U.S. patent application number 15/472075 was filed with the patent office on 2018-02-01 for uveoscleral drug delivery implant and methods for implanting the same.
The applicant listed for this patent is DOSE MEDICAL CORPORATION. Invention is credited to Kenneth Curry, David Haffner.
Application Number | 20180028361 15/472075 |
Document ID | / |
Family ID | 42562300 |
Filed Date | 2018-02-01 |
United States Patent
Application |
20180028361 |
Kind Code |
A1 |
Haffner; David ; et
al. |
February 1, 2018 |
UVEOSCLERAL DRUG DELIVERY IMPLANT AND METHODS FOR IMPLANTING THE
SAME
Abstract
Devices and methods for treating intraocular pressure are
disclosed. The devices include drug delivery implants for treating
ocular tissue. Optionally, the devices also include shunts for
draining aqueous humor from the anterior chamber to the uveoscleral
outflow pathway, including the supraciliary space and the
suprachoroidal space. The drug delivery implants can be implanted
in ab interno or ab externo procedures.
Inventors: |
Haffner; David; (Mission
Viejo, CA) ; Curry; Kenneth; (Oceanside, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DOSE MEDICAL CORPORATION |
San Clemente |
CA |
US |
|
|
Family ID: |
42562300 |
Appl. No.: |
15/472075 |
Filed: |
March 28, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13201423 |
Mar 2, 2012 |
9636255 |
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PCT/US2010/024128 |
Feb 12, 2010 |
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15472075 |
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61152651 |
Feb 13, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/00 20130101;
A61M 37/00 20130101; A61M 25/0105 20130101; A61L 2300/604 20130101;
A61F 9/0017 20130101; A61M 2210/0612 20130101; A61M 27/00 20130101;
A61L 27/54 20130101; A61F 9/00781 20130101; A61M 25/00 20130101;
A61L 27/18 20130101; A61M 2025/0286 20130101; A61L 27/18 20130101;
C08L 67/04 20130101; A61L 2430/16 20130101 |
International
Class: |
A61F 9/007 20060101
A61F009/007; A61L 27/18 20060101 A61L027/18; A61L 27/54 20060101
A61L027/54; A61M 27/00 20060101 A61M027/00; A61F 9/00 20060101
A61F009/00; A61K 31/00 20060101 A61K031/00; A61M 37/00 20060101
A61M037/00 |
Claims
1.-20. (canceled)
21. An intraocular implant comprising: a proximal end; a distal
end; a central plane extending from the proximal end to the distal
end and bisecting the implant along a central longitudinal axis of
the implant; only one lumen extending from the proximal end to the
distal end generally in axial alignment with a second plane that is
parallel to and offset from the central plane; and a recess
configured to receive a therapeutic agent to treat the eye, the
recess generally in axial alignment with a third plane that is
parallel to and offset from the central plane, wherein the second
plane is positioned on one side of the central plane and the third
plane is positioned on another side of the central plane.
22. The implant of claim 21, wherein the implant comprises a second
recess that extends from one end of the implant towards the other
end and generally along the second plane.
23. The implant of claim 21, wherein at least a portion of the
therapeutic agent is configured to be in fluid communication with
the lumen.
24. The implant of claim 21, further comprising a therapeutic agent
disposed on an outer surface of the implant, said therapeutic agent
configured to contact ocular tissue following implantation of the
drug delivery implant.
25. The implant of claim 21, wherein the therapeutic agent is
configured to be compounded with a biodegradable polymer adapted to
provide the desired rate of release.
26. A method for reducing intraocular pressure in an eye of a
mammal, comprising: introducing the ocular implant of claim 21
through an incision in ocular tissue; advancing the implant to an
implantation site in a uveoscleral outflow pathway of the eye such
that the proximal end of the implant is in communication with the
anterior chamber of the eye and the distal end of the implant is in
communication with the suprachoroidal space of the eye.
27. The method of claim 26, wherein introducing the implant
comprises introducing the implant through an incision in the sclera
of the eye made posteriorly of the limbus of the eye, the ocular
implant advanced anteriorly into said position in the uveoscleral
path.
28. The method of claim 26, wherein introducing the implant
comprises introducing the implant across the anterior chamber of
the eye through an incision at or near a limbus of the eye opposite
from the implantation site, advancing the implant across the
anterior chamber and posteriorly along the uveoscleral outflow
pathway into said implantation site such that the distal end of the
implant is located in the suprachoroidal space and the proximal end
of the implant is located in the anterior chamber.
29. The method of claim 26, further comprising conducting aqueous
humor through the implant between the proximal and distal ends of
the implant.
30. The implant of claim 21, wherein the therapeutic agent is
selected from the group consisting of timolol, atenolol,
propranolol, metipranolol, betaxolol, carteolol, levobetaxolol, and
levobunolol.
31. An intraocular implant comprising: a proximal end; a distal
end; a central longitudinal axis extending from a center of the
proximal end to a center of the distal end; only one lumen
extending from the proximal end, the lumen including an opening
having a center that is spaced away from the center of the proximal
end; and a recess extending from one or more of the proximal end
and the distal end, the recess configured to receive a therapeutic
agent to treat the eye, and the recess having a center that is
spaced away from the center of the proximal end.
32. The implant of claim 31, wherein the center of the lumen is
spaced away from the center of the recess, wherein the center of
the lumen is positioned along a plane, and wherein the center of
the recess is positioned along the plane.
33. An intraocular implant having an elongate body, the body
comprising: a proximal end; a distal end; a central plane extending
from the proximal end to the distal end and bisecting the implant
along a central longitudinal axis of the implant; a channel
extending from the proximal end to the distal end, the channel
comprising a channel opening, wherein at least a portion of the
channel opening is aligned with a second plane that is parallel to
and offset from the central plane; and an opening configured to
receive a therapeutic agent to treat the eye, wherein at least a
portion of the opening is generally in alignment with a third plane
that is parallel to and offset from the central plane, wherein the
second plane is positioned on one side of the central plane and the
third plane is positioned on another side of the central plane.
34. The implant of claim 33, wherein the channel is generally in
axial alignment with the second plane.
35. The implant of claim 33, wherein the implant comprises a second
opening that extends from one end of the implant towards the other
end and generally along the second plane.
36. The implant of claim 33, wherein at least a portion of the
therapeutic agent is configured to be in fluid communication with
the channel.
37. The implant of claim 33, further comprising a therapeutic agent
disposed on an outer surface of the implant, said therapeutic agent
configured to contact ocular tissue following implantation of the
drug delivery implant.
38. The implant of claim 33, wherein the therapeutic agent is
configured to be compounded with a biodegradable polymer adapted to
provide the desired rate of release.
39. The implant of claim 33, wherein the therapeutic agent is
selected from the group consisting of timolol, atenolol,
propranolol, metipranolol, betaxolol, carteolol, levobetaxolol, and
levobunolol.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/201,423, filed Mar. 2, 2012, which is the
U.S. National Phase application under 35 U.S.C. .sctn.371 of
International Application No. PCT/US2010/024128, filed on Feb. 12,
2010, which claims the benefit of U.S. Provisional Application No.
61/152,651, filed on Feb. 13, 2009, each of which is incorporated
in its entirety by reference herein.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] This disclosure relates to the delivery of a therapeutic
agent to ocular tissue via an implant. The disclosure also relates
to reducing intraocular pressure within the eye and to a treatment
of glaucoma and/or other ocular disorders wherein aqueous humor is
permitted to flow out of an anterior chamber of the eye through a
surgically implanted pathway.
Description of the Related Art
[0003] A human eye is a specialized sensory organ capable of light
reception and is able to receive visual images. Aqueous humor is a
transparent liquid that fills at least the region between the
cornea, at the front of the eye, and the lens. A trabecular
meshwork, located in an anterior chamber angle, which is formed
between the iris and the cornea, normally serves as a drainage
channel for aqueous humor from the anterior chamber so as to
maintain a balanced pressure within the anterior chamber of the eye
by allowing aqueous humor to flow from the anterior chamber.
[0004] About two percent of people in the United States have
glaucoma. Glaucoma is a group of eye diseases encompassing a broad
spectrum of clinical presentations, etiologies, and treatment
modalities. Glaucoma causes pathological changes in the optic
nerve, visible on the optic disk, and it causes corresponding
visual field loss, resulting in blindness if untreated. Lowering
intraocular pressure is the major treatment goal in all
glaucomas.
[0005] In glaucomas associated with an elevation in eye pressure
(intraocular hypertension), the source of resistance to outflow is
mainly in the trabecular meshwork. The tissue of the trabecular
meshwork normally allows the aqueous humor (hereinafter referred to
as "aqueous") to enter Schlemm's canal, which then empties into
aqueous collector channels in the posterior wall of Schlemm's canal
and then into aqueous veins, which form the episcleral venous
system. Aqueous is continuously secreted by a ciliary body around
the lens, so there is a constant flow of aqueous from the ciliary
body to the anterior chamber of the eye. Pressure within the eye is
determined by a balance between the production of aqueous and its
exit through the trabecular meshwork (major route) and uveoscleral
outflow (minor route). The trabecular meshwork is located between
the outer rim of the iris and the back of the cornea, in the
anterior chamber angle. The portion of the trabecular meshwork
adjacent to Schlemm's canal (the juxtacanilicular meshwork) causes
most of the resistance to aqueous outflow.
[0006] While a majority of the aqueous leaves the eye through the
trabecular meshwork and Schlemm's canal, it is believed that about
10 to about 20 percent of the aqueous in humans leaves through the
uveoscleral pathway. The degree with which uveoscleral outflow
contributes to the total outflow of the eye appears to be species
dependent. As used herein, the term "uveoscleral outflow pathway"
is to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and it is not to be limited to a special
or customized meaning), and refers without limitation to the space
or passageway whereby aqueous exits the eye by passing through the
ciliary muscle bundles located angle of the anterior chamber and
into the tissue planes between the choroid and the sclera, which
extend posteriorly to the optic nerve. From these tissue planes, it
is believed that the aqueous travels through the surrounding
scleral tissue and drains via the scleral and conjunctival vessels,
or is absorbed by the uveal blood vessels. It is unclear from
studies whether the degree of physiologic uveoscleral outflow is
pressure-dependent or pressure-independent. As used herein, the
term "supraciliary space" is to be given its ordinary and customary
meaning to a person of ordinary skill in the art (and it is not to
be limited to a special or customized meaning), and refers without
limitation to the portion of the uveoscleral pathway through the
ciliary muscle and between the ciliary body and the sclera, and the
term "suprachoroidal space" is to be given its ordinary and
customary meaning to a person of ordinary skill in the art (and it
is not to be limited to a special or customized meaning), and
refers without limitation to the portion of the uveoscleral pathway
between the choroid and sclera. Although it is not completely
understood, some studies have suggested that there may be a
"compact zone" of connective tissue associated with the junction
between the retina and ciliary body, known as the ora serrata. This
"compact zone" may act as a site of resistance along the
uveoscleral outflow pathway. The ora serrata can vary in length
from about 5.75 mm to 7.5 mm nasally to about 6.5 mm to about 8.5
mm temporally. Other studies suggest that the ciliary muscle
bundles are the primary site of resistance.
[0007] Certain therapeutic agents have been shown to reduce
intraocular pressure by increasing uveoscleral outflow, but the
mechanism by which uveoscleral outflow is increased is unclear.
Some studies have suggested that relaxation of the ciliary muscle
may reduce resistance through the ciliary muscle bundles to
increase flow. Other studies suggest that dilation of the
post-capillary venules or constriction of the pre-capillary
arterioles may reduce downstream fluid pressure and increase
uveoscleral outflow.
[0008] Glaucoma is broadly classified into two categories:
closed-angle glaucoma, also known as angle closure glaucoma, and
open-angle glaucoma. Closed-angle glaucoma is caused by closure of
the anterior chamber angle by contact between the iris and the
inner surface of the trabecular meshwork. Closure of this
anatomical angle prevents normal drainage of aqueous from the
anterior chamber of the eye. Open-angle glaucoma is any glaucoma in
which the exit of aqueous through the trabecular meshwork is
diminished while the angle of the anterior chamber remains open.
For most cases of open-angle glaucoma, the exact cause of
diminished filtration is unknown. Primary open-angle glaucoma is
the most common of the glaucomas, and is often asymptomatic in the
early to moderately advanced stages of glaucoma. Patients may
suffer substantial, irreversible vision loss prior to diagnosis and
treatment. However, there are secondary open-angle glaucomas that
may include edema or swelling of the trabecular spaces (e.g., from
corticosteroid use), abnormal pigment dispersion, or diseases such
as hyperthyroidism that produce vascular congestion.
[0009] Current therapies for glaucoma are directed toward
decreasing intraocular pressure. Currently recognized categories of
drug therapy for glaucoma include but are not limited to: (1)
Miotics (e.g., pilocarpine, carbachol, and acetylcholinesterase
inhibitors), (2) Sympathomimetics (e.g., epinephrine and
dipivalylepinephxine), (3) Beta-blockers (e.g., betaxolol,
levobunolol and timolol), (4) Carbonic anhydrase inhibitors (e.g.,
acetazolamide, methazolamide and ethoxzolamide), and (5)
Prostaglandins (e.g., metabolite derivatives of arachidonic acid).
Medical therapy includes topical ophthalmic drops or oral
medications that reduce the production of aqueous or increase the
outflow of aqueous. However, drug therapies for glaucoma are
sometimes associated with significant side effects. The most
frequent and perhaps most serious drawback to drug therapy,
especially the elderly, is patient compliance. Patients often
forget to take their medication at the appropriate times or else
administer eye drops improperly, resulting in under- or overdosing.
Patient compliance is particularly problematic with therapeutic
agents requiring dosing frequencies of three times a day or more,
such as pilocarpine. Because the effects of glaucoma are
irreversible, when patients dose improperly, allowing ocular
concentrations to drop below appropriate therapeutic levels,
further permanent damage to vision occurs. Furthermore, current
drug therapies are targeted to be deposited directly into the
ciliary body where the aqueous is produced. And current therapies
do not provide for a continuous slow-release of the drug. When drug
therapy fails, surgical therapy is pursued.
[0010] Surgical therapy for open-angle glaucoma consists of laser
trabeculoplasty, trabeculectomy, and implantation of aqueous shunts
after failure of trabeculectomy or if trabeculectomy is unlikely to
succeed. Trabeculectomy is a major surgery that is widely used and
is augmented with topically applied anticancer drugs, such as
5-flurouracil or mitomycin-C to decrease scarring and increase the
likelihood of surgical success.
[0011] Approximately 100,000 trabeculectomies are performed on
Medicare-age patients per year in the United States. This number
would likely increase if ocular morbidity associated with
trabeculectomy could be decreased. The current morbidity associated
with trabeculectomy consists of failure (10-15%); infection (a life
long risk of 2-5%); choroidal hemorrhage, a severe internal
hemorrhage from low intraocular pressure, resulting in visual loss
(1%); cataract formation; and hypotony maculopathy (potentially
reversible visual loss from low intraocular pressure). For these
reasons, surgeons have tried for decades to develop a workable
surgery for reducing intraocular pressure.
[0012] The surgical techniques that have been tried and practiced
are goniotomy/trabeculotomy and other mechanical disruptions of the
trabecular meshwork, such as trabeculopuncture, goniophotoablation,
laser trabecular ablation, and goniocurretage. These are all major
operations and are briefly described below.
