U.S. patent application number 15/442543 was filed with the patent office on 2017-06-15 for trans-sclera portal for delivery of therapeutic agents.
The applicant listed for this patent is ABBOTT MEDICAL OPTICS INC.. Invention is credited to Syed Hossainy, John J. Stankus, Mikael Trollsas.
Application Number | 20170165111 15/442543 |
Document ID | / |
Family ID | 50277372 |
Filed Date | 2017-06-15 |
United States Patent
Application |
20170165111 |
Kind Code |
A1 |
Stankus; John J. ; et
al. |
June 15, 2017 |
TRANS-SCLERA PORTAL FOR DELIVERY OF THERAPEUTIC AGENTS
Abstract
A portal through the sclera for delivery of an effective amount
of therapeutic agent to the back of the eye.
Inventors: |
Stankus; John J.; (Campbell,
CA) ; Trollsas; Mikael; (San Jose, CA) ;
Hossainy; Syed; (Hayward, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ABBOTT MEDICAL OPTICS INC. |
Santa Ana |
CA |
US |
|
|
Family ID: |
50277372 |
Appl. No.: |
15/442543 |
Filed: |
February 24, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13837892 |
Mar 15, 2013 |
9597227 |
|
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15442543 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 35/28 20130101;
A61M 2039/0276 20130101; A61K 39/3955 20130101; A61K 9/0004
20130101; A61K 9/0048 20130101; A61F 2210/0061 20130101; A61F
2250/0068 20130101; A61F 9/0017 20130101; A61K 9/06 20130101; A61K
9/0051 20130101; A61F 2250/0067 20130101; A61M 2210/0612 20130101;
A61K 31/573 20130101; A61F 9/0008 20130101; A61K 47/32 20130101;
A61K 31/337 20130101; A61K 47/34 20130101; A61K 31/5377 20130101;
G02B 1/043 20130101; A61K 31/498 20130101; A61K 31/5575 20130101;
A61K 31/4168 20130101 |
International
Class: |
A61F 9/00 20060101
A61F009/00; A61K 35/28 20060101 A61K035/28; A61K 31/5575 20060101
A61K031/5575; A61K 31/5377 20060101 A61K031/5377; G02B 1/04
20060101 G02B001/04; A61K 31/573 20060101 A61K031/573; A61K 31/337
20060101 A61K031/337; A61K 39/395 20060101 A61K039/395; A61K 31/498
20060101 A61K031/498; A61K 9/06 20060101 A61K009/06; A61K 9/00
20060101 A61K009/00; A61K 31/4168 20060101 A61K031/4168 |
Claims
1-10. (canceled)
11. An implantable shunt for delivery of an ophthalmic therapeutic
agent into an eye, comprising a swell loadable polymeric ocular
insert with a micron scale tab that, when inserted into the eye, is
configured to extend through the sclera as an external mass
transport channel.
12. The shunt of claim 11, wherein the polymer is a hydrogel.
13. The shunt of claim 11, wherein the therapeutic agent includes a
drug and/or stem cells.
14. The shunt of claim 11, wherein the hydrogel is impregnated with
therapeutic agent-carrying nanoparticles.
15. The shunt of claim 11, wherein the tab acts as a wick to
deliver the agent from the insert into the intravitreal space.
16. The shunt of claim 11, wherein the insert is reloadable with a
fresh aqueous solution containing the therapeutic agent.
17. The shunt of claim 11, wherein the insert is a two-ended strand
with a diameter between about 100 nanometers and about 2
micrometers, wherein one end of the strand provides a wicking
window into the sclera.
18. The shunt of claim 11, wherein at least a portion of the insert
is formed of at least one of PEG, Poloxamer F127, functionalized
PEG, PVA, HEMA, silicon gel, PVP, GAG, PAA, CMC, CPMC, HPMA
hyaluronic acid, sodium alginate, and PolyMPC.
19. The shunt of claim 11, wherein the insert is operable to
release the therapeutic agent when activated by a stimulus applied
to a sensitivity of the insert.
20. The shunt of claim 19, wherein the insert is sensitive to at
least one of electroactivity, pH level, temperature, pressure,
light, and enzyme catalysis.
21. A system for delivery of an effective amount of a therapeutic
agent to the back of an eye, comprising: a swell loadable polymeric
ocular insert with a micron scale tab that, when inserted into the
eye, extends through the sclera as an external mass transport
channel and presents a wicking window into the sclera; and a
drug-delivering contact lens that covers the insert when worn, the
contact lens having a lens body formed of a block copolymer with a
periodic nanostructure of therapeutic agent-miscible domains
interspersed among a hydrogel matrix and impregnated with a
therapeutic agent.
22-46. (canceled)
Description
FIELD OF THE INVENTION
[0001] The instant disclosure relates to the delivery of
pharmaceuticals and the like to the back of the eye and, more
particularly, to a portal through the sclera for delivery of an
effective amount of therapeutic agent to the back of the eye.
BACKGROUND
[0002] There are three primary structures within the human eye that
are essential to vision and subject to age-related damage: the
cornea, lens and retina. The retina is a multi-layered sensory
tissue that lines the back of the eye. It contains millions of
photoreceptors that capture light rays and convert them into
electrical impulses. These impulses travel along the optic nerve to
the brain where they are turned into images. There are two types of
photoreceptors in the retina: rods and cones. The retina contains
approximately 6 million cones. The cones are contained in the
macula, the portion of the retina responsible for central vision.
