U.S. patent application number 14/724610 was filed with the patent office on 2015-12-03 for implants with controlled drug delivery features and methods of using same.
The applicant listed for this patent is Dose Medical Corporation. Invention is credited to David S. Haffner.
Application Number | 20150342875 14/724610 |
Document ID | / |
Family ID | 53385972 |
Filed Date | 2015-12-03 |
United States Patent
Application |
20150342875 |
Kind Code |
A1 |
Haffner; David S. |
December 3, 2015 |
IMPLANTS WITH CONTROLLED DRUG DELIVERY FEATURES AND METHODS OF
USING SAME
Abstract
Disclosed herein are drug delivery devices and methods for the
treatment of ocular disorders requiring targeted and controlled
administration of a drug to an interior portion of the eye for
reduction or prevention of symptoms of the disorder. The devices
are capable of controlled release of one or more drugs and may also
include structures which allow for treatment of increased
intraocular pressure by permitting aqueous humor to flow out of the
anterior chamber of the eye through the device.
Inventors: |
Haffner; David S.; (Mission
Viejo, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dose Medical Corporation |
Laguna Hills |
CA |
US |
|
|
Family ID: |
53385972 |
Appl. No.: |
14/724610 |
Filed: |
May 28, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62004824 |
May 29, 2014 |
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Current U.S.
Class: |
604/890.1 ;
53/421 |
Current CPC
Class: |
A61F 2250/0068 20130101;
A61K 47/32 20130101; A61F 2250/0067 20130101; A61K 9/0051 20130101;
A61K 47/02 20130101; A61F 9/0017 20130101; A61K 31/5575 20130101;
A61F 9/00781 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61F 9/007 20060101 A61F009/007; A61K 47/02 20060101
A61K047/02; A61F 9/00 20060101 A61F009/00; A61K 31/5575 20060101
A61K031/5575; A61K 47/32 20060101 A61K047/32 |
Claims
1. A drug delivery ocular implant comprising: an outer shell having
a proximal end and a distal end, the outer shell being shaped to
define an interior chamber; a drug positioned within the interior
chamber; a drug release element configured to release the drug from
the interior chamber, the drug release element comprising: a distal
seal member that includes at least one opening; a proximal seal
member that includes at least one opening; and a membrane
compressed between the distal seal member and the proximal seal
member; and a retainer configured to retain the drug release
element in place relative to the outer shell; wherein the drug
release element is configured such that the drug passes through the
at least one opening in the distal seal member, through the
compressed membrane, through the at least one opening in the
proximal seal member, and out the proximal end of the outer
shell.
2. The ocular implant of claim 1, wherein the retainer comprises
one or more tabs that are folded to engage the proximal seal
member.
3. The ocular implant of claim 2, wherein the one or more tabs are
folded to engage the membrane.
4. The ocular implant of claim 1, wherein the outer shell comprises
one or more slots and wherein the retainer extends into the one or
more slots and is positioned proximally of the proximal seal
member.
5. The ocular implant of claim 1, wherein the retainer has a
lateral length that is greater than an inner diameter of the
interior chamber adjacent the retainer and that is less than or
equal to an outer diameter of the outer shell adjacent the
retainer.
6. The ocular implant of claim 1, wherein the interior chamber
includes a shelf, and wherein the distal seal member is seated
against the shelf.
7. The ocular implant of claim 1, wherein the membrane comprises
ethylene vinyl acetate having a concentration of vinyl acetate
between about 10% and about 30%.
8. The ocular implant of claim 1, wherein the compressed membrane
has a thickness of between about 75 microns and about 125
microns.
9. The ocular implant of claim 1, wherein the membrane is
compressed from an uncompressed state by an amount between about 20
microns and about 40 microns.
10. The ocular implant of claim 1, wherein the drug release element
provides an elution rate between about 15 nanograms per day and
about 35 nanograms per day.
11. The ocular implant of claim 1, configured to hold a volume of
the drug between about 40 nanoliters and about 150 nanoliters.
12. The ocular implant of claim 1, wherein the ocular implant has a
total longitudinal length of between about 1 mm and about 3 mm.