[0013] Goniotomy and trabeculotomy are simple and directed
techniques of microsurgical dissection with mechanical disruption
of the trabecular meshwork. These initially had early favorable
responses in the treatment of open-angle glaucoma. However,
long-term review of surgical results showed only limited success in
adults. In retrospect, these procedures probably failed due to
cellular repair and fibrosis mechanisms and a process of "filling
in." Filling in is a detrimental effect of collapsing and closing
in of the created opening in the trabecular meshwork. Once the
created openings close, the pressure builds back up and the surgery
fails.
[0014] Q-switched Neodynium (Nd) YAG lasers also have been
investigated as an optically invasive trabeculopuncture technique
for creating full-thickness holes in trabecular meshwork. However,
the relatively small hole created by this trabeculopuncture
technique exhibits a filling-in effect and fails.
[0015] Goniophotoablation is disclosed by Berlin in U.S. Pat. No.
4,846,172 and involves the use of an excimer laser to treat
glaucoma by ablating the trabecular meshwork. This method did not
succeed in a clinical trial. Hill et al. used an Erbium YAG laser
to create full-thickness holes through trabecular meshwork (Hill et
al., Lasers in Surgery and Medicine 11:341346, 1991). This laser
trabecular ablation technique was investigated in a primate model
and a limited human clinical trial at the University of California,
Irvine. Although ocular morbidity was zero in both trials, success
rates did not warrant further human trials. Failure was again from
filling in of surgically created defects in the trabecular meshwork
by repair mechanisms. Neither of these is a viable surgical
technique for the treatment of glaucoma.
[0016] Goniocurretage is an "ab interno" (from the inside),
mechanically disruptive technique that uses an instrument similar
to a cyclodialysis spatula with a microcurrette at the tip. Initial
results were similar to trabeculotomy: it failed due to repair
mechanisms and a process of filling in.
[0017] Although trabeculectomy is the most commonly performed
filtering surgery, viscocanalostomy (VC) and nonpenetrating
trabeculectomy (NPT) are two new variations of filtering surgery.
These are "ab externo" (from the outside), major ocular procedures
in which Schlemm's canal is surgically exposed by making a large
and very deep scleral flap. In the VC procedure, Schlemm's canal is
cannulated and viscoelastic substance injected (which dilates
Schlemm's canal and the aqueous collector channels). In the NPT
procedure, the inner wall of Schlemm's canal is stripped off after
surgically exposing the canal.
[0018] Trabeculectomy, VC, and NPT involve the formation of an
opening or hole under the conjunctiva and scleral flap into the
anterior chamber, such that aqueous is drained onto the surface of
the eye or into the tissues located within the lateral wall of the
eye. These surgical operations are major procedures with
significant ocular morbidity. When trabeculectomy, VC, and NPT are
thought to have a low chance for success, a number of implantable
drainage devices have been used to ensure that the desired
filtration and outflow of aqueous through the surgical opening will
continue. The risk of placing a glaucoma drainage device also
includes hemorrhage, infection, and diplopia (double vision).
[0019] All of the above embodiments and variations thereof have
numerous disadvantages and moderate success rates. They involve
substantial trauma to the eye and require great surgical skill in
creating a hole through the full thickness of the sclera into the
subconjunctival space. The procedures are generally performed in an
operating room and involve a prolonged recovery time for vision.
The complications of existing filtration surgery have prompted
ophthalmic surgeons to find other approaches to lowering
intraocular pressure or treating tissue of trabecular meshwork.
[0020] Because the trabecular meshwork and juxtacanilicular tissue
together provide the majority of resistance to the outflow of
aqueous, they are logical targets for surgical removal in the
treatment of open-angle glaucoma. In addition, minimal amounts of
tissue need be altered and existing physiologic outflow pathways
can be utilized. Some procedures bypass the trabecular meshwork and
juxtacanilicular tissue to drain fluid to physiologic outflow
channels. However, in severe cases, it has been found that these
procedures do not sufficiently reduce intraocular pressure.
[0021] As reported in Arch. Ophthalm. (2000) 118:412, glaucoma
remains a leading cause of blindness, and filtration surgery
remains an effective, important option in controlling glaucoma.
However, modifying existing filtering surgery techniques in any
profound way to increase their effectiveness appears to have
reached a dead end.
[0022] Examples of implantable shunts and surgical methods for
maintaining an opening for the release of aqueous from the anterior
chamber of the eye to the sclera or space beneath the conjunctiva
have been disclosed in, for example, Hsia et al., U.S. Pat. No.
6,059,772 and Baerveldt, U.S. Pat. No. 6,050,970.
[0023] Examples of implantable shunts or devices for maintaining an
opening for the release of aqueous humor from the anterior chamber
of the eye to the sclera or space underneath conjunctiva have been
disclosed in U.S. Pat. No. 6,007,511 (Prywes), U.S. Pat. No.
6,007,510 (Nigam), U.S. Pat. No. 5,893,837 (Eagles et al.), U.S.
Pat. No. 5,882,327 (Jacob), U.S. Pat. No. 5,879,319 (Pynson et
al.), U.S. Pat. No. 5,807,302 (Wandel), U.S. Pat. No. 5,752,928 (de
Roulhac et al.), U.S. Pat. No. 5,743,868 (Brown et al.), U.S. Pat.
No. 5,704,907 (Nordquist et al.), U.S. Pat. No. 5,626,559
(Solomon), U.S. Pat. No. 5,626,558 (Suson), U.S. Pat. No. 5,601,094
(Reiss), U.S. Pat. No. 35,390 (Smith), U.S. Pat. No. 5,558,630
(Fisher), U.S. Pat. No. 5,558,629 (Baerveldt et al.), U.S. Pat. No.
5,520,631 (Nordquist et al.), U.S. Pat. No. 5,476,445 (Baerveldt et
al.), U.S. Pat. No. 5,454,796 (Krupin), U.S. Pat. No. 5,433,701
(Rubinstein), U.S. Pat. No. 5,397,300 (Baerveldt et al.), U.S. Pat.
No. 5,372,577 (Ungerleider), U.S. Pat. No. 5,370,607 (Memmen), U.S.
Pat. No. 5,338,291 (Speckman et al.), U.S. Pat. No. 5,300,020
(L'Esperance, Jr.), U.S. Pat. No. 5,178,604 (Baerveldt et al.),
U.S. Pat. No. 5,171,213 (Price, Jr.), U.S. Pat. No. 5,041,081
(Odrich), U.S. Pat. No. 4,968,296 (Ritch et al.), U.S. Pat. No.
4,936,825 (Ungerleider), U.S. Pat. No. 4,886,488 (White), U.S. Pat.
No. 4,750,901 (Molteno), U.S. Pat. No. 4,634,418 (Binder), U.S.
Pat. No. 4,604,087 (Joseph), U.S. Pat. No. 4,554,918 (White), U.S.
Pat. No. 4,521,210 (Wong), U.S. Pat. No. 4,428,746 (Mendez), U.S.
Pat. No. 4,402,681 (Haas et al.), U.S. Pat. No. 4,175,563 (Arenberg
et al.), and U.S. Pat. No. 4,037,604 (Newkirk).
[0024] All of the above embodiments and variations thereof have
numerous disadvantages and moderate success rates. They involve
substantial trauma to the eye and require great surgical skill in
creating a hole through the full thickness of the sclera into the
subconjunctival space. The procedures are generally performed in an
operating room and involve a prolonged recovery time for vision.
The complications of existing filtration surgery have prompted
ophthalmic surgeons to find other approaches to lowering
intraocular pressure.
SUMMARY OF THE INVENTION
[0025] Disclosed herein are systems for treating an ocular disorder
in a patient. In one embodiment, the system comprises a drug
delivery implant comprising one or more drug delivery portion
which, following implantation at an implantation site in the eye,
delivers one or more therapeutic agent to one or more of the
anterior chamber and the uveoscleral outflow pathway of an eye, and
a delivery instrument releasably coupleable to the drug delivery
implant for implanting the drug delivery implant. In a preferred
embodiment, the instrument is configured to deliver the implant
through an insertion site in the sclera to a location in the
suprachoroidal space proximate the anterior chamber, and comprises
a plurality of members longitudinally moveable relative to each
other.
[0026] In another embodiment, there is provided a system for
treating glaucoma that comprises a plurality of implants configured
for implantation into eye tissue, one or more of the implants
comprising one or more drug delivery portion which, following
implantation at an implantation site in the eye, delivers one or
more therapeutic agent to one or more of the anterior chamber and
the suprachoroidal space of the eye, and an instrument having a
chamber in which the implants are loaded for serial delivery into
eye tissue, wherein at least a first implant of the plurality of
implants is configured to extend generally alongside a second
implant of said plurality of implants.
[0027] In another embodiment, there is provided an intraocular
implant that comprises a generally elongated body configured for
implantation in eye tissue, one or more recess formed in the body
and extending from an end of the body generally along an axis, and
a therapeutic agent disposed in the recess in a sufficient quantity
to treat the eye over a desired period of time and configured to be
released to the eye at a desired rate over said period of time. The
implant may comprise a lumen extending along the length of the
implant about a second axis generally parallel to the axis, the
lumen configured to allow flow therethrough.
[0028] In another embodiment, there is provided an implant for
treating glaucoma that comprises a body configured for implantation
in an eye between an anterior chamber and suprachoroidal space of
the eye, the body including a therapeutic agent, said body having a
lumen extending between an inlet portion and an outlet portion of
the body, said inlet portion configured to transport aqueous fluid
from the anterior chamber of the eye to the outlet portion, where
the outlet portion is disposed in the suprachoroidal space of the
eye, said outlet portion having an outflow opening.
[0029] Certain embodiments may additionally include one or more of
the following features or characteristics : (i) the implant is
configured to deliver one or more therapeutic agents to the
suprachoroidal space of the uveoscleral outflow pathway; (ii) the
instrument and/or device has a sufficiently small cross section
such that the insertion site self seals without suturing upon
withdrawal of the instrument from the eye; (iii) the implant
comprises a lumen extending configured to allow fluid communication
between the anterior chamber of the eye and the uveoscleral outflow
pathway following implantation of the implant; (iv) at least one of
the one or more drug delivery portion comprises at least one of the
one or more therapeutic agent compounded with a biodegradable PLGA
copolymer, wherein the lactic acid to glycolic acid ratio and/or
average molecular weight of the PLGA copolymer is selected to
achieve a desired delivery rate of the therapeutic agent over time;
(v) a therapeutic agent in fluid communication with the lumen such
that the aqueous fluid contacts the therapeutic agent as it flows
through the lumen; (vi) a therapeutic agent disposed on an outer
surface of the elongated body, where the therapeutic agent is
configured to contact ocular tissue following implantation of the
drug delivery implant; and (vii) a therapeutic agent compounded
with a biodegradable polymer adapted to provide a desired rate of
release..
[0030] In another embodiment there is provided a method for
reducing intraocular pressure in an eye of a mammal, comprising
introducing an ocular implant through an incision in ocular tissue,
the ocular implant comprising a therapeutic agent and having
proximal and distal ends; and advancing the implant to an
implantation site in a uveoscleral outflow pathway of the eye such
that one of the ends of the implant is in communication with the
anterior chamber of the eye and the other of the ends of the
implant is in communication with the suprachoroidal space of the
eye. Further embodiments may include (i) introducing the implant
comprises introducing the implant through an incision in the sclera
of the eye made posteriorly of the limbus of the eye, the ocular
implant advanced anteriorly into said position in the uveoscleral
path, and/or (ii) introducing the implant comprises introducing the
implant across the anterior chamber of the eye through an incision
at or near a limbus of the eye opposite from the implantation site,
advancing the implant across the anterior chamber and posteriorly
along the uveoscleral outflow pathway into said implantation site
such that the distal end of the implant is located in the
suprachoroidal space and the proximal end of the implant is located
in the anterior chamber.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] These and other features, aspects, and advantages of the
present disclosure will now be described with reference to the
drawings of embodiments, which embodiments are intended to
illustrate and not to limit the disclosure.
[0032] FIG. 1 illustrates a schematic cross-sectional view of an
eye.
[0033] FIG. 2A is a longitudinal cross-section of one embodiment of
a drug delivery implant.
[0034] FIG. 2B is a transverse cross-section of the drug delivery
implant of FIG.
[0035] 2A.
[0036] FIG. 3 is a longitudinal cross-section of another embodiment
of a drug delivery implant.
[0037] FIG. 4A is a longitudinal cross-section of another
embodiment of a drug delivery implant.
[0038] FIG. 4B is a transverse cross-section of the drug delivery
implant of FIG. 4A.
[0039] FIG. 5 is a longitudinal cross-section of another embodiment
of a drug delivery implant.
[0040] FIG. 6 is a longitudinal cross-section of another embodiment
of a drug delivery implant.
[0041] FIG. 7 is a longitudinal cross-section of another embodiment
of a drug delivery implant.
[0042] FIG. 8A is a longitudinal cross-section of another
embodiment of a drug delivery implant.
[0043] FIG. 8B is a transverse cross-section of the drug delivery
implant of FIG. 8A.
[0044] FIG. 9A is a longitudinal cross-section of another
embodiment of a drug delivery implant.
[0045] FIG. 9B is a transverse cross-section of the drug delivery
implant of FIG. 9A.
[0046] FIG. 10 is a longitudinal cross-section of another
embodiment of a drug delivery implant.
[0047] FIG. 11A is a partial top view of an eye showing one
embodiment of a method for implantation of a drug delivery implant
into the eye.
[0048] FIG. 11B is an enlarged cross-sectional detailed view of
FIG. 11A.
[0049] FIG. 12A is a partial top view of an eye into which a drug
delivery implant has been implanted.
[0050] FIG. 12B is an enlarged cross-sectional detailed view of the
implant in FIG. 12A.
[0051] FIG. 13A illustrates a schematic cross-sectional view of an
eye with a delivery device containing an implant being advanced
across the anterior chamber.
[0052] FIG. 13B illustrates a schematic cross-sectional view of an
eye with a delivery device being advanced adjacent the anterior
chamber angle.
[0053] FIG. 13C illustrates a schematic cross-section view of an
eye with a delivery device implanting an implant that extends
between the anterior chamber and the uveoscleral outflow
pathway.
[0054] FIG. 14 illustrates a schematic cross-sectional view of an
eye with another delivery device being advanced across the anterior
chamber for use in delivering an implant into ocular tissue.
[0055] FIG. 15 illustrates a schematic cross-sectional view of an
eye with another delivery device being advanced across the anterior
chamber for use in delivering an implant into ocular tissue.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0056] An ophthalmic implant system is provided that comprises a
drug delivery implant, which can include a shunt, and a delivery
instrument for implanting the drug delivery implant. While this and
other systems and associated methods are described herein in
connection with glaucoma treatment, the disclosed systems and
methods can be used to treat other types of ocular disorders in
addition to glaucoma.
[0057] FIG. 1 illustrates the anatomy of an eye, which includes the
sclera 11, which joins the cornea 12 at the limbus 21, the iris 13
and the anterior chamber 20 between the iris 13 and the cornea 12.
The eye also includes the lens 26 disposed behind the iris 13, the
ciliary body 16 and Schlemm's canal 22. The eye also includes the
uveoscleral outflow pathway 24a, which defines the suprachoroidal
space 24 between the choroids 28 and the sclera 11.