They are most densely packed within the fovea, the very center
portion of the macula. Cones function best in bright light and
allow us to appreciate color. There are approximately 125 million
rods. They are spread throughout the peripheral retina and function
best in dim lighting. The rods are responsible for peripheral and
night vision. The retina is essential for vision and is easily
damaged by prolonged unprotected exposure to visible and near
visible light. Light-induced retinal pathologies include cystoid
macular oedema, solar retinopathy, ocular melanomas and age-related
macular degeneration (ARMD). Light-induced retinal damage is
classified as structural, thermal or photochemical and is largely
determined by the exposure time, power level and wavelength of
light.
[0003] In healthy adults the retina is generally protected from the
most severe forms of light-induced damage by the outer eye
structures, including the cornea and crystalline lens. The cornea
is a transparent proteinaceous ocular tissue located in front of
the iris and is the only transparent eye structure exposed directly
to the external environment. The cornea is essential for protecting
the delicate internal structures from damage and facilitates the
transmission of light through the aqueous humor to the crystalline
lens.
[0004] The crystalline lens is an accommodating biological lens
lying in back of the cornea, anterior chamber filled with aqueous
humor, and the iris. Between the lens and the retina is the
vitreous chamber filled with vitreous humor. The optical pathway
through the eye acts to refract the light entering the eye, with
the cornea providing most of the optical power, and the
accommodating lens facilitating the convergence of both far and
near images onto the retina. Ocular elements in the optical pathway
absorb various wavelengths of light, while permitting others to
pass through. In the normal human eye, only wavelengths of light
between about 400 nm and 1,400 nm can pass through the refracting
elements of the eye to the retina. However, high transmittance
levels of blue and violet light (wavelengths from about 390 nm to
about 500 nm) has been linked to conditions such as retinal damage,
macular degeneration, retinitis pigmentosa, and night
blindness.
[0005] Intraocular pressure (IOP) in the eye can significantly
affect the elements of the ocular pathway, and is maintained by the
formation and drainage of aqueous humor, a clear, colorless fluid
that fills the anterior and posterior chambers of the eye. Aqueous
humor normally flows from the anterior chamber of the eye out
through an aqueous outflow channel at a rate of 2 to 3 microliters
per minute.
[0006] Glaucoma, for example, is a progressive disease of the eye
characterized by a gradual loss of nerve axons at the optic nerve
head. In many cases, the damage to the optic nerve head is due to
increased intraocular pressure. This increase in pressure is most
commonly caused by stenosis or blockage of the aqueous outflow
channel, resulting in excessive buildup of aqueous fluid within the
eye. Other causes include increase in venous pressure outside the
eye which is reflected back through the aqueous drainage channels
and increased production of aqueous humor. In a "normal" eye, IOP
ranges from 8 to 21 mm mercury. In an eye with glaucoma, IOP can
range between normal pressures up to as much as 50 mm mercury. This
increase in IOP produces gradual and permanent loss of vision in
the afflicted eye.
[0007] Existing corrective methods for the treatment of glaucoma
include drugs, surgery, and implants. In many cases therapy can
require delivery of various therapeutic agents to various portions
of the eye over a lengthy period of time, typically by injection of
the agent directly into the eye.
[0008] There are numerous examples of surgical procedures that have
been developed in an effort to treat victims of glaucoma. An
iridectomy, removal of a portion of the iris, is often used in
angle-closure glaucoma wherein there is an occlusion of the
trabecular meshwork by iris contact. Removal of a piece of the iris
then gives the aqueous humor free passage from the posterior to the
anterior chambers in the eye. A trabeculotomy, opening the inner
wall of Schlemm's canal, is often performed in cases of
developmental or juvenile glaucoma so as to increase the outflow of
the aqueous humor, thereby decreasing IOP. In adults, a
trabeculectomy shunts fluid through a trapdoor flap in the eye that
performs a valve-like function for the first few weeks after
surgery.
[0009] While often successful, these surgical techniques possess
inherent risks associated with invasive surgery on an already
afflicted or compromised eye. Furthermore, the tissue of the eye
can scar over this small area and the eye reverts to the
pre-operative condition, thereby necessitating the need for further
treatment.
[0010] Ocular implants are sometimes used in long-term glaucoma
treatment. One early implant is called the Molteno Implant, after
A. C. B. Molteno. The implant is a small circular plate with a
rigid translimbal drainage tube attached. The plate was 8.5 mm in
diameter and formed a surface area of about 100 mm.sup.2. This
implant is sutured to the sclera in the anterior segment of the eye
near the limbus and the drainage tube is inserted into the anterior
chamber of the eye. Once implanted, the body forms scar tissue
around the plate. Fluid causes the tissue above the plate to lift
and form a bleb into which aqueous humor flows from the anterior
chamber via the drainage tube. A bleb is a fluid filled space
surrounded by scar tissue, somewhat akin to a blister. The fluid
within the bleb then flows through the scar tissue, at a rate which
can regulate IOP.
[0011] A newer implant has been redesigned for insertion into the
posterior segment of the eye to avoid problems with early designs.
This implant is referred to as a long tube Molteno implant. The
implant comprises a flexible drainage tube connected to one or more
rigid plate reservoirs. The plates are shaped to conform to the
curvature of the eye. The reservoir plate is placed under Tenon's
capsule in the posterior segment of the eye and sutured to the
sclera. The drainage tube is implanted into the anterior chamber
through a scleral incision. However, the long tube Molteno implant
is still disadvantageous, as the plates are formed of a rigid
plastic which makes insertion beneath the eye tissue difficult and
time-consuming.
