease. It has been useful in the investigation of the transscleral delivery of drugs
administered by the periocular route. Drugs labeled with NaF permit accurate detection and measurement of drug concentration using fluorophotometry both in vitro
and in vivo. Even though NaF has proven useful in drug delivery research its use is
limited to some extent by photobleaching and pH sensitivity. More stable alternative fluorescent agents such as Oregon Green (OG, Molecular Probes, Eugene, OR)
have recently been developed, providing a fluorescent agent without the photobleaching and pH sensitivity limitations of NaF. Its higher level of fluorescence
provides an additional advantage. Since Oregon Green has nearly the same structure, molecular weight and emission and excitation characteristics as NaF, efficient
utilization of existing equipment and research protocols is possible.
To investigate its potential application in drug delivery research, we evaluated
the transscleral permeability and pharmacokinetics of OG compared to NaF using
vitro and in vivo experimental models (Lee et al. 2008a, b). The results of
both in
these initial studies demonstrated that although the sclera had a lower permeability
to OG, this fluorescent agent was able to diffuse across the sclera. In vivo, following
subtenon injection, Oregon Green does penetrate the sclera and cross the bloodretinal barrier. Vitreous and anterior segment concentrations of OG were directly
influenced by the retina/choroid concentration. These initial experiments thus demonstrate the pharmacokinetic differences between OG and NaF after subtenon injection and provide an important starting point for future interpretation of transscleral
drug delivery studies utilizing OG.
In vivo ocular fluorophotometry following periocular injection has been used to
study the intraocular pharmacokinetics of NaF (Ghate et al. 2007), Oregon Green
488 (Lee et al. 2008a, b), and Oregon Green labeled triamcinolone (Lee et al.
2008b). Results of these studies have shown that these agents are capable of diffus-
ing across the sclera in vivo from a subtenon depot. In experiments with Oregon
Green labeled triamcinolone (OGTA), peak OGTA concentrations in the retina/
choroid were achieved at 3 h after injection. This level was maintained for 3 h and
then was observed to decrease to a baseline at 7 h after injection. These studies
demonstrate that OGTA can diffuse through the sclera and accumulate in the vitreous in rabbit eyes after a subtenon injection. Although the dose was low (1 mg),
the vitreous concentrations were still measurable by ocular fluorophotometry. Once
the OGTA has diffused into the choroid, it has to cross the blood-retinal barrier
to the vitreous. The OGTA levels in the mid vitreous and anterior segment were
observed to peak at 3–4 h after subtenon injection in live rabbits, immediately after
the retina/choroid peaks were observed to occur. This finding suggests that the vitreous and anterior segment concentrations of OGTA are closely and quickly affected
by the retina/choroid circulation.
Conjunctival, lymphatic, and choroidal vessels provide barriers to drug delivery. Euthanization stops the conjunctival and choroidal circulation and enhances
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transscleral drug delivery. In our OGTA studies, peak choroid/retinal following
subtenon injection in euthanized rabbits was observed to be approximately 3 times
greater compared to injection in vivo. Vitreous concentrations with euthanization
were 12 times greater than observed after in vivo injection. These results the significance of the dynamic barriers presented by the conjunctival and choroidal circulations as demonstrated by Robinson et al. (2006).
Taken together, the results of these in vivo studies have investigated and
defined the diffusion characteristics of several agents administered by periocular
injection. The dynamic barriers to transscleral drug delivery are clearly significant and are best studied in an in
vivo model. If a drug is formulated in a sustained delivery vehicle or system, significant vitreous concentrations could be
maintained over longer periods, as demonstrated with carboplatin in a fibrin sealant vehicle (Simpson et al. 2002). These studies also demonstrate that periocular
drug delivery can achieve effective local delivery, with significant vitreous drug
concentrations and minimal systemic levels. Limitations of the anatomic and
dynamic barriers to the transscleral approach must be considered. Additionally,
potential delivery limitations include drug/solute molecular weight, radius, partition coefficient, and charge. Despite potential limitations, however, periocular
drug delivery can provide effective drug delivery to the posterior segment tissues
of the eye.
7.7 Conclusions and Future Directions
Much experimental evidence currently indicates that transscleral delivery of
therapeutic solutes can be achieved. This approach to intraocular drug delivery
shows great promise in providing new therapeutic approaches for treating diseases of the posterior segment of the eye. The past results of these experiments
have added to the understanding of solute flux across the sclera and provide new
data on in vivo transscleral drug permeability and sustained-release delivery of
drugs and therapeutic agents for retinal degenerations and disease. The longterm goal of these transscleral delivery studies is to provide a more effective
drug delivery to the retina and posterior eye for the treatment of retinal degenerations and posterior segment disease. Delivering drugs across the permeable
sclera would be safer and less invasive than intravitreal injection or devices, yet
potentially could provide a more effective retinal dose than systemic or topical
delivery.
Ultimately, a delivery device (biodegradable and/or refillable) needs to be developed that will provide a sustained release of the drug or protein to the episclera. In
this case the sclera will come in equilibrium with the delivery device and provide a
slow release of the drug to the suprachoroidal space, where it can then directly diffuse to the choroid, RPE, and neuroretina.
Acknowledgments Supported in part by R24EY017045 and Research to Prevent Blindness Inc.
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