[0058] In embodiments that include the shunt, the shunt, following
implantation at an implantation site, can drain fluid from the
anterior chamber into a physiologic outflow space. In some
embodiments, the shunt can be configured to provide a fluid flow
path for draining aqueous humor from the anterior chamber of an eye
to the uveoscleral outflow pathway to reduce intraocular pressure.
In some embodiments, an instrument is provided for delivering
and/or implanting the drainage shunt ab interno in an eye to divert
aqueous humor from the anterior chamber to the uveoscleral outflow
pathway. In some embodiments, a method is provided for implanting a
drainage shunt ab interno in an eye to divert aqueous humor from
the anterior chamber to the uveoscleral outflow pathway. In some
embodiments, the aqueous humor is diverted to the supraciliary
space or the suprachoroidal space of the uveoscleral outflow
pathway.
[0059] The term "shunt" as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to an implant
defining one or more fluid passages. The fluid passage(s) in some
embodiments remains patent and, in other embodiments, the
passage(s) is fully or partially occluded under at least some
circumstances (e.g., at lower intraocular pressure levels). The
shunts may feature a variety of characteristics, described in more
detail below, which facilitate the regulation of intraocular
pressure. The mechanical aspects and material composition of the
shunt can be important for controlling the amount and direction of
fluid flow. Therefore, various examples of shunt dimensions,
features, tip configurations, material flexibility, coatings, and
valve design, in accordance with some embodiments of the present
disclosure, are discussed in detail below.
[0060] The delivery instruments, described in more detail below,
may be used to facilitate delivery and/or implantation of the drug
delivery implant to the desired location of the eye. The delivery
instrument preferably is used to place the implant into a desired
position by application of a continual implantation force, by
tapping the implant into place using a distal portion of the
delivery instrument, or by a combination of these methods. The
design of the delivery instruments may take into account, for
example, the angle of implantation and the location of the implant
relative to an incision. For example, in some embodiments, the
delivery instrument may have a fixed geometry, be shape-set, or
actuated. In some embodiments, the delivery instrument may have
adjunctive or ancillary functions. In some embodiments, the
delivery instrument may additionally be used to, for example,
inject dye and/or viscoelastic fluid, to dissect, or be used as a
guidewire.
[0061] In one embodiment, the implant can be advanced through the
ciliary attachment tissue, which lies to the posterior of the
scleral spur, during implantation. This tissue typically is fibrous
or porous, which is relatively easy to pierce or cut with a
surgical device, and lies inward of the scleral spur. The implant
can be advanced through this tissue and abut against the sclera
once the implant extends into the uveoscleral outflow pathway. The
implant can then slide within the uveoscleral outflow pathway along
the interior wall of the sclera. As the implant is advanced into
the uveoscleral outflow pathway and against the sclera, the implant
will likely be oriented at an angle with respect to the interior
wall of the sclera. The implant is advanced until it reaches the
desired implantation site within the uveoscleral outflow pathway.
In some embodiments, an implant that includes a shunt is advanced
into the ciliary body or ciliary muscle bundles to achieve drainage
into the supraciliary space. In other embodiments, the implant with
the shunt is advanced through the ciliary body or ciliary muscle
bundles to achieve fluid communication between the anterior chamber
and the suprachoroidal space. In still other embodiments, the
implant with the shunt is advanced into the compact zone or through
the compact to drain aqueous humor into the more distal portions of
the suprachoroidal space.
Shunts
[0062] At least some of the disclosed embodiments include shunts
that provide a fluid flow path for conducting aqueous humor from
the anterior chamber of an eye to the uveoscleral outflow pathway
to reduce intraocular pressure, preferably below episcleral venous
pressure without hypotony. The shunts can have an inflow portion
and an outflow portion. The outflow portion of the shunt preferably
is disposed at or near a distal end of the shunt. When the shunt is
implanted, the inflow portion may be sized and configured to reside
in the anterior chamber of the eye and the outflow portion may be
sized and configured to reside in the uveoscleral outflow pathway.
In some embodiments, the outflow portion may be sized and
configured to reside in the supraciliary region of the uveoscleral
outflow pathway or in the suprachoroidal space.
[0063] One or more lumens can extend through the shunt to form at
least a portion of the flow path. Preferably, there is at least one
lumen that operates to conduct the fluid through the shunt. Each
lumen preferably extends from an inflow end to an outflow end along
a lumen axis. In some embodiments the lumen extends substantially
through the longitudinal center of the shunt. In other embodiments,
the lumen can be offset from the longitudinal center of the shunt.
In still other embodiments, the flow path can be defined by
grooves, channel or reliefs formed on an outer surface of the shunt
body.
[0064] One or more openings can extend through the wall of the
shunt. In some embodiments, the openings can extend through a
middle portion of the shunt. In other embodiments the openings can
extend through other portions of the shunt. The openings can be one
or more of a variety of functions. One such function is that when
the shunt is inserted into the suprachoroidal or supraciliary
space, the openings provide a plurality of routes through which the
aqueous humor can drain. For example, once the shunt is inserted
into the eye, if the shunt only has one outflow channel (e.g., one
end of a lumen), that outflow channel can be plugged, for example,
by the shunt's abutment against the interior surface of the sclera
or the outer surface of the choroid. Additionally, the outflow
channel can be clogged with tissue that is accumulated or cored
during the advancement of the shunt through the fibrous or porous
tissue. A plurality of openings can provide a plurality of routes
through which the fluid may flow to maintain patency and
operability of the drainage shunt. In embodiments where the shunt
has a porous body, the openings can define surface discontinuities
to assist in anchoring the shunt once implanted.
[0065] The shunt in some embodiments can include a distal portion
that is sufficiently sharp to pierce eye tissue near the scleral
spur of the eye, and that is disposed closer to the outlet portion
than to the inlet portion. In some embodiments, the distal portion
is located at the distal end of the implant. In another embodiment,
the distal portion can be sufficiently blunt so as not to
substantially penetrate scleral tissue of the eye. In some
embodiments, the shunts have a generally sharpened forward end and
are self-trephinating, i.e., self-penetrating, so as to pass
through tissue without pre-forming an incision, hole or aperture.
The sharpened forward end can be, for example, conical or tapered.
The tip can be sufficiently sharp to pierce eye tissue near the
scleral spur of the eye. The tip also can be sufficiently blunt so
as not to substantially penetrate scleral tissue of the eye. The
taper angle of the sharpened end can be, for example, about
30.degree..+-.15.degree. in some embodiments. The radius of the tip
can be about 70 to about 200 microns. In other embodiments, where
an outlet opening is formed at the distal end of the shunt, the
distal portion can gradually increase in cross-sectional size in
the proximal direction, preferably at a generally constant taper or
radius or in a parabolic manner.
[0066] In some embodiments, the body of the shunt can include at
least one surface irregularity. The surface irregularity can
comprise, for example, a ridge, groove, relief, hole, or annular
groove. The surface discontinuities or irregularities can also be
formed by barbs or other projections, which extend from the outer
surface of the shunt, to inhibit migration of the shunt from its
implanted position. In some embodiments, the projections may
comprise external ribbing to resist displacement of the shunt. The
surface irregularity in some embodiments can interact with the
tissue of the interior wall of the sclera and/or with the tissue of
the ciliary attachment tissue. In some embodiments, the shunts are
anchored by mechanical interlock between tissue and an irregular
surface and/or by friction fit. In other embodiments, the shunt
includes cylindrical recessed portions (e.g., annular groves) along
an elongate body to provide enhanced gripping features during
implantation and anchoring following implantation within the eye
tissue.
[0067] The shunt may also incorporate fixation features, such as
flexible radial (i.e., outwardly extending) extensions. The
extensions may be separate pieces attached to the shunt, or may be
formed by slitting the shunt wall, and thermally forming or
mechanically deforming the extensions radially outward. If the
extensions are separate pieces, they may be comprised of flexible
material such as nitinol or polyimide. The extensions may be
located at the proximal or distal ends of the shunt, or both, to
prevent extrusion of the shunt from its intended location. The
flexibility of the fixation features will facilitate entry through
the corneal incision, and also through the ciliary muscle
attachment tissue.
[0068] In some embodiments, the body of the shunt has an outlet
opening on a side surface to allow fluid flow. In some embodiments,
the body of the shunt has a plurality of outlet openings on a side
surface to allow fluid flow. In other embodiments, there is a
plurality of outlet openings at one end of the shunt, such as the
distal end. The openings can facilitate fluid flow through the
shunt.
[0069] The shunt can in some embodiments have a cap, or tip, at one
end. The cap can include a tissue-piercing end and one or more
outlet openings. Each of the one or more outlet openings can
communicate with at least one of the one or more lumens. In some
embodiments the cap can have a conically shaped tip with a
plurality of outlet openings disposed proximal of the tip's distal
end. In other embodiments, the cap can have a tapered angle tip.
The tip can be sufficiently sharp to pierce eye tissue near the
scleral spur of the eye. The tip also can be sufficiently blunt so
as not to substantially penetrate scleral tissue of the eye. In
some embodiments, the conically shaped tip facilitates delivery of
the shunt to the desired location. In some embodiments, the cap has
an outlet opening on a side surface to allow fluid flow. In some
embodiments, the cap has a plurality of outlet openings on a side
surface to allow fluid flow. In other embodiments, there is a
plurality of outlet openings on the conical surface of the cap. The
openings on the cap can facilitate fluid flow through the shunt.
The opening may provide an alternate route for fluid flow which is
beneficial in case the primary outflow portion of the shunt becomes
blocked.
[0070] In some embodiments, multiple shunts are configured to be
delivered during a single procedure. In some embodiments when
multiple shunts are delivered, the shunts can be arranged tandemly.
In one embodiment, the shunt can include a tip protector at one
end. The tip protector can comprise a recess shaped to receive and
protect, for example, the tip of an adjacent shunt. In some
embodiments, the tip of the adjacent shunt has a conical shape. The
recess may be shaped to contact the sides of the conical tip while
protecting the more tapered tip, or end, from impact. The tip
protector is particularly useful for delivery of multiple
shunts.
[0071] The shunts may be of varied lengths to optimize flows. In
some preferred embodiments, the shunt has sufficient length such
that the outflow portion resides in the suprachoroidal space and
the inflow portion is exposed to the anterior chamber. In other
preferred embodiments, the length of the shunt is a length such
that the outflow portion resides in the supraciliary space of the
uveoscleral outflow pathway. In some embodiments, the length of the
shunt is a length such that the outflow portion resides in the
membranous region of the uveoscleral outflow pathway adjacent to
the retina, while in other embodiments, the shunt has a length that
extends distally past the membranous region. In some embodiments,
the length of the shunt from the portion residing in the anterior
chamber to the portion residing in the uveoscleral outflow pathway
may be about 0.5 mm to about 5 mm. In preferred embodiments, the
length of the shunt may be about 1.5 mm to about 5 mm. In more
preferred embodiments, the length of the shunt may be about 2.0 mm.
In some embodiments, the length of the shunt is about 0.5, 0.6,
0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,
2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2,
3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5,
4.6, 4.7, 4.8, 4.9, or 5.0 mm.
[0072] In some embodiments, the shunt can have an outer diameter
that will permit the shunt to fit within a 23-gauge needle during
implantation. The shunt can also have a diameter that is designed
to be inserted with larger needles. For example, the shunt can also
be delivered with 18-, 19- or 20-gauge needles. In other
embodiments, smaller gauge applicators, such as a 23-gauge (or
smaller) applicator, may be used. The shunt can have a
substantially constant cross-sectional shape through most of the
length of the shunt, or the shunt can have portions of reduced or
enlarged cross-sectional size (e.g., diameter), or cylindrical
channels, e.g., annular grooves, disposed on the outer surface
between the proximal end and the distal end. The distal end of the
shunt can have a tapered portion, or a portion having a continually
decreasing radial dimension with respect to the lumen axis along
the length of the axis. The tapered portion preferably in some
embodiments terminates with a smaller radial dimension at the
outflow end. During implantation, the tapered portion can operate
to form, dilate, and/or increase the size of, an incision or
puncture created in the tissue. The tapered portion may have a
diameter of about 23 gauge to about 30 gauge, and preferably about
25 gauge. However, other dimensions are possible.
[0073] The diameter of one or more drainage lumens within the shunt
may be varied to alter flow characteristics. The cross-sectional
size of a shunt may be, for example, 0.1 mm to about 1.0 mm, or
preferably about 0.3 mm to about 0.4 mm. A small cross-sectional
size can be used to restrict flow. The cross-sectional shape of the
shunt or a shunt may be any of a variety of cross-sectional shapes
suitable for allowing fluid flow. For example, the cross-sectional
shape of the shunt or shunt may be circular, oval, square,
trapezoidal, rectangular, or any combination thereof.
[0074] In some embodiments, the shunt is configured to expand,
either radially or axially, or both radially and axially. In some
embodiments, the shunt may be self-expanding. In other embodiments,
the shunt may be expanded by, for example, using a balloon
device.
[0075] In some embodiments, the structure of the shunt may be
flexible. At least a portion of the structure of the shunt may be
flexible, or the whole structure may be flexible. In some
embodiments, the structure of the shunt is accordion- or
balloon-like. This pleated like structure provides flexibility. In
other embodiments, at least a portion of the shunt is curved. In
some embodiments, at least a portion of the shunt is straight. In
some embodiments, the shunt has both curved and straight portions,
and in some embodiments, the shunt is generally rigid (i.e.,
maintains its preformed shape when implanted).
[0076] The shunt is preferably made of one or more biocompatible
materials. Suitable biocompatible materials include, for example,
polypropylene, polyimide, glass, nitinol, polyvinyl alcohol,
polyvinyl pyrolidone, collagen, chemically-treated collagen,
polyethersulfone (PES), poly(styrene-isobutyl-styrene), Pebax,
acrylic, polyolefin, polysilicon, polypropylene, hydroxyapetite,
titanium, gold, silver, platinum, other metals, ceramics, plastics
and a mixture thereof. The shunts can be manufactured by
conventional sintering, micro machining, laser machining, and/or
electrical discharge machining. However, other suitable
manufacturing methods can be used
[0077] In some embodiments, the shunt is made of a flexible
material. In other embodiments, the shunt is made of a rigid
material. In some embodiments, a portion of the shunt is made from
flexible material while another portion of the shunt is made from
rigid material. The body can have an outer surface of which at
least a portion is porous. Some embodiments include porosity that
can be varied by masking a portion of the exterior with a band.
Where the shunts include a porous body, the cross-section and
porosity can be calibrated (down to 0.5 micrometers) to control the
flow rates of aqueous humor through the shunt.
[0078] In some embodiments, at least a portion of the shunt (e.g.,
an internal spine or an anchor) is made of a material capable of
shape memory. A material capable of shape memory may be compressed
and, upon release, may expand axially or radially, or both axially
and radially, to assume a particular shape. In some embodiments, at
least a portion of the shunt has a preformed shape. In other
embodiments, at least a portion of the shunt is made of a
superelastic material. In some embodiments, at least a portion of
the shunt is made up nitinol. In other embodiments, at least a
portion of the shunt is made of a deformable material.
[0079] In some embodiments, the body of the shunt can comprise
material that includes a therapeutic agent, and/or can house,
anchor, or support a therapeutic agent, or can include a coating.