[0012] After such an implant is attached, IOP tends to fall as
aqueous fluid flows immediately through the drainage tube. However,
an open drainage tube may release too much of the fluid too fast,
which is detrimental to the eye. It is not until 2-6 weeks later
that the bleb forms around the plate to sufficiently regulate the
fluid flow. Some prior devices have therefore incorporated valves
in the fluid drain path designed to function for a limited time
until the bleb forms. However, such valved devices sometimes clog
later, requiring another surgery.
[0013] More recently introduced implants feature a flexible plate
that attaches to the sclera, and a drainage tube positioned for
insertion into the anterior chamber of the eye. A bleb forms around
the plate and fluid drains into and out of the bleb to regulate
IOP. This type of shunt is called a Baerveldt shunt. One such
device has an open tube with no flow restricting elements.
Temporary sutures are used to restrict fluid flow for a
predetermined period after which the bleb forms and fluid drainage
is properly regulated. The temporary sutures are either
biodegradable or removed in a separate procedure. This method works
well, but the timing of suture dissolution is inexact and may
operate improperly, and a second procedure undesirable.
[0014] Some shunts also include fenestrations through the plate to
promote fibrous adhesion, which may reduce bleb height. Though a
bleb is thought to have a beneficial function in regulating aqueous
humor diffusion, too large of a bleb may cause the patient some
pain or may be aesthetically unacceptable. Some doctors even prefer
to use anti-proliferatives such as mitomycin C or 5-FU at the time
of surgery to prevent formation of the fibrous bleb. Another
potential complication is endophthalmitis, an inflammation of the
internal tissue of the eye. This complication may occur in any
intraocular surgery, with possible loss of vision and even of the
eye itself. Infectious etiology is the most common cause, and
various bacteria and fungi have been isolated as the cause of the
endophthalmitis. The risk of infection is more pronounced early in
a shunt implant procedure, when a passage to the interior of the
eye is created and fluid flows therethrough. Later, the bleb acts
as a filter to prevent microorganisms such as bacteria from
entering the eye.
[0015] Some eye diseases can be treated with pharmaceuticals.
However, where the diseases primarily affect the back of the eye,
it can be difficult to administer and achieve effective levels of
therapeutic agents in that portion of the eye. Such diseases are
typically treated by direct injection of biologically active
pharmaceutical agents, such as anti-inflammatory steroids and
target-specific antibodies. Treatment may entail repeated
injections that can put the patient at risk of complications
involving conditions such as infection, endophthalmitis, high
intraocular pressure (IOP), glaucoma, cataract, retinal detachment
and bleeding, and lack of wound-healing. A new approach is needed
that can deliver pharmaceuticals and the like to the back of the
eye while mitigating the adverse effects that attend the prior art.
However, any solutions requiring patient compliance or repeated
injection run the risk of failure due to noncompliance of the
patient.
SUMMARY OF THE DISCLOSURE
[0016] An apparatus and method for delivery of an effective amount
of therapeutic agent to the back of the eye via a portal through
the sclera is disclosed. In an embodiment of the present invention,
the portal comprises an implantable shunt for repeated injection of
ophthalmic pharmaceutical treatments into an eye. The shunt and
associated method may include a partition wall or septum configured
to provide separation between the intraocular and intraorbital
spaces of the eye. The wall may be re-sealable or self-healing
after each injection.
[0017] The implantable shunt and associated method may also
comprise a swell loadable polymeric ocular insert with a micron
scale tab that, when inserted into the eye, may extend through the
sclera into the intravitreal space as a transport channel. Such a
tab may wick a therapeutic agent from the insert into the
intravitreal space. It is to be understood that both the foregoing
general description and the following detailed description are
exemplary and explanatory and are intended to provide further
explanation of the invention as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The accompanying drawings are included to provide a further
understanding of the invention, and are incorporated in and
constitute a part of this specification. The drawings illustrate
disclosed embodiments and/or aspects and, together with the
description, serve to explain the principles of the invention, the
scope of which is determined by the claims.
[0019] In the drawings:
[0020] FIG. 1A illustrates a human eye in cross section.
[0021] FIG. 1B illustrates in greater detail the portion of the eye
of FIG. 1A enclosed in the dotted box.
[0022] FIG. 2A is an exemplary embodiment of a shunt in accordance
with the disclosure.
[0023] FIG. 2B illustrates in greater detail the front portion of
FIG. 2A.
[0024] FIGS. 2C and 2D illustrate various exemplary embodiments of
shunts in accordance with the disclosure.
[0025] FIGS. 3A, 3B, and 3C illustrate other disclosed exemplary
embodiments.
[0026] FIG. 4A illustrates an agent-loadable contact lens used in
conjunction with a trans-sclera portal.
[0027] FIG. 4B is a micrograph of a portion of the contact lens of
FIG. 4A.
DETAILED DESCRIPTION
[0028] The figures and descriptions provided herein may be
simplified to illustrate aspects of the described embodiments that
are relevant for a clear understanding of the herein disclosed
processes, machines, manufactures, and/or compositions of matter,
while eliminating for the purpose of clarity other aspects that may
be found in typical optical and surgical devices, systems, and
methods. Those of ordinary skill may recognize that other elements
and/or steps may be desirable or necessary to implement the
devices, systems, and methods described herein. Because such
elements and steps are well known in the art, and because they do
not facilitate a better understanding of the disclosed embodiments,
a discussion of such elements and steps may not be provided herein.
However, the present disclosure is deemed to inherently include all
such elements, variations, and modifications to the described
aspects that would be known to those of ordinary skill in the
pertinent art.