13. The ocular implant of claim 1, wherein the outer shell
comprises a ceramic material.
14. The ocular implant of claim 1, further comprising at least one
fluid inflow pathway and at least one fluid outflow pathway wherein
the at least one fluid inflow pathway and the at least one fluid
outflow pathway are configured to deliver ocular fluid to a
physiological outflow pathway.
15. The ocular implant of claim 14, wherein the outer shell
includes an opening between the interior chamber and the inflow
pathway, and wherein the ocular implant further comprises a seal
configured to impede fluid communication between the interior
chamber the fluid inflow pathway.
16. The ocular implant of claim 15, wherein the seal comprises a
recess on a proximal side, and wherein a portion of the drug is
positioned inside the recess of the seal.
17. The ocular implant of claim 14, further comprising a flange
extending laterally outwardly between the at least one fluid inflow
pathway and the at least one fluid outflow pathway.
18. The ocular implant of claim 14, further comprising one or more
standoffs configured to reduce compression of the physiological
outflow pathway by the implant.
19. The ocular implant of claim 14, wherein the physiological
outflow pathway is Schlemm's Canal.
20. The ocular implant of claim 14, further comprising a
positioning protrusion configured to engage an implantation tool to
facilitate rotation of the implant about a longitudinal axis during
implantation.
21. The ocular implant of claim 1, wherein the drug is formulated
as an oil.
22. The ocular implant of claim 1, wherein the drug comprises one
or more of a prostaglandin, a prostaglandin analog, a prostaglandin
inhibitor, and a beta-adrenergic receptor antagonist.
23. The ocular implant of claim 1, further comprising one or more
retention features configured to anchor the ocular implant in
ocular tissue.
24. The ocular implant of claim 23, wherein the one or more
retention features includes a retention protrusion on the distal
end of the outer shell, wherein the retention protrusion is
configured to anchor the ocular implant at a target tissue
site.
25. The ocular implant of claim 1, wherein the ocular implant is
configured to be positioned in the supraciliary space.
26. The ocular implant of claim 25, wherein the ocular implant is
configured to be positioned in the suprachoroidal space.
27. The ocular implant of claim 1, wherein the ocular implant is
configured to be positioned in the suprachoroidal space.
28. The ocular implant of claim 1, wherein the outer shell is
flexible.
29. A method of making a drug delivery ocular implant, the method
comprising: providing an outer shell having a proximal end and a
distal end, the outer shell defining an interior chamber; placing a
drug into the interior chamber; inserting a distal seal member into
the interior chamber; inserting a membrane into the interior
chamber; inserting a proximal seal member into the interior
chamber; pressing the proximal seal member towards the distal seal
member to compress the membrane into a compressed state; and
attaching a retainer to retain the membrane in the compressed
state.
30. The method of claim 29, wherein the outer shell comprises one
or more slots and wherein attaching the retainer comprises
inserting the retainer laterally through the one or more slots such
that the retainer is disposed proximally of the proximal seal
member.
31. The method of claim 29, wherein the retainer comprises one or
more tabs, and wherein the method further comprises folding the
tabs of the retainer to engage the proximal seal member.
32. The method of claim 29, wherein the outer shell includes at
least one fluid inflow pathway and at least one fluid outflow
pathway wherein the at least one fluid inflow pathway and the at
least one fluid outflow pathway are configured to deliver ocular
fluid to a physiological outflow pathway, wherein the outer shell
includes an opening between the interior chamber and the inflow
pathway, and wherein the method further includes inserting a seal
configured to impede fluid communication between the interior
chamber the fluid inflow pathway.
33. The method of claim 29, wherein the distal seal member, the
membrane, and the proximal seal member are inserted together.
34. The method of claim 29, wherein the outer shell includes one or
more retention features configured to anchor the ocular implant in
ocular tissue.
35. A drug delivery ocular implant comprising: an outer shell
having an interior chamber providing a drug reservoir; a distal
seal member; a proximal seal member; a membrane configured to be
pressed between the distal seal member and the proximal seal member
such that the membrane is in a compressed state, wherein the
membrane in the compressed state is configured to be permeable to a
drug such that the drug elutes through the membrane; and a retainer
configured to maintain the membrane in the compressed state.