The coating can include a therapeutic agent. The coatings can be,
for example, a drug eluting coating, an antithrombogenic coating,
and a lubricious coating. The therapeutic agent can be selected
from the group consisting of: heparin, TGF-beta, an intraocular
pressure-lowering drug, and an anti-proliferative agent. Materials
that may be used for a drug-eluting coating include parylene C,
poly (butyl methacrylate), poly (methyl methacrylate),
polyethylene-co-vinyl acetate, and other materials known in the
art.
[0080] In some embodiments, the shunt can further comprise a
biodegradable material in or on the shunt. Such biodegradable
copolymers may be situated within a lumen of the shunt, on the tip
of the shunt, or on the cap of the shunt. In some embodiments, at
least a portion of the shunt itself may comprise a biodegradable
material. Still other embodiments may comprise a shunt made
entirely of a biodegradable material, such that the entire shunt is
degraded over time. The biodegradable material can be any suitable
material including, but not limited to, poly(lactic acid),
polyethylene-vinyl acetate, poly(lactic-co-glycolic acid),
poly(D,L-lactide), poly(D,L-lactide-co-trimethylene carbonate),
collagen, heparinized collagen, poly(caprolactone), poly(glycolic
acid), and/or other polymer or copolymer. All or a portion of the
shunt may be coated with a therapeutic agent, e.g. with heparin,
preferably in the flow path, to reduce blood thrombosis or tissue
restenosis. The biodegradable material may also include a
therapeutic agent, such as a drug, mixed or compounded therein such
that the therapeutic agent is released as the biodegradable
material degrades or erodes following implantation.
[0081] The biodegradable material used in the shunt or any other
device disclosed herein includes any suitable material that
degrades or erodes over time when placed in the human or animal
body. Accordingly, as the term is used herein, biodegradable
material includes bioerodible materials. Biodegradable materials
may be advantageously used to deliver one or more drugs or
therapeutic agents. Therefore, it will be understood that
embodiments incorporating a therapeutic agent as described herein
can include having the therapeutic agent compounded with a
biodegradable material or other agent modifying the release
characteristics of the therapeutic agent.
[0082] One or more therapeutic agents may be compounded with one or
more types of biodegradable polymers (including copolymers),
providing release of the therapeutic agent(s) as the polymer
degrades or erodes in vivo. Depending on the ocular disorder to be
treated and the placement of the device in the eye, it may be
advantageous to place a biodegradable polymer incorporating a
therapeutic agent at different locations in or on the device, such
that the therapeutic agent(s) may be released at a target site or
region of the eye. Devices comprising biodegradable polymer with a
therapeutic agent may also be coated (fully or partially) with one
or more coatings comprising one or more drugs or other therapeutic
agent(s).
[0083] Preferred biodegradable materials include copolymers of
lactic acid and glycolic acid, also known as poly
(lactic-co-glycolic acid) or PLGA. It will be understood by one
skilled in the art that although some disclosure herein
specifically describes use of PLGA, other suitable biodegradable
materials may be substituted for PLGA or used in combination with
PLGA in such embodiments. It may be desirable, in some embodiments,
to provide for a particular rate of release of therapeutic agent
from a PLGA copolymer. As the release rate of a therapeutic agent
from a PLGA copolymer correlates with the degradation rate of that
copolymer, control of the degradation rate provides a means for
control of the delivery rate of a therapeutic agent. Variation of
the average molecular weight of the polymer or copolymer chains
which make up the PLGA copolymer can be used to control the
degradation rate of the copolymer, thereby achieving a desired
duration or other release profile of therapeutic agent delivery to
the eye. In certain other embodiments employing PLGA copolymers,
rate of biodegradation of the PLGA copolymer may be controlled by
varying the ratio of lactic acid to glycolic acid units in a
copolymer. Still other embodiments may utilize combinations of
varying the average molecular weights of the constituents of the
copolymer and varying the ratio of lactic acid to glycolic acid in
the copolymer to achieve a desired biodegradation rate. In
addition, as described in more detail below, the incorporation of a
copolymer in or on a device in a particular location may affect the
biodegradation rate of the copolymer, thus providing another means
of controlling the release rate of the therapeutic agent.
[0084] In some ocular disorders, therapy may require a defined
kinetic profile of administration of therapeutic agents to the eye.
In certain embodiments, devices made from PLGA copolymers or which
incorporate PLGA copolymers, wherein the copolymer is compounded
with a therapeutic agent, may provide particular kinetic profiles
of release of such therapeutic agent. By tailoring the ratio of
lactic to glycolic acid in a copolymer and/or average molecular
weight of polymers or copolymers having the therapeutic agent
therein, sustained release of a therapeutic agent, or other
desirable release profile, may be achieved. In certain embodiments,
zero-order release of a therapeutic agent may be achieved by
tailoring the ratio of lactic to glycolic acid and/or average
molecular weights in the copolymer composition so that that the
biodegradation of the PLGA copolymer is the principal factor
controlling therapeutic agent release from the copolymer. In
certain embodiments, pseudo zero-order release (or other desired
release profile) may be achieved by using multiple PLGA copolymer
formulations in or on one or more devices, each copolymer
formulation achieving a different therapeutic agent release profile
such that the additive effect over time replicates true zero-order
kinetics. For example, a series of devices or a single device
having multiple regions incorporating PLGA with one or more
therapeutic agents may be delivered to the eye, wherein the devices
or regions incorporate at least two different PLGA copolymer
formulations. As each copolymer biodegrades or erodes at its
individual and desired rate, the sum total of therapeutic agent
released to the eye over time is in effect released with zero-order
kinetics.
[0085] Non-continuous or pulsatile release may also be desirable.
This may be achieved, for example, by incorporating multiple PLGA
formulations with varying biodegradation rates into a single device
or a series of devices so that, with clearance of a therapeutic
agent from the eye and/or varying rates of release of therapeutic
agent from the copolymers results in a concentration of a
therapeutic agent that is not constant over time.
[0086] The flow path through the shunt can be configured to be
regulated to a flow rate that will reduce the likelihood of
hypotony in the eye. In some embodiments, the intraocular pressure
is maintained at about 8 mm Hg. In other embodiments, the
intraocular pressure is maintained at pressures less than about 8
mmHg, for example the intraocular pressure may be maintained
between about 6 mm Hg and about 8 mm Hg. In other embodiments, the
intraocular pressure is maintained at pressures greater than about
8 mm Hg. For example, the pressures may be maintained between about
8 mmHg and about 18 mm Hg, and more preferably between 8 mm Hg and
16 mm Hg, and most preferably not greater than 12 mm Hg. In some
embodiments, the flow rate can be limited to about 2.5 .mu.L/min or
less. In some embodiments the flow rate can be limited to between
about 1.9 .mu.L/min and about 3.1 .mu.L/min.
[0087] For example, the Hagen-Poiseuille equation suggests that a 4
mm long stent at a flow rate of 2.5 .mu.L/min should have an inner
diameter of 52 82 m to create a pressure gradient of 5 mm Hg above
the pressure in the suprachoroidal space.
[0088] The shunt may or may not include a mechanism for regulating
fluid flow through the shunt. Mechanisms for regulating fluid flow
can include flow restrictors, pressure regulators, or both.
Alternatively, in some embodiments the shunt has neither a flow
restrictor nor a pressure regulator. Regulating flow of aqueous
humor can comprise varying between at least first and second
operational states in which aqueous humor flow is more restricted
in a first state and less restricted in a second state. Increasing
the restriction to flow when changing from the second state to the
first state can involve moving a valve toward a valve seat in a
direction generally parallel or generally normal to a line
connecting the proximal and distal ends of the shunt.
[0089] As noted above, the outflow portion of the shunt, in some
embodiments is sized and configured to reside in the supraciliary
region of the uveoscleral outflow pathway. In such embodiments,
there is a lesser need for a mechanism for regulating fluid flow
through the shunt.
[0090] The mechanism for flow restriction may be, for example, a
valve, a long lumen length, small lumen cross section, or any
combination thereof. In some embodiments, the flow of fluid is
restricted by the size of a lumen within the shunt, which produces
a capillary effect that limits the fluid flow for given pressures.
The capillary effect of the lumen allows the shunt to restrict flow
and provides a valveless regulation of fluid flow.
[0091] In one embodiment, the flow path length may be increased
without increasing the overall length of the shunt by creating a
lumen with a spiral flow path. A lumen within the shunt is
configured to accommodate placement therein of a spiral flow
channel core that is configured to provide preferred flow
restriction. In effect, the spiral flow channel provides an
extended path for the flow of fluid between the inlet(s) and
outlet(s) of the shunt that is greater than a straight lumen
extending between the ends of the shunt. The extended path provides
a greater potential resistance of fluid flow through the shunt
without increasing the length of the shunt. The core could have a
single spiral flow channel, or a plurality of spiral flow channels
for providing a plurality of flow paths through which fluid may
flow through the shunt. For example, the core can have two or more
spiral flow channels, which can intersect.
[0092] In some embodiments, the mechanism for flow regulation can
include a pressure regulating valve. In one embodiment, the valve
can open when fluid pressure within the anterior chamber exceeds a
predetermined level (e.g., a preset pressure). Intraocular pressure
may be used to apply a force to move a valve surface within the
shunt in a direction transverse to a longitudinal axis of the shunt
such that aqueous humor flows from the anterior chamber to the
uveoscleral outflow pathway at intraocular pressures greater than a
threshold pressure.
[0093] In some embodiments, the shunt may have any number of valves
to restrict flow and/or regulate pressure. The valve can be located
between the anterior chamber and one or more effluent openings such
that movement of the valve regulates flow from the anterior chamber
to the one or more effluent openings. A variety of valves are
useful with the shunt for restricting flow. In some embodiments,
the valve is a unidirectional valve and/or is a pressure relief
valve. The pressure relief valve can comprise a ball, a ball seat
and a biasing member urging the ball towards the ball seat. In some
embodiments, the valve is a reed-type valve. In a reed valve, for
example, one end of the valve may be fixed to a portion of the
shunt. The body of the reed valve can be deflected in order to
allow flow through the valve. Pressure from fluid in the anterior
chamber can deflect the body of the reed valve, thereby causing the
valve to open.
[0094] In some embodiments, the shunt can include a pressure
regulation valve having a deflectable plate or diaphragm with a
surface area exposed to fluid within the anterior chamber, the
surface area being substantially greater than the total
cross-sectional flow area of the one or more influent openings of
the shunt. Such a valve can be disposed between an anterior chamber
of the shunt and the one or more effluent openings such that
movement of the deflectable plate regulates flow from the anterior
chamber to the one or more effluent openings. The plate can extend
in a direction generally parallel to the inlet flow path and to the
outlet flow path.
[0095] When the intraocular pressure exceeds a predetermined
pressure, the check pressure relief valve can open and permit fluid
to flow between the anterior chamber and the uveoscleral outflow
pathway. When the intraocular pressure decreases to a second, lower
pressure, the valve can close to limit or inhibit fluid from
flowing to the suprachoroidal space. In one embodiment, the valve
can remain closed until the intraocular pressure again reaches the
predetermined pressure, at which time the valve can reopen to
permit or enhance drainage of fluid to the uveoscleral outflow
pathway. Accordingly, the shunt can provide drainage of the
anterior chamber through the shunt based on the intraocular
pressure levels and reduce the likelihood for over-draining the
anterior chamber and causing hypotony.
Delivery Instruments
[0096] Another aspect of the systems and methods described herein
relates to delivery instruments for implanting the drug delivery
implant, which may include a shunt for draining fluid from the
anterior chamber into a physiologic outflow space. In some
embodiments, the drug delivery implant is inserted from a site
transocularly situated from the implantation site. The delivery
instrument can be sufficiently long to advance the implant
transocularly from the insertion site across the anterior chamber
to the implantation site. At least a portion of the instrument can
be flexible. Alternatively, in other embodiments the instrument can
be rigid. The instrument can include a plurality of members
longitudinally moveable relative to each other. In some
embodiments, at least a portion of the delivery instrument is
curved or angled. In some embodiments, a portion of the delivery
instrument is rigid and another portion of the instrument is
flexible.
[0097] In some embodiments, the delivery instrument has curved
distal portion. The curvature of the distal portion of the delivery
instrument can have as a radius of between about 10 mm and about 30
mm, and preferably about 20 mm.
[0098] In some embodiments, the delivery instrument can have an
angled distal segment. For example, the angle of the distal segment
can be between about 90.degree. and about 170.degree. relative to
an axis of the proximal segment of the delivery instrument, and
preferably about 145.degree.. In one embodiment, the angle can
incorporate a small radius of curvature at the "elbow" between the
proximal and distal segments so as to define a smooth transition
from the proximal segment of the delivery instrument to the distal
segment. In one embodiment, the length of the distal segment may be
between approximately 0.5 to 7 mm, and preferably about 2 to 3 mm.
However, the distal segment of the delivery instrument can have
other suitable lengths.
[0099] In some embodiments, the instrument can have a sharpened
forward end and be self-trephinating, i.e., self-penetrating, so as
to pass through tissue without pre-forming an incision, hole or
aperture. Alternatively, a trocar, scalpel, or similar instrument
can be used to pre-form an incision in the eye tissue before
passing the implant into such tissue.
[0100] For delivery of some embodiments of the drug delivery
implant, the instrument can have a sufficiently small cross section
such that the insertion site self seals without suturing upon
withdrawal of the instrument from the eye. In one embodiment, an
outer diameter of the delivery instrument is preferably no greater
than about 18 gauge and not smaller than about 27 gauge. However,
the delivery instrument can have other suitable outer diameter
dimensions.
[0101] For delivery of some embodiments of the drug delivery
implant, the incision in the corneal tissue is preferable made with
a hollow needle through which the implant can be passed. The needle
can have a small diameter size (e.g., 18 or 19 or 20 or 21 or 22 or
23 or 24 or 25 or 26 or 27 gauge) so that the incision is self
sealing and the implantation occurs in a closed chamber with or
without viscoelastic. A self-sealing incision also can be formed
using a conventional "tunneling" procedure in which a
spatula-shaped scalpel is used to create a generally inverted
V-shaped incision through the cornea. In a preferred mode, the
instrument used to form the incision through the cornea remains in
place (that is, extends through the corneal incision) during the
procedure and is not removed until after implantation. Such
incision-forming instrument either can be used to carry the implant
or can cooperate with a delivery instrument to allow implantation
through the same incision without withdrawing the incision-forming
instrument. Of course, in other embodiments, various surgical
instruments can be passed through one or more corneal incisions
multiple times.
[0102] Once into the anterior chamber, a delivery instrument can be
advanced from the insertion site transocularly into the anterior
chamber angle and positioned at a location near the scleral spur.
Using the scleral spur as a reference point, the delivery
instrument can be advanced further in a generally posterior
direction to drive the implant into the uveoscleral pathway. The
placement and implantation of the implant can be performed using a
gonioscope or other conventional imaging equipment. The delivery
instrument preferably is used to force the implant into a desired
position by application of a continual implantation force, by
tapping the implant into place using a distal portion of the
delivery instrument, or by a combination of these methods. Once the
implant is in the desired position, it may be further seated by
tapping using a distal portion of the delivery instrument.