[0029] FIG. 1A illustrates a human eye in cross section with the
eye in an upward orientation relative to the page. FIG. 1B
illustrates in greater detail the portion of the eye of FIG. 1A
enclosed in the dotted box. The relevant structures of the eye are
described briefly to provide background and context for anatomical
terms incorporated herein. A number of anatomical details have been
omitted for clarity.
[0030] Referring to FIG. 1A, the sclera is a tough outer membrane
of the eye that covers most of the eye except the portion in the
front of the eye, which is covered by the cornea. The sclera forms
the posterior five-sixths or so of the connective tissue coat of
the eyeball. It maintains the shape of the eyeball, and is
resistant to internal and external forces. It also provides
attachments for the extraocular muscle insertions. The choroid is a
vascular layer lying adjacent to the inside surface of the sclera.
It contains connective tissue to the sclera on the outside, and to
the retina on the inside. The choroid provides oxygen and
nourishment to the outer layers of the retina. The retina is a
light-sensitive layer of tissue, adjacent to the choroid and lining
the inner surface of the globe of the eye. The optics of the eye
create an image of the field of vision on the retina, which
initiates processes that ultimately trigger nerve impulses. The
impulses are conveyed by the optic nerve to the visual centers of
the brain.
[0031] The cornea is the transparent anterior (front) part of the
eye that covers the iris, pupil, and anterior chamber. Light enters
the eye through the cornea, proceeds through the aqueous humor in
the anterior chamber, through the pupil, lens, and vitreous humor,
and on to the retina. The cornea, lens, and humors refract the
light to form the image on the retina, with the cornea accounting
for approximately two-thirds of the eye's total optical power. The
pupil is defined by an aperture in the iris, which is located in
front of the lens.
[0032] The cornea merges into the sclera at a juncture called the
limbus. The ciliary muscle and ciliary processes form the ciliary
body, located near the limbus on the inside surface of the eye.
Aqueous humor is secreted by the ciliary processes, and passes
through the pupil into the anterior chamber, which is defined by
the space between the iris and the cornea. In a healthy eye, the
aqueous humor is absorbed through the trabecular meshwork, then
proceeds through Schlemm's canal and on through veins which merge
into venous blood circulation. Intraocular pressure (IOP) is
maintained in the eye largely by the balance of secretion,
absorption, and outflow of the aqueous humor through the mechanism
described above.
[0033] The vitreous humor (or humour) is a clear gel that fills the
space between the lens and the retina of the eye, called the
vitreous chamber. Unlike the aqueous humor which is dynamic and
continuously replenished, the vitreous humor is static and is not
replenished. One common abnormal eye condition, glaucoma, is a
disease in which the optic nerve at the back of the eye is damaged
in a characteristic manner. Abnormally high fluid pressure in the
aqueous humor in the anterior chamber is a significant risk factor
for developing glaucoma. If left untreated, glaucoma can lead to
permanent damage of the optic nerve and resultant visual field
loss, which can progress to blindness.
[0034] Another condition, Macular Degeneration (MD), which may be
Age-related (AMD), results in a loss of vision in the center of the
visual field due to damage to the central region of the retina,
called the macula. Specifically, the macula is an oval-shaped spot
near the center of the retina at the back of the eye, with a
diameter of about 1.5 mm. Toward the center of the macula is the
fovea, a small pit that contains the largest concentration of cone
cells in the eye and is thus responsible for central, high
resolution vision. Consequently, degeneration of the macula can
result in the loss of abilities that require sharp central vision,
such as reading.
[0035] Treatment for these and other conditions often includes the
introduction of therapeutically effective agents, including but not
limited to drugs, into the vitreous chamber of the eye. In the
prior art, the most common way to introduce such agents is by
injecting them directly into the eye, and in many cases the course
of treatment requires repeated injections. This can put the patient
at risk of complications such as infection, endophthalmitis, high
intraocular pressure, glaucoma, cataract, retinal detachment and
bleeding, and poor wound-healing. Recently, the use of ocular
shunts is becoming more and more common. Most commonly, the shunt
may be implanted under a flap cut into the sclera, with a flow tube
inserted into the anterior chamber of the eye. This may allow the
aqueous humor to drain, preventing intraocular pressure (IOP) from
rising too high. The humor typically drains into a plate that is
implanted underneath the flap in the sclera to form a blister-like
chamber called a bleb. A common and potentially catastrophic early
postoperative complication is hypotony, i.e., excessive leakage of
aqueous humor resulting in low intraocular pressure. Extreme
hypotony can cause a devastating deflation of the eyeball. Thus,
common methods of treatment are fraught with challenges. The herein
disclosed apparatus, systems, and methods can be used to address
some of those challenges.
[0036] Referring now to FIG. 2A, a shunt 200 may be implanted
through the sclera of the eye and on into the vitreal chamber. When
implanted, the shunt has a proximal end 210 protruding through the
surface of the sclera, and a distal end 220 within the vitreal
chamber. Preferably, the shunt may be inserted into the eye in a
manner to position the distal end near to the back of the eye that
is being treated. The shunt may provide access to the interior of
the eye for a plurality of applications of pharmaceutical agents to
the back of the eye while mitigating potential complications from
repeated intraocular injections. In an embodiment of the present
invention, at least a portion of the outer and/or inner surface(s)
of the shunt, particularly where it passes through the sclera, may
be coated with one or more agents, such as silver ions,
anti-proliferative drug/polymer coatings, and/or antibiotics, to
mitigate the possibility of trans-scleral infection and/or
inflammation.
