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Fig. 13.11 Refillable episcleral-placed silicone device for trans-scleral delivery of active agents.
Fluid-conducting passageways are disposed within the device that is coupled to the anterior injection
port. Reprinted from Yaacobi (2006a)
Yaacobi (2006b) allowing for fluid channels to carry drug from the anterior port
position to multiple locations around the eye equator similar to an encircling silicone
buckle (Fig. 13.12). In order to be positioned under the four rectus muscles, this
device style is made as a band that is threaded under the muscles and then secured
to itself using a sleeve which tethers the two ends.
Variations in the above concepts have subsequently been reported. Avery (
2006)
proposed a slightly different design but essentially followed a similar approach to
the original concepts of Yaacobi, showing a device (Fig. 13.13) with an anteriorly
located hollow funnel-shaped needle insertion section (see element 220 in Fig. 13.13)
connected to a delivery tube extending posteriorly; the device also is positioned
below the inferior oblique muscle. Franklin (2007) further discusses a refillable
device approach using the same anatomical placement. However, the refill method
is accomplished through a two-part design in which a disposable refill portion containing an implant at the distal end can be interconnected to a second base portion
which is attached or sutured to the eye. Because of this connection to a permanently
positioned base segment, the refill section containing the implant should contact the
eye in the exact position as the previously removed disposable.
Episcleral devices which communicate from an anterior to posterior position are
generally designed with the thought of bringing high levels of the drug closer to
the macula. However, if high levels can be trans-sclerally delivered or if drug is
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13 Refillable Devices for Therapy of Ophthalmic Diseases
40
42
126
124
44
64
220
50
142
200
140
152
212
68
240
144
142’
150
50
158
204
210
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Fig. 13.12 Refillable episcleral band design with anterior injection port (element 24). Drug distribution
from the device is 360° around the eye with effluent ports (element 25) spaced at intervals around
the band. Reprinted from Yaacobi (2006b)
Fig. 13.13
(element 220), hollow reservoir (element 204), and delivery tube to posterior location. Reprinted
from Avery (2006)
Refillable episcleral device with anteriorly located funnel-shaped injection port
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Fig. 13.14 Refillable episcleral exoplant design forms a seal on the tissue without tight suturing.
Bottom surface has opening to allow injected fluid reservoir to maintain direct contact with the sclera.
Reprinted from de Carvalho et al. (2006). Copyright 2006 Association for Research in Vision and
Ophthalmology. Reproduced with permission of INVESTIGATIVE OPHTHAL MOLOGY &
VISUAL SCIENCE in the format Other Book via Copyright Clearance Center
extremely potent, then a sufficient gradient might be established which could
achieve necessary therapeutic concentrations at the macula. Furthermore for disease
conditions which do not involve the macula or have etiology with loci more anteriorly,
then it may not be a requirement to deliver drug to the far posterior. De Carvalho and
colleagues (De Carvalho et
al. 2003, 2005, 2006; Krause et al. 2005) have described
an episcleral refillable device that is more anteriorly located to deliver therapy for
retinoblastoma. In one style of the device, a flexible silicone reservoir that is secured
by sutures forms a seal with the sclera (Fig.
13.14). On the side of the reservoir
directly contacting the sclera is an opening permitting direct communication with a
solution containing the active agent. The outer perimeter adjacent to the conjunctiva
incorporates a knob that can be manually palpated to confirm the device location.
Refill is accomplished via direct injection through designated port areas on the
device. A similar style device was independently reported by Adamis et al. (2004).
13.4.4 Subretinal and Suprachoroidal Implantation
Theoretically, a cannulated episcleral device would be capable of delivering its contents to locations in the eye other than the anterior or posterior chambers. In a patent
application in 2002 that was allowed 7 years later, Greenberg (2009) reported a
design having a refillable multi-compartment reservoir which could be implanted
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Fig. 13.15 Episcleral reservoir design with an attached cannula leading to the subretinal space.