[0103] In one embodiment, the delivery instrument can include an
open distal end with a lumen extending therethrough. Positioned
within the lumen is preferably a pusher tube that is axially
movable within the lumen. The pusher tube can be any device
suitable for pushing or manipulating the implant in relation to the
delivery instrument, such as, for example, but without limitation a
screw, a rod, a stored energy device such as a spring. A wall of
the delivery instrument can extend beyond pusher tube to
accommodate placement within the lumen of a drug delivery implant.
The implant can be secured in position. For example, the implant
can be secured by viscoelastic or mechanical interlock with the
pusher tube or wall. When the implant is brought into position
adjacent the uveoscleral pathway in the anterior chamber angle, the
pusher tube is advanced axially toward the open distal end of the
delivery instrument. As the pusher tube is advanced, the implant is
also advanced. When the implant is advanced into the uveoscleral
pathway and such that it is no longer in the lumen of the delivery
instrument, the delivery instrument can be retracted, leaving the
drug delivery implant in the uveoscleral pathway.
[0104] Some embodiments can include a spring-loaded or
stored-energy pusher system. The spring-loaded pusher preferably
includes a button operably connected to a hinged rod device. The
rod of the hinged rod device engages a depression in the surface of
the pusher, keeping the spring of the pusher in a compressed
conformation. When the user pushes the button, the rod is
disengaged from the depression, thereby allowing the spring to
decompress, thereby advancing the pusher forward.
[0105] In some embodiments, an over-the wire system can be used to
deliver the drug delivery implant. The implant can be delivered
over a wire. Preferably, the wire is self-trephinating. In one
embodiment, the wire can function as a trocar. The wire can be
superelastic, flexible, or relatively inflexible with respect to
the implant. The wire can be pre-formed to have a certain shape.
The wire can be curved. The wire can have shape memory, or be
elastic. In some embodiments, the wire is a pull wire. The wire can
be a steerable catheter.
[0106] In some embodiments, the wire is positioned within a lumen
in the drug delivery implant, such as a lumen of a shunt of the
implant. The wire can be axially movable within the lumen. The
lumen may or may not include valves or other flow regulatory
devices.
[0107] In some embodiments, the delivery instrument is a trocar.
The trocar may be angled or curved. The trocar can be rigid,
semi-rigid or flexible. In embodiments where the trocar can be
stiff, the implant can be, but need not be relatively flexible. The
diameter of the trocar can be about 0.001 inches to about 0.01
inches. In some embodiments, the diameter of the trocar is 0.001,
0.002, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, or 0.01
inches.
[0108] In some embodiments, delivery of the drug delivery implant
is achieved by applying a driving force at or near the distal end
of the implant. The driving force can be a pulling or a pushing
applied generally to the end of the implant.
[0109] The instrument can include a seal to prevent aqueous humor
from passing through the delivery instrument and/or between the
members of the instrument when the instrument is in the eye. The
seal can also aid in preventing backflow of aqueous humor through
the instrument and out the eye. Suitable seals for inhibiting
leakage include, for example, an o-ring, a coating, a hydrophilic
agent, a hydrophobic agent, and combinations thereof. The coating
can be, for example, a silicone coat such as MDX.TM. silicone
fluid. In some embodiments, the instrument is coated with the
coating and a hydrophilic or hydrophobic agent. In some
embodiments, one region of the instrument is coated with the
coating plus the hydrophilic agent, and another region of the
instrument is coated with the coating plus the hydrophobic agent.
The delivery instrument can additionally comprise a seal between
various members comprising the instrument. The seal can comprise a
hydrophobic or hydrophilic coating between slip-fit surfaces of the
members of the instrument. The seal can be disposed proximate of
the drug delivery implant when carried by the delivery instrument.
Preferably, the seal is present on at least a section of each of
two devices that are machined to fit closely with one another.
[0110] In some embodiments, the delivery instrument can include a
distal end having a beveled shape. The delivery instrument can
include a distal end having a spatula shape. The beveled or spatula
shape can have a sharpened edge. The beveled or spatula shape can
include a recess to contain the drug delivery implant. The recess
can include a pusher or other suitable means to push out or eject
the implant.
[0111] The delivery instrument further can be configured to deliver
multiple drug delivery implants. In some embodiments, when multiple
drug delivery implants are delivered, the implants can be arranged
in tandem, as described in greater detail below.
Therapeutic Agents
[0112] The therapeutic agents utilized with the drug delivery
implant, may include one or more drugs provided below, either alone
or in combination. The drugs utilized may also be the equivalent
of, derivatives of, or analogs of one or more of the drugs provided
below. The drugs may include but are not limited to pharmaceutical
agents including anti-glaucoma medications, ocular agents,
antimicrobial agents (e.g., antibiotic, antiviral, antiparasitic,
antifungal agents), anti-inflammatory agents (including steroids or
non-steroidal anti-inflammatory), biological agents including
hormones, enzymes or enzyme-related components, antibodies or
antibody-related components, oligonucleotides (including DNA, RNA,
short-interfering RNA, antisense oligonucletides, and the like),
DNA/RNA vectors, viruses (either wild type or genetically modified)
or viral vectors, peptides, proteins, enzymes, extracellular matrix
components, and live cells configured to produce one or more
biological components. The use of any particular drug is not
limited to its primary effect or regulatory body-approved treatment
indication or manner of use. Drugs also include compounds or other
materials that reduce or treat one or more side effects of another
drug or therapeutic agent. As many drugs have more than a single
mode of action, the listing of any particular drug within any one
therapeutic class below is only representative of one possible use
of the drug and is not intended to limit the scope of its use with
the ophthalmic implant system.
[0113] Examples of drugs may include various anti-secretory agents;
antimitotics and other anti-proliferative agents, including among
others, anti-angiogenesis agents such as angiostatin, anecortave
acetate, thrombospondin, VEGF receptor tyrosine kinase inhibitors
and anti-vascular endothelial growth factor (anti-VEGF) drugs such
as ranibizumab (LUCENTIS.RTM.) and bevacizumab (AVASTIN.RTM.),
pegaptanib (MACUGEN.RTM.), sunitinib and sorafenib and any of a
variety of known small-molecule and transcription inhibitors having
anti-angiogenesis effect; classes of known ophthalmic drugs,
including: glaucoma agents, such as adrenergic antagonists,
including for example, beta-blocker agents such as atenolol
propranolol, metipranolol, betaxolol, carteolol, levobetaxolol,
levobunolol and timolol; adrenergic agonists or sympathomimetic
agents such as epinephrine, dipivefrin, clonidine, aparclonidine,
and brimonidine; parasympathomimetics or cholingeric agonists such
as pilocarpine, carbachol, phospholine iodine, and physostigmine,
salicylate, acetylcholine chloride, eserine, diisopropyl
fluorophosphate, demecarium bromide); muscarinics; carbonic
anhydrase inhibitor agents, including topical and/or systemic
agents, for example acetozolamide, brinzolamide, dorzolamide and
methazolamide, ethoxzolamide, diamox, and dichlorphenamide;
mydriatic-cycloplegic agents such as atropine, cyclopentolate,
succinylcholine, homatropine, phenylephrine, scopolamine and
tropicamide; prostaglandins such as prostaglandin F2 alpha,
antiprostaglandins, prostaglandin precursors, or prostaglandin
analog agents such as bimatoprost, latanoprost, travoprost and
unoprostone.
[0114] Other examples of drugs may also include anti-inflammatory
agents including for example glucocorticoids and corticosteroids
such as betamethasone, cortisone, dexamethasone, dexamethasone
21-phosphate, methylprednisolone, prednisolone 21-phosphate,
prednisolone acetate, prednisolone, fluroometholone, loteprednol,
medrysone, fluocinolone acetonide, triamcinolone acetonide,
triamcinolone, triamcinolone acetonide, beclomethasone, budesonide,
flunisolide, fluorometholone, fluticasone, hydrocortisone,
hydrocortisone acetate, loteprednol, rimexolone and non-steroidal
anti-inflammatory agents including, for example, diclofenac,
flurbiprofen, ibuprofen, bromfenac, nepafenac, and ketorolac,
salicylate, indomethacin, ibuprofen, naxopren, piroxicam and
nabumetone; anti-infective or antimicrobial agents such as
antibiotics including, for example, tetracycline,
chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,
cephalexin, oxytetracycline, chloramphenicol, rifampicin,
ciprofloxacin, tobramycin, gentamycin, erythromycin, penicillin,
sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole,
sulfisoxazole, nitrofurazone, sodium propionate, aminoglycosides
such as gentamicin and tobramycin; fluoroquinolones such as
ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin,
norfloxacin, ofloxacin; bacitracin, erythromycin, fusidic acid,
neomycin, polymyxin B, gramicidin, trimethoprim and sulfacetamide;
antifungals such as amphotericin B and miconazole; antivirals such
as idoxuridine trifluorothymidine, acyclovir, gancyclovir,
interferon; antimicotics; immune-modulating agents such as
antiallergenics, including, for example, sodium chromoglycate,
antazoline, methapyriline, chlorpheniramine, cetrizine, pyrilamine,
prophenpyridamine anti-histamine agents such as azelastine,
emedastine and levocabastine; immunological drugs (such as vaccines
and immune stimulants); MAST cell stabilizer agents such as
cromolyn sodium, ketotifen, lodoxamide, nedocrimil, olopatadine and
pemirolastciliary body ablative agents, such as gentimicin and
cidofovir; and other ophthalmic agents such as verteporfin,
proparacaine, tetracaine, cyclosporine and pilocarpine; inhibitors
of cell-surface glycoprotein receptors; decongestants such as
phenylephrine, naphazoline, tetrahydrazoline; lipids or hypotensive
lipids; dopaminergic agonists and/or antagonists such as
quinpirole, fenoldopam, and ibopamine; vasospasm inhibitors;
vasodilators; antihypertensive agents; angiotensin converting
enzyme (ACE) inhibitors; angiotensin-1 receptor antagonists such as
olmesartan; microtubule inhibitors; molecular motor (dynein and/or
kinesin) inhibitors; actin cytoskeleton regulatory agents such as
cyctchalasin, latrunculin, swinholide A, ethacrynic acid, H-7, and
Rho-kinase (ROCK) inhibitors; remodeling inhibitors; modulators of
the extracellular matrix such as tert-butylhydro-quinolone and
AL-3037A; adenosine receptor agonists and/or antagonists such as
N-6-cylclophexyladenosine and (R)-phenylisopropyladenosine;
serotonin agonists; hormonal agents such as estrogens, estradiol,
progestational hormones, progesterone, insulin, calcitonin,
parathyroid hormone, peptide and vasopressin hypothalamus releasing
factor; growth factor antagonists or growth factors, including, for
example, epidermal growth factor, fibroblast growth factor,
platelet derived growth factor, transforming growth factor beta,
somatotrapin, fibronectin, connective tissue growth factor, bone
morphogenic proteins (BMPs); cytokines such as interleukins, CD44,
cochlin, and serum amyloids, such as serum amyloid A.
[0115] Other therapeutic agents may include neuroprotective agents
such as lubezole, nimodipine and related compounds, and including
blood flow enhancers, sodium channels blockers, glutamate
inhibitors such as memantine, neurotrophic factors, nitric oxide
synthase inhibitors; free radical scavengers or anti-oxidants;
chelating compounds; apoptosis-related protease inhibitors;
compounds that reduce new protein synthesis; radiotherapeutic
agents; photodynamic therapy agents; gene therapy agents; genetic
modulators; and dry eye medications such as cyclosporine A,
delmulcents, and sodium hyaluronate.
[0116] Other therapeutic agents that may be used include: other
beta-blocker agents such as acebutolol, atenolol, bisoprolol,
carvedilol, asmolol, labetalol, nadolol, penbutolol, and pindolol;
other corticosteroidal and non-steroidal anti-inflammatory agents
such aspirin, betamethasone, cortisone, diflunisal, etodolac,
fenoprofen, fludrocortisone, flurbiprofen, hydrocortisone,
ibuprofen, indomethacine, ketoprofen, meclofenamate, mefenamic
acid, meloxicam, methylprednisolone, nabumetone, naproxen,
oxaprozin, prednisolone, prioxicam, salsalate, sulindac and
tolmetin; COX-2 inhibitors like celecoxib, rofecoxib and.
Valdecoxib; other immune-modulating agents such as aldesleukin,
adalimumab (HUMIRA.RTM.), azathioprine, basiliximab, daclizumab,
etanercept (ENBREL.RTM.), hydroxychloroquine, infliximab
(REMICADE.RTM.), leflunomide, methotrexate, mycophenolate mofetil,
and sulfasalazine; other anti-histamine agents such as loratadine,
desloratadine, cetirizine, diphenhydramine, chlorpheniramine,
dexchlorpheniramine, clemastine, cyproheptadine, fexofenadine,
hydroxyzine and promethazine; other anti-infective agents such as
aminoglycosides such as amikacin and streptomycin; anti-fungal
agents such as amphotericin B, caspofungin, clotrimazole,
fluconazole, itraconazole, ketoconazole, voriconazole, terbinafine
and nystatin; anti-malarial agents such as chloroquine, atovaquone,
mefloquine, primaquine, quinidine and quinine; anti-mycobacterium
agents such as ethambutol, isoniazid, pyrazinamide, rifampin and
rifabutin; anti-parasitic agents such as albendazole, mebendazole,
thiobendazole, metronidazole, pyrantel, atovaquone, iodoquinaol,
ivermectin, paromycin, praziquantel, and trimatrexate; other
anti-viral agents, including anti-CMV or anti-herpetic agents such
as acyclovir, cidofovir, famciclovir, gangciclovir, valacyclovir,
valganciclovir, vidarabine, trifluridine and foscarnet; protease
inhibitors such as ritonavir, saquinavir, lopinavir, indinavir,
atazanavir, amprenavir and nelfinavir;
nucleotide/nucleoside/non-nucleoside reverse transcriptase
inhibitors such as abacavir, ddl, 3TC, d4T, ddC, tenofovir and
emtricitabine, delavirdine, efavirenz and nevirapine; other
anti-viral agents such as interferons, ribavirin and trifluridiene;
other anti-bacterial agents, including cabapenems like ertapenem,
imipenem and meropenem; cephalosporins such as cefadroxil,
cefazolin, cefdinir, cefditoren, cephalexin, cefaclor, cefepime,
cefoperazone, cefotaxime, cefotetan, cefoxitin, cefpodoxime,
cefprozil, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone,
cefuroxime and loracarbef; other macrolides and ketolides such as
azithromycin, clarithromycin, dirithromycin and telithromycin;
penicillins (with and without clavulanate) including amoxicillin,
ampicillin, pivampicillin, dicloxacillin, nafcillin, oxacillin,
piperacillin, and ticarcillin; tetracyclines such as doxycycline,
minocycline and tetracycline; other anti-bacterials such as
aztreonam, chloramphenicol, clindamycin, linezolid, nitrofurantoin
and vancomycin; alpha blocker agents such as doxazosin, prazosin
and terazosin; calcium-channel blockers such as amlodipine,
bepridil, diltiazem, felodipine, isradipine, nicardipine,
nifedipine, nisoldipine and verapamil; other anti-hypertensive
agents such as clonidine, diazoxide, fenoldopan, hydralazine,
minoxidil, nitroprus side, phenoxybenzamine, epoprostenol,
tolazoline, treprostinil and nitrate-based agents; anti-coagulant
agents, including heparins and heparinoids such as heparin,
dalteparin, enoxaparin, tinzaparin and fondaparinux; other
anti-coagulant agents such as hirudin, aprotinin, argatroban,
bivalirudin, desirudin, lepirudin, warfarin and ximelagatran;
anti-platelet agents such as abciximab, clopidogrel, dipyridamole,
optifibatide, ticlopidine and tirofiban; prostaglandin PDE-5
inhibitors and other prostaglandin agents such as alprostadil,
carboprost, sildenafil, tadalafil and vardenafil; thrombin
inhibitors; antithrombogenic agents; anti-platelet aggregating
agents; thrombolytic agents and/or fibrinolytic agents such as
alteplase, anistreplase, reteplase, streptokinase, tenecteplase and
urokinase; anti-proliferative agents such as sirolimus, tacrolimus,
everolimus, zotarolimus, paclitaxel and mycophenolic acid;
hormonal-related agents including levothyroxine, fluoxymestrone,
methyltestosterone, nandrolone, oxandrolone, testosterone,
estradiol, estrone, estropipate, clomiphene, gonadotropins,
hydroxyprogesterone, levonorgestrel, medroxyprogesterone,
megestrol, mifepristone, norethindrone, oxytocin, progesterone,
raloxifene and tamoxifen; anti-neoplastic agents, including
alkylating agents such as carmustine lomustine, melphalan,
cisplatin, fluorouracil3, and procarbazine antibiotic-like agents
such as bleomycin, daunorubicin, doxorubicin, idarubicin, mitomycin
and plicamycin; anti proliferative agents (such as 1,3-cis retinoic
acid, 5-fluorouracil, taxol, rapamycin, mitomycin C and cisplatin);
antimetabolite agents such as cytarabine, fludarabine, hydroxyurea,
mercaptopurine and 5-fluorouracil (5-FU); immune modulating agents
such as aldesleukin, imatinib, rituximab and tositumomab; mitotic
inhibitors docetaxel, etoposide, vinblastine and vincristine;
radioactive agents such as strontium-89; and other anti-neoplastic
agents such as irinotecan, topotecan and mitotane.