36. The ocular implant of claim 35, wherein the retainer comprises
one or more tabs that are configured to fold to secure the
retainer.
37. The ocular implant of claim 35, wherein the outer shell
comprises one or more slots and wherein the retainer is configured
to extend into the one or more slots.
38. The ocular implant of claim 35, wherein the membrane comprises
ethylene vinyl acetate having a concentration of vinyl acetate
between about 10% and about 30%, wherein the ocular implant is
configured such that the membrane in the compressed state has a
thickness of between about 75 microns and about 125 microns and
such that the membrane is compressed from an uncompressed state by
an amount between about 20 microns and about 40 microns.
39. The ocular implant of claim 35, wherein the drug reservoir is
configured to hold a volume of the drug between about 40 nanoliters
and about 150 nanoliters.
40. The ocular implant of claim 35, further comprising one or more
retention features configured to anchor the ocular implant in
ocular tissue.
41. The ocular implant of claim 35, wherein the ocular implant is
configured to be positioned in the supraciliary space.
42. The ocular implant of claim 41, wherein the ocular implant is
configured to be positioned in the suprachoroidal space.
43. The ocular implant of claim 35, wherein the ocular implant is
configured to be positioned in the suprachoroidal space.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Provisional Patent Application No. 62/004,824,
filed May 29, 2014, and titled IMPLANTS WITH CONTROLLED DRUG
DELIVERY FEATURES AND METHODS OF USING SAME, which is hereby
incorporated by reference in its entirety and made a part of this
specification for all that it discloses.
BACKGROUND
[0002] 1. Field
[0003] This disclosure relates to implantable intraocular drug
delivery devices structured to provide targeted and/or controlled
release of a drug to a desired intraocular target tissue and
methods of using such devices for the treatment of ocular diseases
and disorders. In certain embodiments, this disclosure relates to a
treatment of increased intraocular pressure wherein aqueous humor
is permitted to flow out of an anterior chamber of the eye through
a surgically implanted pathway. In certain embodiments, this
disclosure also relates particularly to a treatment of ocular
diseases with drug delivery devices affixed to the eye, such as to
fibrous tissue within the eye.
[0004] 2. Description of the Related Art
[0005] The mammalian eye is a specialized sensory organ capable of
light reception and is able to receive visual images. The retina of
the eye consists of photoreceptors that are sensitive to various
levels of light, interneurons that relay signals from the
photoreceptors to the retinal ganglion cells, which transmit the
light-induced signals to the brain. The iris is an intraocular
membrane that is involved in controlling the amount of light
reaching the retina. The iris consists of two layers (arranged from
anterior to posterior), the pigmented fibrovascular tissue known as
a stroma and pigmented epithelial cells. The stroma connects a
sphincter muscle (sphincter pupillae), which contracts the pupil,
and a set of dilator muscles (dilator pupillae) which open it. The
pigmented epithelial cells block light from passing through the
iris and thereby restrict light passage to the pupil.
[0006] Numerous pathologies can compromise or entirely eliminate an
individual's ability to perceive visual images, including trauma to
the eye, infection, degeneration, vascular irregularities, and
inflammatory problems. The central portion of the retina is known
as the macula. The macula, which is responsible for central vision,
fine visualization and color differentiation, may be affected by
age related macular degeneration (wet or dry), diabetic macular
edema, idiopathic choroidal neovascularization, or high myopia
macular degeneration, among other pathologies.