Reprinted from Humayun et al. (2006)
adjacent to the retina having a cable containing multiple feeder tubes run trans-scleral
through the pars plana, terminating in the refill port. In a reverse of that sequence,
Humayan and De Juan (2006) describe a device showing a refillable reservoir in the
episcleral pars plana location and a cannula penetrating through to the vitreous and
secured at its terminal end under the retina posteriorly (Fig. 13.15). These authors
further propose that the reservoir for such a device could be led from either an epiretinal position (an unlikely spot for refilling) or within the lens capsule as a hollow
ring configuration.
Recently, investigations have progressed evaluating the suprachoroidal space as
a zone that can accommodate devices. The essential description of this approach has
been presented by Peyman (2005) showing design concepts for locating devices
anchored suprachoroidally in the anterior-most location. But in addition, posterior
invasion of the suprachoroidal space can be accomplished by feeding specially
designed cannulas like the iTrack™ (iScience Interventional™) from an anterior
insertion point (Olsen et al. 2006; Yamamoto et al. 2007). Adaptations of a suprachoroidal cannula to an anterior reservoir have not yet been reported.
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Fig. 13.16 Capsule ring device prototype compared to a penny showing valve assembly with a
27-gauge cannula in the valve access port. Reprinted from Molokhia et al. (2010a, b). Copyright
2010, with permission from Elsevier
13.4.5 Lens Capsule Delivery
Traditionally, the lens capsule has not been thought of as a primary location for delivery
devices if other more accessible sites prove successful. The issue of repetitive surgical
replacement of devices in this location has historically been a roadblock. Therefore,
the concept of being able to refill a one-time implanted capsule device offers greater
attractiveness. That being said, the target population that can accommodate a device
in this anatomical location may be more limited to cataract patients who require therapy
for the IOL surgery itself or who have other concurrent ophthalmic disease. Despite
the possible caveats, studies continue to progress on a refillable capsule ring device
which has been reported on recently (Molokhia et
al. 2009, 2010a, b; Bishop et al.
2010). This device contains two small ports made of polyimide with a polydimethyl-
siloxane plug acting as a one-way valve (Fig. 13.16). Using noncoring needles, the
valve continued to seal and hold 40 mm pressure up to 30 punctures. Prepuncturing
the other valve allowed for release of pressure upon fill. The reservoir accommodates
up to 80 mL and studies evaluating Avastin® release through the semi-permeable
membrane demonstrated zero-order type rates over 2 months.
13.5 Conclusions
It is clear that significant development is still needed to advance various refillable
ophthalmic device designs to a commercial level. There appear to be only a limited
handful where theoretical designs have actually been reduced to practice, fabricated
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by an approvable manufacturing process, implanted in preclinical or clinical studies,
and evaluated sufficiently to show validated safety or efficacy. What can be said,
however, is that the sophistication of the designs and understanding of the necessary
engineering to achieve the above goals has advanced greatly. With better comprehension and utilization of available compatible biomaterials, evolution of microand nano-fabrication techniques and application of more minimally invasive design
elements, there is great hope for the future that more convenient therapeutic regimens will emerge as a result of new devices offering capabilities to conduct safer
refill procedures instead of surgical interventions.
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Chapter 14
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Targeted Drug Delivery to the Eye Enabled
by Microneedles
Samirkumar R. Patel, Henry F. Edelhauser, and Mark R. Prausnitz
Abstract Drug delivery targeted to specific tissues within the eye represents an
important advance over conventional methods of topical and injectable delivery that
have poor specificity for particular ocular tissues requiring therapy. This level of
intraocular targeting can be achieved using microneedles, which are solid and
hollow needles of micron dimensions. Microneedles can selectively target intraocular tissues by delivering drug formulations within the cornea, sclera, and suprachoroidal space in a minimally invasive manner. Intrastromal delivery in the cornea,
intrascleral delivery, and suprachoroidal delivery using microneedles have been
shown to deliver small molecules and macromolecules, as well as nanoparticles and
microparticles. Delivery strategies have employed a variety of microneedle designs
including coated microneedles that administer solid formulations and hollow
microneedles for injection of liquid formulations. The work reported in this chapter
highlights the capabilities of microneedles to provide targeted delivery to the eye in
a minimally invasive way through in vitro and in vivo animal studies.