[0117] The therapeutic agents may be released or eluted from the
drug delivery implant, bound to a surface of the implant, and/or
disposed in the implant. The therapeutic agents may also be
released from a separate drug eluting implant that is implantable
in the same or a different location in the eye or orbital cavity.
The separate drug eluting implant may be located in a physiologic
outflow pathway or physiologic cavity of the eye or body, or may be
implanted into an artificially formed site of the eye or body. A
variety of controlled-release technologies may be used with the
drug delivery implant, including non-degradable and biodegradable
polymeric and non-polymeric release platforms that are known in the
art and that which is described hereinabove including with respect
to biodegradable polymers such as PLGA.
[0118] In one embodiment, an injection/infusion/implantation routes
or sites include a suprachoroidal site and other sites along the
uveoscleral pathway.
[0119] In some embodiments, combinations of agents having
synergistic and/or complementary effects for a particular disease
or set of related conditions or symptoms may be used. In one
example, a disease-treating agent may be used in combination with a
metabolism-altering agent affecting the cytochrome P450 system to
affect the pharmacokinetics of the disease-treating agent. In
another example, an anti-infective agent may be combined with an
anti-inflammatory agent to treat inflammation resulting from the
infection.
[0120] As is well known in the art, an implant device coated or
loaded with a slow-release substance can have prolonged effects on
local tissue surrounding the device. The slow-release delivery can
be designed such that an effective amount of substance is released
over a desired duration. "Substance," as used herein, is defined as
any therapeutic or bioactive drug or agents that can stop,
mitigate, slow-down or reverse undesired disease processes.
[0121] In one embodiment, the drug delivery implant may be coated,
loaded or made in whole or in part of a biodegradable (also
including bioerodible) material admixed or compounded with a
substance for substance slow-release into ocular tissues.
Accordingly, in the embodiments described herein, it is to be
understood that incorporation of a therapeutic agent(s) in or on a
device includes having the therapeutic agent included alone, with
one or more pharmaceutically acceptable excipients, and compounded
or admixed with a biodegradable polymer or other material to
deliver the therapeutic agent(s) at a desired rate over time.
[0122] In another embodiment, polymer films may function as
substance containing release devices whereby the polymer films may
be coupled or secured to the drug delivery implant. The polymer
films may be designed to permit the controlled release of the
substance at a chosen rate and for a selected duration, which may
also be episodic or periodic. Such polymer films may be synthesized
such that the substance is bound to the surface or resides within a
pore in the film so that the substance is relatively protected from
enzymatic attack. The polymer films may also be modified to alter
their hydrophilicity, hydrophobicity and vulnerability to platelet
adhesion and enzymatic attack. In one embodiment, the polymer film
is made of biodegradable material.
[0123] Furthermore, the film may be coupled (locally or remotely)
to a power source such that when substance delivery is desired, a
brief pulse of current is provided to alter the potential on the
film to cause the release of a particular amount of the substance
for a chosen duration. Application of current causes release of a
substance from the surface of the film or from an interior location
in the film such as within a pore. The rate of substance delivery
is altered depending on the degree of substance loading on the
film, the voltage applied to the film, and by modifying the
chemical synthesis of substance delivery polymer film.
[0124] The power-activated substance delivery polymer film may be
designed to be activated by an electromagnetic field, such as, by
way of example, NMR, MRI, or short range RF transmission (such as a
Bluetooth.RTM. apparatus). In addition, ultrasound can be used to
cause a release of a particular amount of substance for a chosen
duration. This is particularly applicable to a substance coated
implant or an implant made of a substrate containing the desired
substance.
[0125] The drug delivery implant can be used for a direct release
of pharmaceutical preparations into ocular tissues. As discussed
above, the pharmaceuticals may be compounded within the drug
delivery implant or form a coating on the implant. Any known drug
therapy for glaucoma may be utilized, including but not limited to,
the following:
[0126] U.S. Pat. No. 6,201,001, issued Mar. 13, 2001, the entire
contents of which are incorporated herein by reference, discloses
Imidazole antiproliferative agents useful for neovascular
glaucoma.
[0127] U.S. Pat. No. 6,228,873, issued May 8, 2001, the entire
contents of which are incorporated herein by reference, discloses a
new class of compounds that inhibit function of sodium chloride
transport in the thick ascending limb of the loop of Henle, wherein
the preferred compounds useful are furosemide, piretanide,
benzmetanide, bumetanide, torasernide and derivatives thereof.
[0128] U.S. Pat. No. 6,194,415, issued Feb. 27, 2001, the entire
contents of which are incorporated herein by reference, discloses a
method of using quinoxalines (2-imidazolin-2-ylamino) in treating
neural injuries (e.g., glaucomatous nerve damage).
[0129] U.S. Pat. No. 6,060,463, issued May 9, 2000, and U.S. Pat.
No. 5,869,468, issued Feb. 9, 1999, the entire contents of which
are incorporated herein by reference, disclose treatment of
conditions of abnormally increased intraocular pressure by
administration of phosphonylmethoxyalkyl nucleotide analogs and
related nucleotide analogs.
[0130] U.S. Pat. No. 5,925,342, issued Jul. 20, 1999, the entire
contents of which are incorporated herein by reference, discloses a
method for reducing intraocular pressure by administration of
potassium channel blockers.
[0131] U.S. Pat. No. 5,814,620, issued Sep. 29, 1998, the entire
contents of which are incorporated herein by reference, discloses a
method of reducing neovascularization and of treating various
disorders associated with neovascularization. These methods include
administering to a tissue or subject a synthetic
oligonucleotide.
[0132] U.S. Pat. No. 5,767,079, issued Jun. 16, 1998, the entire
contents of which are incorporated herein by reference, discloses a
method for treatment of ophthalmic disorders by applying an
effective amount of Transforming Growth Factor-Beta (TGF-beta) to
the affected region.
[0133] U.S. Pat. No. 5,663,205, issued Sep. 2, 1997, the entire
contents of which are incorporated herein by reference, discloses a
pharmaceutical composition for use in glaucoma treatment which
contains an active ingredient
5-[1-hydroxy-2-[2-(2-methoxyphenoxyl)ethylamino]ethyl]-2-methylbenzenesul-
fonamide. This agent is free from side effects, and stable and has
an excellent intraocular pressure reducing activity at its low
concentrations, thus being useful as a pharmaceutical composition
for use in glaucoma treatment.
[0134] U.S. Pat. No. 5,652,236, issued Jul. 29, 1997, the entire
contents of which are incorporated herein by reference, discloses
pharmaceutical compositions and a method for treating glaucoma
and/or ocular hypertension in the mammalian eye by administering
thereto a pharmaceutical composition which contains as the active
ingredient one or more compounds having guanylate cyclase
inhibition activity. Examples of guanylate cyclase inhibitors
utilized in the pharmaceutical composition and method of treatment
are methylene blue, butylated hydroxyanisole and
N-methylhydroxylamine.
[0135] U.S. Pat. No. 5,547,993, issued Aug. 20, 1996, the entire
contents of which are incorporated herein by reference, discloses
that 2-(4methylaminobutoxy) diphenylmethane or a hydrate or
pharmaceutically acceptable salt thereof have been found useful for
treating glaucoma.
[0136] U.S. Pat. No. 5,502,052, issued Mar. 26, 1996, the entire
contents of which are incorporated herein by reference, discloses
use of a combination of apraclonidine and timolol to control
intraocular pressure. The compositions contain a combination of an
alpha-2 agonist (e.g., para-amino clonidine) and a beta blocker
(e.g., betaxolol).
[0137] U.S. Pat. No. 6,184,250, issued Feb. 6, 2001, the entire
contents of which are incorporated herein by reference, discloses
use of cloprostenol and fluprostenol analogues to treat glaucoma
and ocular hypertension. The method comprises topically
administering to an affected eye a composition comprising a
therapeutically effective amount of a combination of a first
compound selected from the group consisting of beta-blockers,
carbonic anhydrase inhibitors, adrenergic agonists, and cholinergic
agonists, together with a second compound.
[0138] U.S. Pat. No. 6,159,458, issued Dec. 12, 2000, the entire
contents of which are incorporated herein by reference, discloses
an ophthalmic composition that provides sustained release of a
water soluble medicament formed by comprising a cross-linked
carboxy-containing polymer, a medicament, a sugar and water.
[0139] U.S. Pat. No. 6,110,912, issued Aug. 29, 2000, the entire
contents of which are incorporated herein by reference, discloses
methods for the treatment of glaucoma by administering an
ophthalmic preparation comprising an effective amount of a
non-corneotoxic serine-threonine kinase inhibitor, thereby
enhancing aqueous outflow in the eye and treatment of the glaucoma.
In some embodiments, the method of administration is topical,
whereas it is intracameral in other embodiments. In still further
embodiments, the method of administration is intracanalicular.
[0140] U.S. Pat. No. 6,177,427, issued Jan. 23, 2001, the entire
contents of which are incorporated herein by reference, discloses
compositions of non-steroidal glucocorticoid antagonists for
treating glaucoma or ocular hypertension.
[0141] U.S. Pat. No. 5,952,378, issued Sep. 14, 1999, the entire
contents of which are incorporated herein by reference, discloses
the use of prostaglandins for enhancing the delivery of drugs
through the uveoscleral route to the optic nerve head for treatment
of glaucoma or other diseases of the optic nerve as well as
surrounding tissue. The method for enhancing the delivery to the
optic nerve head comprises contacting a therapeutically effective
amount of a composition containing one or more prostaglandins and
one or more drug substances with the eye at certain intervals.
Drug Delivery Implants
[0142] Embodiment Illustrated in FIGS. 2A-2B
[0143] FIGS. 2A-2B show one embodiment of a drug delivery implant
30. The drug delivery implant 30 can have an elongated body 32
extending from a proximal end 32a to a distal end 32b that in one
embodiment can be generally cylindrical with a circular
cross-section. However, in other embodiments the elongated body 32
can have other cross-sectional shapes, such as a semi-sphere, a
paraboloid, or a hyperboloid.
[0144] The drug delivery implant 30 preferably has an outer
diameter that will permit the implant 30 to fit within a 21-gauge
or 23-gauge needle or hollow instrument during implantation;
however, larger or smaller gauge instruments can also be used. The
implant 30 can also have a diameter that is designed to be
delivered with larger needles. For example, the implant 30 can also
be delivered with 18-, 19- or 20-gauge needles. The implant 30 can
have a constant diameter through most of the length of the implant
30, or the implant 30 can have portions of reduced diameter, e.g.,
annular grooves (not shown), between the proximal end 32a and the
distal end 32b. The annular grooves can produce an irregular outer
surface on the body 32 that can operate to mechanically lock or
anchor the implant 30 in place when implanted. Of course, such
surface discontinuities or irregularities can also be formed by
barbs or other projections, which extend from the outer surface of
the implant 30, to inhibit migration of the implant 30 from its
implanted position, as described above.
[0145] In one embodiment, at least one of the proximal and distal
ends, 32a, 32b can include a tapered portion. During implantation,
the tapered end can operate to form, dilate, and/or increase the
size of, an incision or puncture created in the tissue. For
example, the distal end 32b can operate as a trocar to puncture or
create an incision in the tissue. Following advancement of the
distal end 32b of the implant 30, the tapered portion can be
advanced through the puncture or incision. The tapered portion can
operate to stretch or expand the tissue around the puncture or
incision to accommodate the increasing size of the tapered portion
as it is advanced through the tissue. The interaction of the tissue
and the edges of the implant 30 will provide an anchor for the
implant 30 following implantation to inhibit migration of the drug
delivery implant 30.
[0146] The tapered portion can also facilitate proper location of
the drug delivery implant 30 into the supraciliary or
suprachoroidal spaces. For example, the implant 30 is preferably
advanced through the tissue within the anterior chamber angle
during implantation. This tissue typically is fibrous or porous,
which is relatively easy to pierce or cut with a surgical device,
such as the tip of the implant 30. The implant 30 can be advanced
through this tissue and abut against the sclera once the implant 30
extends into the uveoscleral outflow pathway. As the implant 30
abuts against the sclera, the tapered portion can preferably
provide a generally rounded edge or surface that facilitates
sliding of the implant 30 within the suprachoroidal space along the
interior wall of the sclera 11. For example, as the implant 30 is
advanced into the uveoscleral outflow pathway and against the
sclera 11, the implant 30 will likely be oriented at an angle with
respect to the interior wall of the sclera 11. As the tip of the
implant 30 engages the sclera 11, the tip preferably has a radius
that will permit the implant 30 to slide along the sclera 11
instead of piercing or substantially penetrating the sclera 11. As
the implant 30 slides along the sclera 11, the tapered portion will
provide an edge against which the implant 30 can abut against the
sclera 11 and reduce the likelihood that the drug delivery implant
30 will pierce the sclera.
[0147] In one embodiment, once the implant 30 is implanted in
position, the distal portion 32b can reside in the anterior chamber
20 and the proximal portion 32a can reside in the suprachoroidal
space 24 of the uveoscleral outflow pathway 24a.