[0037] In alternative arrangements, the distal end of a shunt tube
may be introduced into the anterior chamber instead of into the
vitreal chamber. If so, miotic agents such as pilocarpine may also
be delivered with the shunt to increase the outflow of aqueous
humor to alleviate high IOP.
[0038] As shown in FIG. 2B, in an embodiment of the present
invention the shunt may comprise a hydrogel portion 230 that
contains one or more pharmaceutical agents to be introduced into
the eye. The hydrogel portion may be formed into an appliance that
is placed at the surface of the sclera in the intraorbital space,
or alternatively, under a flap that is surgically cut into the
sclera. The appliance may be formed with one or more edges or tabs
that contain holes by which it can be sutured into place.
Preferably, the hydrogel may be formed of a non-degradable
biomedical material having well accepted biocompatibility. As such,
there are a plurality of acceptable hydrogel and non-hydrogel
materials for use in the instant invention.
[0039] By way of non-limiting example, hydrogels having varying
degrees of equilibrium water uptake (such as in a range of 5% to
500% w/w) may be synthesized by reacting combinations of monomers
and macromers as discussed immediately below and by way of
non-limiting example only. Monomers leading to high water content
hydrogels may include acrylic monomers, hydroxyethylmethacrylate
(HEMA), vinylalcohol, Methacryloyl phosphorylcholine (MPC),
Acrylamide (Am), di-methyl aminoethyl methacrylate (DMAEMA), and
acrylic acid (AA). Macromers leading to high water content
hydrogels may include sodium polyacrylate, polyurethane, PEG,
hydrophilic segmented polyurethane urea, polyether block amide,
hydrophilic polyamide, agarose, carboxymethyl cellulose, alginate,
chitosan, hyaluronan, and Glycosaminoglycan (GAG) such as heparan
sulfate.
[0040] Correspondingly, and also by way of non-limiting example
only, monomers leading to minimal to low water content polymeric
structures may include methyl methacrylate monomer (MMA) and
perfluorinated mononers. Macromers leading to minimal to low water
content polymeric structures may include polyurethane, polyurethane
urea, polypropylene copolymers, polyether block amide, polyamide,
thiol-ene polymers, and Diels-Alder polymers.
[0041] In another embodiment illustrated in FIG. 2C, the shunt may
provide a safe portal for a plurality of injections, and may not
extend far past either the interior or exterior surface of the eye
wall. As shown, the shunt may include a self-healing septum 240
that may act as a partition wall to provide physical separation
between the intraocular and intraorbital spaces, while maintaining
a safe conduit for repeated needle insertion. The septum may be
disposed at any convenient location at or near the sclera. In
certain embodiments, the outer and/or inner surface(s) of the shunt
may be coated with one or more agents, such as silver ions and/or
antibiotics, to mitigate the possibility of trans-scleral
infection. The septum is preferably constructed of a silicone
elastomer, although other materials may be used. In addition, the
shunt may be formed of or include polymers or polymer composites
with added healing agents, catalysts, or reactive agents that may
provide enhanced mechanical performance and resistance to
degradation and oxidation. Healing of polymer materials can also be
induced by applying heat, ultraviolet light (UV), or an electric
field to the shunt. For example, heating may encourage further
polymerization to repair a damaged shunt and/or UV light may
initiate free radical polymerization to repair a damaged shunt.
Alternatively or in addition, silicone elastomers may be
incorporated with polymerization initiators that yield silanolate
end groups capable of living type reactions via heating.
[0042] Unwanted increase in intraocular pressure (IOP) may arise
due to repeated intraocular injections. This can be treated or
prevented with one or more of prostaglandin analogs, beta blockers,
alpha agonists, and carbonic anhydrase inhibitors.
Anti-inflammatory and immunosuppressant agents such as
dexamethasone or other corticosteroids or corticosteroid
derivatives, and mammalian Target Of Rapamycin (mTOR) inhibitors
may serve to treat multiple eye diseases such as uveitis. Further,
antibiotics such as besifloxacin, ciprofloxacin, moxifloxacin,
azithromycin, and the like may also be included in treatments to
prevent microbiologic growth due to repeated intraocular
injections.
[0043] In an alternative embodiment illustrated in FIG. 2D, the
shunt 250 may be re-sealed with a biocompatible polymer plug 260
after each injection. The plug may be impregnated with one or more
timed-release therapeutic agents before being inserted within the
shunt tube. Timed-release therapeutic agents may include, for
example, prostaglandin analogs (e.g. Xalatan, Lumigan, Travatan Z),
Beta blockers (e.g. timolol), alpha agonists (e.g. Alphagan P,
iopidine), carbonic anhydrase inhibitors, or combinations of these.
Corticosteroids, dexamethasone, mTOR inhibitors, paclitaxel, Eylea
(a Vascular Endothelial Growth Factor (VEGF) receptor), anti-VEGF
antibodies, Avastin, and Lucentis can also be applied. In
embodiments, the plug may be used in conjunction with a septum of
self healing polymer biomaterial located in the interior of the
shunt. The plug may include a structure 270 that fits into a
homologous structure in the shunt 250, which together serve to
secure the plug within the shunt and prevent its inadvertent
removal.
[0044] In certain embodiments, at least a portion of the shunt may
be formed by extrusion from a thermoplastic polymer in a relative
biocompatible solvent such as N-methylpyrrolidone or a
solvent/water based mixture. One method of installing a shunt is to
use a small gauge needle to create a track through the sclera into
which the shunt is inserted. Alternatively, a laser may be used to
create the track.