14.1 Introduction
On the one hand, local drug delivery to the eye is facilitated by the fact that the eye
is one of the few organs that is visible and directly accessible from outside the
body. However, the direct exposure of the eye to the outside environment results in
M.R. Prausnitz (*)
School of Chemical and Biomolecular Engineering, Georgia Institute of Technology,
311 Ferst Drive, Atlanta, GA 30332-0100, USA
e-mail: prausnitz@gatech.edu
H.F. Edelhauser (
Emory University Eye Center, Emory University, 1365 Clifton Road NE, Atlanta,
GA 30332, USA
e-mail: ophthfe@emory.edu
U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye,
AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_14,
© American Association of Pharmaceutical Scientists, 2011
*)
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the eye possessing natural barriers that prevents drugs from effectively penetrating
the outer surface of the eye to reach their target intraocular sites. A few of these
barriers include the complex nature of the tear fluid, the reflex of blinking and
associated tear fluid drainage, clearance from lymphatic and blood flow within the
conjunctiva, and diffusion-limited transport across the epithelial barriers of the
cornea and conjunctiva (Koevary 2003; Urtti 2006). As an additional constraint,
any pharmacological treatment procedure should not hinder the natural function of
the eye. This primarily means that any drug formulation or method of delivering
that formulation should not hinder the ability of light to reach the retina. Barriers
and requirements such as these make effective pharmacological treatment of eye
diseases a challenging endeavor.
One of the most challenging aspects of drug delivery to the eye is to provide sustained and targeted delivery in a minimally invasive way. Many of the most prevalent
vision-threatening diseases, such as age-related macular degeneration (AMD), glaucoma, uveitis, and diabetic retinopathy, are chronic conditions that require continued
therapy to maintain or improve vision (Friedman et al. 2004). This is especially true
for diseases of the back of the eye, because access is more limited.
14.2 Current Methods of Drug Delivery to the Eye
Current focus of research and development of ophthalmic devices and formulations has been aimed at dealing with sustained or controlled drug delivery over
time. A number of commercial products have recently been marketed that can provide drug delivery for a period of months to years. Examples include Medidur®,
which delivers fluocinolone for 18 or 36 months to treat diabetic macular edema,
Retisert®, which also delivers fluocinolone for approximately 32 months to treat
uveitis, Vitrasert®, which delivers gancyclovir for up to 8 months to treat cytomegalovirus retinitis (Kuppermann
which delivers dexamethasone for 6 months to treat macular edema (Chang-Lin
et al. 2010). Many of these products are implants that are placed in the vitreous
and, in some cases, are attached to the globe so that the drug formulation is released
into the vitreous over time (Yasukawa and Ogura 2010). Implants such as Medidur®,
Vitrasert® and Retisert® are nonbiodegradable and have to be removed once the
drug has been fully released from the device (Kuppermann 2007). Ozurdex® is a
biodegradable implant that does not have to be removed at the end of treatment
(Kuno and Fujii 2010). These devices enable sustained or controlled delivery and
help maintain drug levels in the eye without frequent administration.
All the above-mentioned devices, however, suffer from poor targeting to the tissues that need treatment for the most common diseases of the back of the eye. As an
example, even though the complete pathophysiology of wet-AMD is still uncertain,
the affected tissues are the choroid and retina, not the vitreous (Janoria et al. 2007;
Bressler 2009). Yet, these devices are all aimed at delivering drugs directly to the
vitreous. Since the vitreous humor is a gel-like medium that fills a large volume of
the eye, the drugs that are released into the vitreous come into contact with other
2007) and Ozurdex® (formerly Posurdex®),
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