[0148] The implant 30 preferably comprises any of the materials
previously described above. The implant 30 can be fabricated
through micro machining techniques or through procedures commonly
used for fabricating optical fibers. For example, in some
embodiments, the implant 30 is drawn with a recess extending
therethrough. In the illustrated embodiment, the drug delivery
implant 30 includes a first elongated recess 34 extending along an
axis of the implant body 32 from the proximal end 32a of the
implant 30, and a second elongated recess 36 extending along the
axis of the implant body 32 from the distal end of the implant 30.
In one embodiment a therapeutic agent 38, as described herein, can
be disposed in the recesses 34, 36 of the drug delivery implant
30.
[0149] In one embodiment, the drug delivery implant 30 can be
implanted in the uveoscleral outflow pathway 24a such that the
proximal portion 32a is in the suprachoroidal space 24 and the
distal portion 32b is near the anterior chamber 20, so that the
therapeutic agent 38 in the implant 30 can be delivered to both the
suprachoroidal space 24 and the anterior chamber 20. In one
embodiment, the same therapeutic agent 38 can be disposed in the
recesses 34, 36. In another embodiment, the therapeutic agents 38
in the recesses 34, 36 can be different so as to provide different
therapies to the anterior chamber 20 and the suprachoroidal space
24.
[0150] Embodiment Illustrated in FIG. 3
[0151] FIG. 3 shows another embodiment of a drug delivery implant
30'. The drug delivery implant 30' is similar to the drug delivery
implant 30 of FIGS. 2A-2B, except as noted below. Thus, the
reference numerals used to designate the various features of the
drug delivery implant 30' are identical to those used for
identifying the corresponding features of the drug delivery implant
30, except that a "'" has been added to the reference numerals.
[0152] The drug delivery implant 30' includes a first elongated
body 32a with a recess 34' at a proximal end 33a thereof that can
have a therapeutic agent 38a therein. The drug delivery implant 30'
also includes a second elongated body 32b with a recess 36' at a
distal end 33b thereof that can include a therapeutic agent 38b
therein. In one embodiment, the therapeutic agents 38a, 38b are the
same. In another embodiment, the therapeutic agents 38a, 38b are
different.
[0153] Preferably, the first and second elongated bodies 32a, 32b
have the same length and can couple to each other along their
lengths so that the first and second elongated bodies 32a, 32b can
define a unitary body. For example, the first and second elongated
bodies 32a, 32b can define an interlocking mechanism on at least a
portion of their respective outer surfaces (e.g., interlocking key
and groove features) to allow for said coupling of the elongated
bodies 32a, 32b. In one embodiment, the elongated bodies 32a, 32b
can be delivered sequentially to the implantation site and coupled
together following implantation. In another embodiment, the
elongated bodies 32a, 32b can be coupled prior to implantation and
delivered to the implantation site as a unitary body. In one
embodiment, the first and second elongated bodies 32a, 32b can be
oriented so that the therapeutic agents 38a, 38b are directed in
opposite directions (e.g., one toward the anterior chamber 20 and
the second toward the suprachoroidal space 24). In another
embodiment, the first and second elongated bodies 32a, 32b can be
oriented so that the therapeutic agents 38a, 38b are directed in
the same direction.
[0154] Embodiment Illustrated in FIGS. 4A-4B
[0155] FIGS. 4A-4B illustrate another embodiment of a drug delivery
implant 40. The drug delivery implant 40 is similar to the drug
delivery implant 30 of FIGS. 2A-2B, except as noted below.
[0156] The drug delivery implant 40 includes an elongated body 42
that can extend along an axis between a proximal end 42a and a
distal end 42b. The implant 40 can include a first recess 44 at the
proximal end 42a thereof and a second recess 46 at the distal end
42b thereof, where each of the recesses 44, 46 can have a
therapeutic agent 47 therein. In the illustrated embodiment, the
recesses 44, 46 are aligned along a first axis X1.
[0157] The drug delivery implant 40 also defines a shunt with a
lumen 48 that extends through the implant 40 along a second axis X2
generally parallel to the first axis X1. Preferably, the lumen 48
is sized to allow flow of aqueous humor therethrough. In one
embodiment, where the drug delivery implant 40 is implanted in the
uveoscleral outflow pathway 24a so that the proximal end 42a is
oriented toward the suprachoroidal space 24 and the distal end 42b
is directed toward the anterior chamber 20, the lumen 48 preferably
enhances the drainage of aqueous humor from the anterior chamber 20
to the suprachoroidal space 24 via the implant 40.
[0158] The flow of fluid is preferably restricted by the size of
the lumen 48, which produces a capillary effect that limits the
fluid flow for given pressures. The capillary effect of the lumen
48 allows the shunt of the implant 40 to restrict flow and provides
a valveless regulation of fluid flow. The flow of fluid through the
implant 40 is preferably configured to be restricted to flow rated
that will reduce the likelihood of hypotony in the eye. For
example, in some embodiments, the flow rate can be limited to about
2.5 .mu.L/min or less. In some embodiments the flow rate can be
limited to between about 1.9 .mu.L/min and about 3.1 .mu.L/min. In
other applications, a plurality of drug delivery implants 40 can be
used in a single eye to conduct fluid from the anterior chamber to
the uveoscleral outflow pathway. In such applications, the
cumulative flow rate through the shunts of the implants 40
preferably is within the range of about 1.9 .mu.L/min to about 3.1
.mu.L/min, although the flow rate for each of the shunts of the
implants 40 can be significantly less than about 2.5 .mu.L/min. For
example, if an application called for implantation of five shunts,
then each implant 40 can be configured to have a flow rate of about
0.5 .mu.L/min.
[0159] In the illustrated embodiment, the lumen 48 of the implant
40 is depicted as extending along the axis X2 and offset from the
longitudinal center of the implant 40. In another embodiment, the
lumen 48 can extend along the longitudinal center of the implant
40. Additionally, the lumen 48 can vary in direction along its
length. Also, though the illustrated embodiment shows the lumen 48
having a generally straight configuration between the proximal and
distal ends 42a, 42b of the implant, in one embodiment the lumen 48
can have a non-linear (e.g., spiral) configuration. In the
illustrated embodiment, the lumen 48 has a generally constant
diameter from the proximal to the distal ends 42a, 42b. In another
embodiment, the diameter of the lumen 48 can vary (e.g., taper)
along its length, or there can be a discontinuity in the diameter
of the lumen 48 at a location along its length (e.g., to control
the flow rate of aqueous humor therethrough).
[0160] The drug delivery implant 40 can be of any of the materials
described herein. The implant 40 can be fabricated through
conventional micro machining techniques or through procedures
commonly used for fabricating optical fibers. Other materials can
be used for the implant 40, and other methods of manufacturing the
implant 40 can also be used. For example, the implant 40 can be
constructed of metals or plastics, and the implant 40 can be
machined with a bore that is drilled as described above.
[0161] Embodiment Illustrated in FIG. 5
[0162] FIGS. 5 illustrates another embodiment of a drug delivery
implant 40'. The drug delivery implant 40' is similar to the drug
delivery implant 40 of FIGS. 4A-4B, except as noted below. Thus,
the reference numerals used to designate the various features of
the drug delivery implant 40' are identical to those used for
identifying the corresponding features of the drug delivery implant
40, except that a "'" has been added to the reference numerals.
[0163] In the illustrated embodiment, the drug delivery implant 40'
has a lumen 48' that extends between a proximal end 43a and a
distal end 43b of an elongated body 41a (e.g., shunt) that is
separate from an elongated body 41b that includes the recesses 44',
46' and therapeutic agent 47'. The recesses 44', 46' extend along
the central axis of the elongated body 41b and the lumen 48 extends
along the central axis of the elongated body 41a.
[0164] Preferably, the first and second elongated bodies 41a, 41b
have the same length and can couple to each other along their
lengths, prior to or following implantation, so that the first and
second elongated bodies 41a, 41b can define a unitary body. For
example, the first and second elongated bodies 41a, 41b can define
an interlocking mechanism, as discussed above, on at least a
portion of their respective outer surfaces (e.g., interlocking key
and groove features) to allow for said coupling of the elongated
bodies 41a, 41b. In one embodiment, the elongated bodies 41a, 41b
can be delivered sequentially to the implantation site and coupled
together following implantation. In another embodiment, the
elongated bodies 41a, 41b can be coupled prior to implantation and
delivered to the implantation site as a unitary body.
[0165] Embodiment Illustrated in FIG. 6
[0166] FIGS. 6 illustrates another embodiment of a drug delivery
implant 40''. The drug delivery implant 40'' is similar to the drug
delivery implant 40' of FIG. 5, except as noted below. Thus, the
reference numerals used to designate the various features of the
drug delivery implant 40'' are identical to those used for
identifying the corresponding features of the drug delivery implant
40', except that a "''" has been added to the reference
numerals.
[0167] In the illustrated embodiment, the drug delivery implant
40'' includes a shunt 41a that defines the lumen 48', a first
elongated body 41b'' that has a recess 44'' at a proximal end 42a
thereof, and a second elongated body 41c'' that has a recess 46''at
a distal end 42b thereof, where the therapeutic agent 47' can be
disposed in the recesses 44'', 46''. In one embodiment, the lumen
48', recess 44'' and recess 46'' can extend along the central axes
of the shunt 41a, first elongated body 41b'' and second elongated
boy 41c'', respectively.
[0168] Preferably, at least two of the shunt 41a and first and
second elongated bodies 41b'', 41c'' have the same length and can
be coupled to each other along their lengths (e.g., via an
interlocking mechanism defined on their outer surfaces) so as to
define a unitary body. In one embodiment, the shunt 41a and first
and second elongated bodies 41b'', 41c'' can be delivered
sequentially to the implantation site and coupled together
following implantation. In another embodiment, the shunt 41a and
first and second elongated bodies 41b'', 41c'' can be coupled prior
to implantation and delivered to the implantation site as a unitary
body. The first and second elongated bodies 41b'', 41c'' can be
oriented so that the therapeutic agents 47' are directed in
opposite directions (e.g., one toward the anterior chamber 20 and
the second toward the suprachoroidal space 24). In another
embodiment, the first and second elongated bodies 41b'', 41c'' can
be oriented so that the therapeutic agents 47' are directed in the
same direction.
[0169] Embodiment Illustrated in FIG. 7
[0170] FIGS. 7 illustrates another embodiment of a drug delivery
implant 50. In the illustrated embodiment, the drug delivery
implant 50 includes a shunt 52a that defines a lumen 58
therethrough, and a first elongated body 52b that has a recess 56
at one end thereof, where a therapeutic agent 57 can be disposed in
the recess 56. In one embodiment, the lumen 58 and recess 56 can
extend along the central axes of the shunt 52a and elongated body
52b, respectively. The lumen 58 can be generally linear in one
embodiment. In another embodiment, the lumen 58 can be
non-linear.
[0171] Preferably, the shunt 52a and elongated body 52b have the
same length and can be coupled to each other along their lengths
(e.g., via an interlocking mechanism defined on their outer
surfaces) so as to define a unitary body, prior to or following
implantation.
[0172] Embodiment Illustrated in FIGS. 8A-8B
[0173] FIGS. 8A-8B illustrates another embodiment of a drug
delivery implant 60. In the illustrated embodiment, the drug
delivery implant 60 includes an elongate body 62 that extends
between a proximal end 62a and a distal end 62b and defines a lumen
64 that extends though the elongate body 62. In the illustrate
embodiment, the lumen 64 extends along a central axis of the
elongate body 62. However, in another embodiment, the lumen 64 can
extend along an axis offset from the central axis of the body 62.
The lumen 64 can be generally linear. In another embodiment, the
lumen 64 can be non-linear.
[0174] The drug delivery implant 60 also includes a first recesses
66 formed in the proximal portion 62a of the elongate body 62 about
the lumen 64. The drug delivery implant 60 also includes a second
recesses 68 formed in the distal portion 62b of the elongate body
62 about the lumen 64. The drug delivery implant 60 also includes a
therapeutic agent 67 that can be disposed in the recesses 66, 68.
In one embodiment, the therapeutic agent 67 in the recesses 66, 68
can be the same. In another embodiment, the therapeutic agent 67 in
the recesses 66, 68 can be different.
[0175] Advantageously, the drug delivery implant 60 allows for
fluid flow therethrough via the lumen 64, and said fluid flow is
exposed to the therapeutic agent 67 and can carry it to a desired
location. Where the implant 60 is implanted in the uveoscleral
outflow pathway 24a so that the proximal end 62a is oriented toward
the suprachoroidal space 24 and the distal end 62b is oriented
toward the anterior chamber 20, the lumen 64 allows for aqueous
humor to flow from the anterior chamber 20, through the elongate
body 62 where the therapeutic agent 67 enters the fluid stream, and
toward the suprachoroidal space 24.
[0176] In one embodiment, the recesses 66, 68 can be
circumferential recesses formed in the proximal and distal portions
62a, 62b of the elongate body 62, respectively. In another
embodiment, the recesses 66, 68 can each include two separate and
distinct recesses at the formed in the elongate body 62 on radially
opposite sides of the lumen 64. In another embodiment, the drug
delivery implant 60 can include only one circumferential recess at
a proximal portion, distal portion, or central portion of the
elongate body 62.
[0177] Embodiment illustrated in FIGS. 9A-9B
[0178] FIGS. 9A-9B illustrate another embodiment of a drug delivery
implant 70. In the illustrated embodiment, the drug delivery
implant 70 includes an elongate body 72 that extends between a
proximal end 72a and a distal end 72b and defines a lumen 74 that
extends though the elongate body 72. In the illustrate embodiment,
the lumen 74 extends along a central axis of the elongate body 72.
However, in another embodiment, the lumen 74 can extend along an
axis offset from the central axis of the body 72. The lumen 74 can
be generally linear. In another embodiment, the lumen 74 can be
non-linear.
[0179] The drug delivery implant 70 also includes a recesses 76
formed in the proximal portion 72a of the elongate body 72 about
the lumen 74. The drug delivery implant 70 also includes a first
therapeutic agent 77 that can be disposed in the recess 76 and a
second therapeutic agent 78 that can be disposed on an outer
surface of the elongate body 72 at the distal portion 72b thereof.
In one embodiment, the therapeutic agent 78 can be a film or a
coating applied to the outer surface of the elongate body 72. In
one embodiment, the therapeutic agents 77, 78 are the same. In
another embodiment, the therapeutic agent 78 can be different from
the therapeutic agent 77.
[0180] Advantageously, the drug delivery implant 70 allows for
fluid to flow therethrough via the lumen 74, and said fluid flow is
exposed to the therapeutic agent 77 and can carry it to a desired
location. Additionally, ocular tissue surrounding the drug delivery
implant 70 can be exposed to the therapeutic agent 78 on the outer
surface of the elongate body 72. Where the implant 70 is implanted
in the uveoscleral outflow pathway 24a so that the proximal end 72a
is oriented toward the suprachoroidal space 24 and the distal end
72b is oriented toward the anterior chamber 20, the lumen 74 allows
for aqueous humor to flow from the anterior chamber 20, through the
elongate body 72 where the therapeutic agent 77 enters the fluid
stream, and toward the suprachoroidal space 24.
[0181] In one embodiment (not shown), the recess 76 can extend
along the length of the elongate body 72 about the lumen 74. In
another embodiment, the recess 76 can include two separate and
distinct recesses at the formed in the elongate body 72 on radially
opposite sides of the lumen 74. In another embodiment, the recess
76 can be located at a proximal portion, distal portion, or central
portion of the elongate body 72. Additionally, in one embodiment,
the second therapeutic agent 78 can be disposed on the outer
surface of the drug delivery implant 70 along the entire length of
the elongate body 72.