[0045] Further, in certain embodiments, the shunt may include an
element built into the shunt's internal lumen to prevent
over-reaching of the needle that injects the therapeutic agent,
which could potentially damage ocular components such as the lens
or the retina. One such element is an internal lumen of gradually
decreasing diameter, ending in a diameter that is a smaller gauge
than that of a select ophthalmic injection needle, or of a range of
commonly used needles. Alternatively, a shunt lumen may be designed
to be used in conjunction with a homologous or otherwise compatibly
designed injection needle, which together implement a stopper
element to prevent accidental damage to internal eye
structures.
[0046] Additionally, in an embodiment, a coating of antibiotic drug
may be applied to the shunt by spray coating, direct fluid
application, and/or dip coating. The coating may also be ablated on
the outer surface of the shunt, or on both outer and internal
surfaces. The coating may include extracellular matrix materials
such as biocompatible polymers or hydrogels, to provide improved
adhesion and stability of the shunt at the trans-scleral implant
site. Such materials may be naturally derived, or may be synthetic.
For example, naturally derived materials may include alginate,
collagen, and the like. Synthetic materials may include
poly(vinylidene fluoride-co-hexafluoropropene) (PVDF-HFP), other
fluorinated polymers, crosslinked polyethylene glycol,
polylactide-co-glycolide, and the like.
[0047] In embodiments, sustained therapeutic agent delivery may be
achieved through use of a plug impregnated with one or more time
release agents. For relatively rapid release (e.g., in the range of
a short portion of one day to several days) a water soluble
excipient, such as polyvinylpyrrolidone (PVP) or a cellulosic, may
be used to form the plug. For sustained release over a period of
time lasting from a few days to several months, such as for a small
molecule drug, the plug may be formed from or using hydrophobic
polymers. This type of plug can include materials such as
poly-DL-lactide (PDLLA),
polyvinylidenefluoride-co-hexafluoropropylene (PVDF-HFP),
polylactic-co-glycolic acid (PLGA), PCL,
poly(ethylene-glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene
glycol (PEG-PLGA PEG), and PLGA-PEGs may be utilized as the matrix
polymer. For larger molecular weight biologics, a hydrogel type
matrix such as crosslinked PVP, polyethylene glycol (PEG), or
biopolymers may be utilized. In embodiments, the hydrogel may be
delivered as a liquid, to then gel in situ within the shunt. The
shunt may also be formed to provide a sustained outflow of drug
solution over time.
[0048] In embodiments, the shunt can be designed to be osmotic and
swell when hydrated, and to release the pharmaceutical agent in a
sustained manner over time. A pressure sensitive design may also be
used to allow for fluid outflow, for example, in the case when
intraocular pressure is high, to thereby alleviate high IOP.
[0049] The shunt may also incorporate a plurality of flow-through
conduits, each conduit serving its own distinct purpose. For
example, a dual conduit configuration may be used, wherein one
conduit is adapted to receive repeated injections using fine gauge
needles, while the other conduit allows for fluid outflow as
necessary during injection, and/or to alleviate subsequent high IOP
complications. Other numbers and combinations of conduits may be
incorporated into a shunt to provide any desired combination of
shunt capabilities, which may be based on, by way of non-limiting
example, drug particle size, required or desired volume, or the
like.
[0050] Referring now to FIG. 3A, another form of re-loadable,
trans-scleral insert is illustrated for sustained release of
anti-angiogenic drug in the posterior segment of the eye. Here, a
swell loadable hydrogel insert 300 may have a micron scale tab 310
(shown much exaggerated for visibility) which juts out of the
sclera as an external mass transport channel when the shunt is
implanted. A therapeutic agent may be impregnated into the
hydrogel. The agent may be or include therapeutic cells, such as
stem cells. Agent-loaded nanoparticles (Np) can also, or
alternatively, be impregnated into the gel.
[0051] As shown in FIG. 3B, the shunt may be used as, or in
conjunction with, a drug depot 320 for sustained drug release. The
depot 320 may be disposed in the vitreous chamber as shown, or can
be disposed on the surface of the sclera or surgically placed under
a scleral flap. Therapeutic agents that can be loaded into the
depot and released over time can include paclitaxel, anti-VEGF
antibodies, and other anti-VEGF biologics for the treatment of
retinal eye diseases such as wet age-related macular degeneration,
diabetic retinopathy, and macular edema, among others. Therapeutic
agents may also be delivered to treat conditions that might
otherwise arise after tube-shunt surgery, such as to reduce scar
tissue and/or to prevent infection.
[0052] In an exemplary operation, at the end of a round of
therapeutic agent delivery near the exhaustion of the agent
reservoir, a fresh agent solution may be added to the reservoir,
for example, by the application of eyedrops or an eyewash. The
agent may wick through the hydrogel tab, through the trans-sclearal
pathway, and on into the intravitreal space, where it may be
conveyed to the vitreous humor.
[0053] In an exemplary embodiment, the hydrogel insert may be or
comprise a nanotube or other strand with an external diameter in
the range of about 100 nm to about 2 .mu.m. Alternatively, the
implant may be or comprise a thin film having a thickness in the
range of about 500 nm to about 2 .mu.m. In either case, the
proximal end of the strand or film (hereinafter collectively
"strand") creates a wicking window through the sclera, and the
distal end can deliver the therapeutic agent to the vitreous
humor.