[0007] Other pathologies, such as abnormalities in intraocular
pressure, can affect vision as well. Aqueous humor is a transparent
liquid that fills at least the region between the cornea, at the
front of the eye, and the lens and is responsible for producing a
pressure within the ocular cavity. Normal intraocular pressure is
maintained by drainage of aqueous humor from the anterior chamber
by way of a trabecular meshwork which is located in an anterior
chamber angle, lying between the iris and the cornea or by way of
the "uveoscleral outflow pathway." The "uveoscleral outflow
pathway" is the space or passageway whereby aqueous exits the eye
by passing through the ciliary muscle bundles located in the angle
of the anterior chamber and into the tissue planes between the
choroid and the sclera, which extend posteriorly to the optic
nerve. About two percent of people in the United States have
glaucoma, which is a group of eye diseases encompassing a broad
spectrum of clinical presentations and etiologies but unified by
increased intraocular pressure. Glaucoma causes pathological
changes in the optic nerve, visible on the optic disk, and it
causes corresponding visual field loss, which can result in
blindness if untreated. Increased intraocular pressure is the only
risk factor associated with glaucoma that can be treated, thus
lowering intraocular pressure is the major treatment goal in all
glaucomas, and can be achieved by drug therapy, surgical therapy,
or combinations thereof.
[0008] Many pathologies of the eye progress due to the difficulty
in administering therapeutic agents to the eye in sufficient
quantities and/or duration necessary to ameliorate symptoms of the
pathology. Often, uptake and processing of the active drug
component of the therapeutic agent occurs prior to the drug
reaching an ocular target site. Due to this metabolism, systemic
administration may require undesirably high concentrations of the
drug to reach therapeutic levels at an ocular target site. This can
not only be impractical or expensive, but may also result in a
higher incidence of side effects. Topical administration is
potentially limited by limited diffusion across the cornea, or
dilution of a topically applied drug by tear-action. Even those
drugs that cross the cornea may be unacceptably depleted from the
eye by the flow of ocular fluids and transfer into the general
circulation. Thus, a means for ocular administration of a
therapeutic agent in a controlled and targeted fashion would
address the limitations of other delivery routes.
SUMMARY
[0009] Various embodiments disclosed herein can relate to a drug
delivery ocular implant. The ocular implant can include an outer
shell having a proximal end and a distal end, and the outer shell
can be shaped to define an interior chamber. A drug can be
positioned within the interior chamber. The ocular implant can
include a drug release element configured to release the drug from
the interior chamber. The drug release element can include a distal
seal member that includes at least one opening, a proximal seal
member that includes at least one opening, and a membrane
compressed between the distal seal member and the proximal seal
member. A retainer can be configured to retain the drug release
element in place relative to the outer shell. The drug release
element can be configured such that the drug passes through the at
least one opening in the distal seal member, through the compressed
membrane, through the at least one opening in the proximal seal
member, and out the proximal end of the outer shell.
[0010] The retainer can include one or more tabs that can be folded
to engage the proximal seal member. In some embodiments, the one or
more tabs can be folded to engage the membrane. The outer shell can
include one or more slots and the retainer can extend into the one
or more slots and can be positioned proximally of the proximal seal
member. The retainer can have a lateral length that is greater than
an inner diameter of the interior chamber adjacent the retainer and
that is less than or equal to an outer diameter of the outer shell
adjacent the retainer. In some embodiments, the interior chamber
can include a shelf, and the distal seal member can be seated
against the shelf.
[0011] The membrane can include ethylene vinyl acetate, which can
have a concentration of vinyl acetate between about 10% and about
30%, or various other concentrations as discussed herein. The
compressed membrane can have a thickness of between about 75
microns and about 125 microns, and/or the membrane can be
compressed from an uncompressed state by an amount between about 20
microns and about 40 microns, although other thicknesses and
amounts of compression can be used as discussed herein.
[0012] The drug release element can provide an elution rate between
about 15 nanograms per day and about 35 nanograms per day, although
other elution rates can be used as discussed herein. The ocular
implant can be configured to hold a volume of the drug between
about 40 nanoliters and about 150 nanoliters, although other
volumes can be used as discussed herein. The ocular implant has a
total longitudinal length of between about 1 mm and about 3 mm,
although other dimensions can be used as discussed herein. In some
embodiments, the outer shell can include a ceramic material.