[0182] Embodiment illustrated in FIG. 10
[0183] FIG. 10 illustrates another embodiment of a drug delivery
implant 80. In the illustrated embodiment, the drug delivery
implant 80 includes an elongate body 82 that extends between a
proximal end 82a and a distal end 82b and defines a lumen 84 that
extends though the elongate body 82. In the illustrate embodiment,
the lumen 84 extends along a central axis of the elongate body 82.
However, in another embodiment, the lumen 84 can extend along an
axis offset from the central axis of the body 82. The lumen 84 can
be generally linear. In another embodiment, the lumen 84 can be
non-linear.
[0184] The drug delivery implant 80 also includes a first
therapeutic agent 86 that can be disposed on the outer surface of
the proximal portion 82a of the elongate body 82 and a second
therapeutic agent 88 that can be disposed on an outer surface of
the elongate body 82 at the distal portion 82b thereof. The
therapeutic agents 86, 88 can be a film or a coating applied to the
outer surface of the elongate body 82. In one embodiment, the
therapeutic agents 86, 88 are the same. In another embodiment, the
therapeutic agent 86 can be different from the therapeutic agent
88.
[0185] In the illustrated embodiment, the therapeutic agents 86, 88
extend circumferentially about the elongate body 82. In another
embodiment, the discreet portions of the therapeutic agents 86, 88
can be disposed on the elongate body 82 at diametrically opposite
locations.
[0186] Advantageously, ocular tissue surrounding the drug delivery
implant 80 can be exposed to the therapeutic agents 86, 88 on the
outer surface of the elongate body 82. Where the implant 80 is
implanted in the uveoscleral outflow pathway 24a so that the
proximal end 82a is oriented toward the suprachoroidal space 24 and
the distal end 82b is oriented toward the anterior chamber 20, the
lumen 84 allows for aqueous humor to flow from the anterior chamber
20, through the elongate body 82 and toward the suprachoroidal
space 24. Additionally, scleral, choroidal and/or ciliary tissue
can be exposed to the therapeutic agents 86, 88 on the drug
delivery implant 80.
[0187] The drug delivery implant described in embodiments herein
can be constructed of metals or plastics, or other suitable
materials for implantation in ocular tissue. The drug delivery
implant also need not have a unitary configuration; that is, be
formed of the same material. For example, a portion of the drug
delivery implant can be formed of a first material and another
portion of the drug delivery implant can be formed of a second
different material.
Procedures
[0188] For delivery of some embodiments of the ocular drug delivery
implant, the implantation occurs in a closed chamber with or
without viscoelastic.
[0189] The drug delivery implants may be placed using an
applicator, such as a pusher, or they may be placed using a
delivery instrument having energy stored in the instrument, such as
disclosed in U.S. Patent Publication 2004/0050392, filed Aug. 28,
2002, the entirety of which is incorporated herein by reference and
made a part of this specification and disclosure. In some
embodiments, fluid may be infused through the delivery instrument
or another instrument used in the procedure to create an elevated
fluid pressure at the distal end of the shunt to ease
implantation.
[0190] FIGS. 11A-12B illustrate one embodiment of a surgical method
for implanting the drug delivery implant into an eye, as described
in the embodiments herein. A first incision or slit is made through
the conjunctiva and the sclera 11 at a location rearward of the
limbus 21, that is, posterior to the region of the sclera 11 at
which the opaque white sclera 11 starts to become clear cornea 12.
Preferably, the first incision is made about 3 mm posterior to the
limbus 21. Also, the first incision is made slightly larger than
the width of the drug delivery implant. In one embodiment, a
conventional cyclodialysis spatula may be inserted through the
first incision into the supraciliary space to confirm correct
anatomic position.
[0191] A portion of the upper and lower surfaces of the drug
delivery implant proximate the back end of the body can be grasped
securely by the surgical tool, for example, a forceps, so that the
forward end of the implant is oriented properly. In one embodiment,
the implant is oriented with a longitudinal axis of the implant
being substantially co-axial to a longitudinal axis of the grasping
end of the surgical tool. The drug delivery implant can then be
disposed through the first incision and into the supraciliary space
of the eye. In one embodiment, the drug delivery implant can have a
shearing edge that can be advanced anteriorly in the supraciliary
space and inserted into and through the anterior chamber angle of
the eye. More particularly, the shearing edge of the insertion head
of the implant can preferably pass between the scleral spur and the
ciliary body 16 posterior to the trabecular meshwork. The drug
delivery implant can be continually advanced anteriorly until a
portion of its insertion head and the first end of the conduit is
disposed within the anterior chamber 20 of the eye. Thus, the first
end of the conduit is placed into fluid communication with the
anterior chamber 20 of the eye. A back end of the elongate body of
the drug delivery implant can be disposed into the suprachoroidal
space 24 of the eye so that the second end of the conduit is placed
into fluid communication with the suprachoroidal space 24.
[0192] In the illustrated embodiment, a shoulder surface of the
forward end of the drug delivery implant can be seated proximate an
interior surface of the supraciliary space and is not introduced
into the anterior chamber 20. The shoulder surface advantageously
aids in forming a tight seal to inhibit leakage of aqueous humor
around the implant body as well as inhibit unwanted further
anterior movement of the implant. In one embodiment, the shape of a
cleft formed by the insertion head forms a tight seal about the
exterior surface of the implant body, and, if used, the fusiform
cross-sectional shape of the body inhibits gaping of the formed
cleft on either elongate edge of the implant.
[0193] In one embodiment, the drug delivery implant can be sutured
to a portion of the sclera 11 to aid in fixating the implant. In
one embodiment, the first incision can subsequently be sutured
closed. As one will appreciate, the suture used to fixate the drug
delivery implant can also be used to close the first incision. In
another embodiment, the drug delivery implant held substantially in
place via the interaction of the implant body's outer surface and
the tissue of the sclera 11 and ciliary body 16 without suturing
the implant to the sclera 11. Additionally, in one embodiment, the
first incision can be sufficiently small so that the incision
self-seals upon withdrawal of the surgical tool following
implantation of the drug delivery implant without suturing the
incision.
[0194] As discussed herein, in some embodiments the drug delivery
implant can include a shunt comprising a lumen configured provide a
drainage device between the anterior chamber 20 and the
suprachoroidal space 24. Upon implantation, the drainage device can
form a cyclodialysis with the implant providing transverse
communication of aqueous humor through the shunt along its length.
Aqueous humor can thus be delivered to the suprachoroidal space
where it can be absorbed, and additional reduction in pressure
within the eye can be achieved.
[0195] The drug delivery implant can be made from any biological
inert and biocompatible materials having the desired
characteristics. The elongate body of the implant can in some
embodiments be substantially rigid or may be substantially
resilient and semi-rigid. Further, in one embodiment the exterior
surface of the elongate implant body can be non-porous. Various
medically suitable acrylics and other plastics are considered
appropriate. The finish of the device preferably meets the standard
for ophthalmic devices and does not irritate surrounding tissue. In
one embodiment, the device may be made by conventional liquid
injection molding or transfer molding process.
[0196] In some embodiments it is desirable to deliver the drug
delivery implant ab interno across the eye, through a small
incision at or near the limbus (FIG. 13a). The overall geometry of
the system makes it advantageous that the delivery instrument
incorporates a distal curvature, or a distal angle. In the former
case, the drug delivery implant can be flexible to facilitate
delivery along the curvature or can be more loosely held to move
easily along an accurate path. In the latter case, the shunt can be
relatively rigid. The delivery instrument can incorporate an
implant advancement element (e.g. pusher) that is flexible enough
to pass through the distal angle.
[0197] In some embodiments, the implant and delivery instrument can
be advanced together through the anterior chamber 20 from an
incision at or near the limbus 21, across the iris 13, and through
the ciliary muscle attachment until the drug delivery implant
outlet portion is located in the uveoscleral outflow pathway 24a
(e.g. exposed to the suprachoroidal space 24 defined between the
sclera 11 and the choroid 12), as shown in FIG. 1. FIG. 13B
illustrates, a transocular implantation approach can be used with
the delivery instrument inserted well above the limbus 21. The
incision, however, can be more posterior and closer to the limbus
21. In other embodiments, the operator can then simultaneously push
on a pusher device while pulling back on the delivery instrument,
such that the drug delivery implant outlet portion maintains its
location in the uveoscleral outflow pathway. The implant can be
released from the delivery instrument, and the delivery instrument
retracted proximally, as illustrated in FIG. 13C. The delivery
instrument then can be withdrawn from the anterior chamber through
the incision.
[0198] FIG. 14 shows a meridional section of the anterior segment
of the human eye and schematically illustrates another embodiment
of a delivery instrument 1130 that can be used with embodiments of
drug delivery implants described herein. In FIG. 14, arrows 1020
show the fibrous attachment zone of the ciliary muscle 16 to the
sclera 11. The ciliary muscle 16 is part of the choroid 28. The
suprachoroidal space 24 is the interface between the choroid 28 and
the sclera 11. Other structures in the eye include the lens 26, the
cornea 12, the anterior chamber 20, the iris 13, and Schlemm' s
canal 22.
[0199] In some embodiments, it is desirable to implant a drug
delivery implant through the fibrous attachment zone, thus
connecting the anterior chamber 20 to the uveoscleral outflow
pathway 24a, in order to reduce the intraocular pressure in
glaucomatous patients. In some embodiments, it is desirable to
deliver the drug delivery implant with a device that traverses the
eye internally (ab interno), through a small incision in the limbus
21.
[0200] The delivery instrument/implant assembly can be passed
between the iris 13 and the cornea 12 to reach the iridocorneal
angle. Therefore, the height of the delivery instrument/shunt
assembly (dimension 1095 in FIG. 14) preferably is less than about
3 mm, and more preferably less than 2 mm.
[0201] The suprachoroidal space 24 between the choroid 28 and the
sclera 11 generally forms an angle .alpha. of about 55.degree. with
the optical axis X of the eye. This angle .alpha., in addition to
the height requirement described in the preceding paragraph, are
features to consider in the geometrical design of the delivery
instrument/implant assembly.
[0202] The overall geometry of the drug delivery implant system
makes it advantageous that the delivery instrument 1130
incorporates a distal curvature 1140, as shown in FIG. 14, or a
distal angle 1150, as shown in FIG. 15. The distal curvature (FIG.
14) is expected to pass more smoothly through the corneal or
scleral incision at the limbus 21. However, in this embodiment, the
drug delivery implant can be curved or flexible. Alternatively, in
the design of FIG. 15, the drug delivery implant can be mounted on
the straight segment of the delivery instrument, distal of the
"elbow" or angle 1150. In this case, the drug delivery implant can
be straight and relatively inflexible, and the delivery instrument
can incorporate a delivery mechanism that is flexible enough to
advance through the angle. In some embodiments, the drug delivery
implant can be a rigid tube, provided that the implant is no longer
than the length of the distal segment 1160.
[0203] The distal curvature 1140 of delivery instrument 1130 may be
characterized as a radius of between about 10 to 30 mm, and
preferably about 20 mm. The distal angle of the delivery instrument
depicted in FIG. 15 may be characterized as between about 90 to 170
degrees relative to an axis of the proximal segment 1170 of the
delivery instrument, and preferably about 145 degrees. The angle
incorporates a small radius of curvature at the "elbow" so as to
make a smooth transition from the proximal segment 1170 of the
delivery instrument to the distal segment 1160. The length of the
distal segment 1160 may be approximately 0.5 to 7 mm, and
preferably about 2 to 3 mm.
[0204] In some embodiments, a viscoelastic can be injected into the
suprachoroidal space to create a chamber or pocket between the
choroid and sclera which can be accessed by a drug delivery
implant. Such a pocket could expose more of the choroidal and
scleral tissue area, and increase uveoscleral outflow in
embodiments where the drug delivery implant includes a shunt,
causing a lower intraocular pressure (TOP). In some embodiments,
the viscoelastic material can be injected with a 25 or 27G cannula,
for example, through an incision in the ciliary muscle attachment
or through the sclera (e.g. from outside the eye). The viscoelastic
material can also be injected through the shunt itself either
before, during or after implantation is completed.
[0205] In some embodiments, a hyperosmotic agent can be injected
into the suprachoroidal space. Such an injection can delay TOP
reduction. Thus, hypotony can be avoided in the acute postoperative
period by temporarily reducing choroidal absorption. The
hyperosmotic agent can be, for example glucose, albumin,
HYPAQUE.TM. medium, glycerol, or poly(ethylene glycol). The
hyperosmotic agent can breakdown or wash out as the patient heals,
resulting in a stable, acceptably low TOP, and avoiding transient
hypotony.
Variations
[0206] In some embodiments, the drug delivery implant can
facilitate delivery of a therapeutic agent. The therapeutic agent
can be, for example, heparin, TGF-beta, an intraocular
pressure-lowering drug, and an anti-proliferative agent. In some
embodiments, the therapeutic agent is introduced concurrently with
the drug delivery implant. The therapeutic agent can be part of the
implant itself. For example, the therapeutic agent can be embedded
in the material of the implant, or coat at least a portion of the
implant. The therapeutic agent may be present on various portions
of the implant. For example, the therapeutic agent may be present
on the distal end of the implant and/or the proximal end of the
implant. The implant can include combination of therapeutic agents.
The different therapeutic agents can be separated or combined. One
kind of therapeutic agent can be present at the proximal end of the
drug delivery implant, and a different kind of therapeutic agent
can be present at the distal end of the drug delivery implant. For
example, an anti-proliferative agent may be present at the distal
end of the implant to prevent growth, and a growth-promoting agent
may be applied to the proximal end of the implant to promote
growth. In some embodiments, the therapeutic agent is delivered
through the implant to the desired location in the eye, such as the
uveoscleral outflow pathway.
[0207] If desired, more than one drug delivery implant of the same
or different type may be implanted. For example, the drug delivery
implants disclosed herein may be used in combination with
trabecular bypass shunts, such as those disclosed in U.S. Patent
Publication 2004/0050392, and those described in U.S. Patent
Publication 2005/0271704, filed Mar. 18, 2005, the entirety of
which is incorporated herein by reference and made a part of this
specification and disclosure. Such shunts may themselves include a
therapeutic agent compounded with a biodegradable polymer such as
PLGA, as discussed above. Additionally, implantation may be
performed in combination with other surgical procedures, such as
cataract surgery. In one embodiment, all or a portion of the drug
delivery implant may be coated, e.g. with heparin, preferably in
the flow path, to reduce blood thrombosis or tissue restenosis.
[0208] While certain embodiments of the disclosure have been
described, these embodiments have been presented by way of example
only, and are not intended to limit the scope of the disclosure.
Indeed, the novel methods, systems, and devices described herein
may be embodied in a variety of other forms. For example,
embodiments of one illustrated or described shunt can be combined
with embodiments of another illustrated or described shunt.
Moreover, the shunts described above can be utilized for other
purposes. For example, the shunts can be used to drain fluid from
the anterior chamber to other locations of the eye or outside the
eye. Furthermore, various omissions, substitutions and changes in
the form of the methods, systems, and devices described herein may
be made without departing from the spirit of the disclosure.
* * * * *