[0054] Alternatively, as shown in FIG. 3C, a swell loadable
hydrogel strand 330 may be inserted between the choroid and the
sclera, again with a micron scale tab 310 jutting out of the sclera
at the proximal end as an external mass transport channel. In such
an embodiment, the distal end of the strand 340 may be placed near
to the area being treated. Thereby, the choroid and sclera may hold
the insert in place to provide a delivery pathway directly to the
area being treated. The hydrogel insert may open into the vitreous
space through a trans choroidal access, as shown. Alternatively,
the insert may not open into the vitreous space. Instead, the agent
can diffuse into the choroidal blood vasculature to treat the back
of the eye.
[0055] In short, the insert is preferably outside the visual field
upon implantation, and should remain so. Accordingly, the insert
may be implanted anywhere about the posterior segment of the eye,
and may be sized and shaped so as not to provide the possibility of
impairment of the visual field. Moreover, in the event of failure
of the insert or entry into or affect on the visual field by the
insert, the insert may be removed.
[0056] A hydrogel for use with the present invention may be made of
or include PEG, PVP, GAG, PAA, CMC, CPMC, HPMA hyaluronic acid,
Poloxamer F127, functionalized PEG, PVA, HEMA, silicon gels, sodium
alginate, PolyMPC, etc., and/or a combination of these. At the end
of a round of therapeutic agent delivery and near the exhaustion of
the agent supply stored in the insert or in a reservoir coupled
thereto, a fresh agent solution may be simply added to the strand,
for example, using eyedrops, an eyewash, or other method of
recharging the storage medium. The agent may wick through the
hydrogel tab and through the trans-sclera tunnel into the swell
loadable insert, and/or to the distal end of the strand.
[0057] In certain embodiments, a hydrogel or polymeric insert may
be reversible, and/or may be triggered to release its therapeutic
agent on demand via appropriate stimuli. For example, the stimuli
may be electroactive (e.g. polyaniline); pH sensitive (e.g.,
administration of slightly acidic eye drops), or temperature
sensitive (e.g., administration of cold drops to eye). The stimuli
may also be based on light sensitivity (e.g., administration of
ultraviolet light, or well-aimed laser light directed at the
insert), or enzyme sensitivity (e.g., administration of an enzyme
to increase insert degradation and accelerate drug release).
Further, an immunosuppressant and/or anti-proliferative agent such
as Zotarolimus may be used to coat the shunt to mitigate certain
conditions that may arise from the use of the shunt. One or more
other agents may also be used in conjunction with Zotarolimus. For
example, Zotarolimus plusan anti-tumor necrosis factor (anti-TNF)
can be used.
[0058] In yet other embodiments, drug conjugation into macromers
for sustained release via lability-controlled dissociation of the
active agent from the macromeric prodrug may be utilized. Here, the
drug may be conjugated, for example, into Hyaluronic acid, GAG
through ester bond or anhydride bonds, or other chemically labile
bonds. In such an embodiment, a macromeric prodrug may be injected
intravitreally. The labile bong may release the drug over time.
Alternatively, the drug may be conjugated into Vitrosin (collagen
in IVT) and injected intravitreally. The drug can be conjugated
into these polymers as a pendant group, or in endgroups, for
example, PEG, PVP, GAG, PAA, CMC, CPMC, HPMA hyaluronic acid,
PolyMPC, etc/, or a combination of these. The drug can also be
conjugated into dynamers and injected Intravitreally. In this way,
drug release may depend on H-bonding strength.
[0059] In certain embodiments, the drug may be conjugated into
Hyaluronic acid, GAG through ester bond or anhydride bonds or other
chemically labile bonds. The macromeric prodrug may be injected
intravitreally, and the labile bong may release the drug over time.
Alternatively the drug may be conjugated into Vitrosin (collagen in
IVT) and injected intravitreally. The drug may be conjugated into
these polymer as a pendant group or endgroups, such as PEG, PVP,
GAG, PAA, CMC, CPMC, HPMA hyaluronic acid, PolyMPC etc and/or a
combination of these.
[0060] In embodiments, conjugated bonds may release a drug in
response to exposure to fluorescent light. Thereby, drug delivery
may be controlled on demand. The macromeric prodrug may again be
delivered intravitreally, and the labile bong may release the drug
on demand using a Fluorescent trigger. Alternatively the drug may
be conjugated into Vitrosin (collagen in IVT), and/or into
dynamers, and delivered intravitreally. Drug release may still
depend on H-bonding strength and use of a fluorescent trigger.
[0061] In embodiments, conjugated bonds may be or include physical
bonds such as H-bonding, electrostatic interaction, Hydrophobic
interaction, Au-S bonds, or the like. This may enable sustained
release drug delivery without covalent chemical bond formation. The
physical complexation of an active agent with an excipient may not
change any chemical bonds in the drug structure, and hence may not
be considered a new entity. The drug can be complexed with
Hyaluronic acid and/or other GAG and then injected Intravitreally.
Either small molecular weight (MW) drugs or biologics, or both, can
be included in this configuaration. In addition to complexation
with polymers already mentioned, oligomeric and monomeric entities
may also be used for physical complexation with the drug, such as
Glycerol, Mannitol, Mannose-6-phosphate, and the like.
[0062] In an embodiment of the present invention a drug coated
angioplasty balloon (not shown) may be used to treat retinal
diseases such as AMD, macular edema, and diabetic retinopathy. A
drug may be conjugated into Hyaaluronic acid through an ester bond
or anhydride bonds. The macromeric prodrug may be delivered
intravitreally as described hereinbefore, and the labile bong may
release the drug over time. Alternatively, a drug may be conjugated
into Vitrosin (collagen in IVT) and delivered intravitreally. In
embodiments, a drug may be conjugated into such polymers as a
pendant group or as end-groups, for example, PEG, PVP, GAG, PAA,
CMC, CPMC, HPMA hyaluronic acid, PolyMPC, or the like, and/or a
combination of these. A drug may also be conjugated into dynamers
and delivered intravitreally, and drug release may depend on
H-bonding strength as before. Anti-angiogenic and neuroprotective
drugs can include, for example, ABT-869 (multi-targeted kinase
inhibitor), Aurora Kinase inhibitor (ABT-348 and 993), JAK Kinase
(ABT-317), TSP-1 (ABT-898, 567), 81 P1 (ABT-413), Zotarolimus,
Bcl-2 (ABT-199), Bcl-2 BU, Cal pain, RGMa antibody, DLL-4 Ab, PGDF
antibodies, pKC small molecule inhibitors, DVD-Ig molecules
combining VEGF, DLL-4, PGDF, EGFR Ab, and RGMa binding domains,
and/or combinations of these.
[0063] In certain embodiments, a drug may be conjugated into
hyaaluronic acid, but through bonds that may release drug in
response to a fluorescent light trigger to enable drug delivery on
demand. A macromeric prodrug, for example, may be delivered
intravitreally, and the labile bong may release the drug on demand
by use of the fluorescent trigger. Alternatively, a drug may be
conjugated into Vitrosin (collagen in IVT) and delivered
intravitreally and/or conjugated into the following polymers as a
pendant group or as end-groups: PEG, PVP, GAG, PAA, CMC, CPMC, HPMA
hyaluronic acid, PolyMPC, etc., and/or a combination of these. The
drug may also be conjugated into dynamers and delivered
intravitreally. Once again, drug release may depend on the
H-bonding strength and fluorescent trigger.
[0064] In embodiments, sustained release of an anti-angiogenic drug
may be performed in the posterior segment of the eye using an
implanted device that may not be particulate. A micron-size
absorbable polymeric monolithic implant (such as a ribbon, mat,
stent, disc, cylinder, etc.) may be loaded with an anti-angiogenic
drug. The implant surface may be coated as described previously.
The implant may be deployed either by intravitreal delivery in a
buffer, or in a viscous, lubricious vehicle such as haluronic acid.
Such a drug may be impregnated into a monolithic structure (such as
an absorbable stent) or coated on the surface (the structure may
incorporate pores to hold the drug). Thereby, the quantity of drug
and the rate of drug release may be tailored by adapting the size
and quantity of pores to suit the particular application.
Illustratively, the structure may be embodied as a stent, which may
be placed in the back of the eye away from the field of vision, and
apposed at the bottom of the retinal wall. Similarly, the surface
of the stent can be coated with swellable hydrophilic polymer such
as PEG, PVP, MPC, etc. so that little to no trauma is induced to
the retina.
[0065] In certain alternative embodiments, an absorbable Np loaded
anti-angiogenic drug may be embedded in a slowly dissolvable strip.
One or more such strips may be injected into intravitreal space. An
Np embedded strips may be placed in multiple locations in IVT. Such
a dissolvable strip may be made of or comprise PEG, PVP, GAG, PAA,
CMC, CPMC, HPMA hyaluronic acid, PolyMPC, etc., and/or a
combination of these. The strip may be blended with hydrophobic
excipient such as stearate, palmitate, or poly glycerol sebacate.
Thereby, tailored and controlled dissolution of therapeutic agents
loaded into the strip may be enabled. In embodiments, an agent may
also be loaded in the strip for a bolus initial release. For
example, Np may be impregnated into the strip as sub populations
based on size and shape. This may also modulate drug release rate.
In such embodiments, the strip may be blended with a hydrophobic
excipient such as stearate, palmitate, or poly glycerol sebacate.
This may enable tailoring controlled dissolution of the strip, as
before. Zotarolimus may also be used as an active agent. As may be
appreciated by those skilled in the art, multiple drugs may also be
used. For example, Zotarolimus may be used in conjunction with
anti-TNF.
[0066] Turning now to FIG. 4A, an illustration of an embodiment of
a drug-loadable contact lens is shown. The lens 400 may function as
an ordinary contact lens, except that it is made of or includes a
portion made of so-called block-copolymers. In a block-copolymer,
the copolymer is microphase separated to form a periodic
nanostructure that may be used as a depot to store the therapeutic
agent. The nanostructure may provide storage regions that are small
enough to not scatter light, and have miscibility with the agent,
thereby providing for a controlled release of the agent.
[0067] FIG. 4B illustrates an exemplary block copolymer
nanostructure comprising a matrix 410 in which microphase separated
regions 420 may be embedded. The matrix, which makes up most of the
lens, may be or comprise a conventional hydrogel such as HEMA or a
silicone material. The regions where the drug is stored may be of a
more hydrophobic nature, such as PEA, polymers made through
metathesis polymerizations, and controlled free radical
polymerization, to provide very well defined block sizes. Used in
conjunction with a shunt comprising one or more strands having a
micron scale tab protruding from the surface of the sclera, the
contact lens may serve as a repository of therapeutic agent that is
absorbed over time by the strand(s), and wicks through the sclera
into the vitreal chamber, or between the sclera and choroid to the
treatment site.
[0068] Although the invention has been described and illustrated in
exemplary forms with a certain degree of particularity, it is noted
that the description and illustrations have been made by way of
example only. Numerous changes in the details of construction,
combination, and arrangement of parts and steps may be made.
Accordingly, such changes are intended to be included within the
scope of the disclosure, the protected scope of which is defined by
the claims.
* * * * *