[0013] The ocular implant can include at least one fluid inflow
pathway and at least one fluid outflow pathway, and the at least
one fluid inflow pathway and the at least one fluid outflow pathway
are configured to deliver ocular fluid to a physiological outflow
pathway. The outer shell can include an opening between the
interior chamber and the inflow pathway, and the ocular implant can
include a seal configured to impede fluid communication between the
interior chamber the fluid inflow pathway. The seal can include a
recess on a proximal side, and a portion of the drug can be
positioned inside the recess of the seal. The ocular implant can
include a flange extending laterally outwardly between the at least
one fluid inflow pathway and the at least one fluid outflow
pathway. The ocular implant can include one or more standoffs
configured to reduce compression of the physiological outflow
pathway by the implant. In some embodiments, the physiological
outflow pathway is Schlemm's Canal. In some embodiments, the ocular
implant can include a positioning protrusion configured to engage
an implantation tool to facilitate rotation of the implant about a
longitudinal axis during implantation.
[0014] In some embodiments, the drug can be formulated as an oil.
The drug can include a prostaglandin, a prostaglandin analog, a
prostaglandin inhibitor, a beta-adrenergic receptor antagonist, or
combinations thereof, although other drugs can be used as discussed
herein. In some embodiments, the drug can include travoprost.
[0015] The ocular implant can include one or more retention
features configured to anchor the ocular implant in ocular tissue.
The one or more retention features can include a retention
protrusion on the distal end of the outer shell. The retention
protrusion can be configured to anchor the ocular implant at a
target tissue site.
[0016] The ocular implant can be configured to be positioned in the
supraciliary space. The ocular implant can be configured to be
positioned in the suprachoroidal space. The ocular implant can be
configured to be positioned in the supraciliary space and the
suprachoroidal space. In some embodiments, the outer shell can be
flexible.
[0017] Various embodiment disclosed herein can relate to a method
of making a drug delivery ocular implant. The method can include
providing an outer shell having a proximal end and a distal end.
The outer shell can define an interior chamber. The method can
include placing a drug into the interior chamber, inserting a
distal seal member into the interior chamber, inserting a membrane
into the interior chamber, inserting a proximal seal member into
the interior chamber, pressing the proximal seal member towards the
distal seal member to compress the membrane into a compressed
state, and attaching a retainer to retain the membrane in the
compressed state.
[0018] The outer shell can include one or more slots and attaching
the retainer can include inserting the retainer laterally through
the one or more slots such that the retainer is disposed proximally
of the proximal seal member. The retainer can include one or more
tabs, and the method can include folding the tabs of the retainer
to engage the proximal seal member and/or the membrane.
[0019] The outer shell can include at least one fluid inflow
pathway and at least one fluid outflow pathway. The at least one
fluid inflow pathway and the at least one fluid outflow pathway can
be configured to deliver ocular fluid to a physiological outflow
pathway. The outer shell can include an opening between the
interior chamber and the inflow pathway and the method can include
inserting a seal configured to impede fluid communication between
the interior chamber the fluid inflow pathway.
[0020] In some embodiments, the distal seal member, the membrane,
and the proximal seal member are inserted together.
[0021] In some embodiments, the outer shell includes one or more
retention features configured to anchor the ocular implant in
ocular tissue. A retention protrusion on the distal end of the
outer shell can be configured to anchor the ocular implant in
ocular tissue.
[0022] Various embodiments disclosed herein can relate to a drug
delivery ocular implant. The ocular implant can include an outer
shell having an interior chamber providing a drug reservoir, a
distal seal member, a proximal seal member, and a membrane
configured to be pressed between the distal seal member and the
proximal seal member such that the membrane is in a compressed
state. The membrane in the compressed state can be configured to be
permeable to a drug such that the drug elutes through the membrane.
The ocular implant can include a retainer configured to maintain
the membrane in the compressed state.
[0023] The retainer can include one or more tabs that are
configured to fold to secure the retainer. The outer shell can
include one or more slots and the retainer can be configured to
extend into the one or more slots.
[0024] The membrane can include ethylene vinyl acetate, which can
have a concentration of vinyl acetate between about 10% and about
30%, although other concentrations can be used as discussed herein.
The ocular implant can be configured such that the membrane in the
compressed state has a thickness of between about 75 microns and
about 125 microns and/or such that the membrane is compressed from
an uncompressed state by an amount between about 20 microns and
about 40 microns, although other thicknesses and amounts of
compression can be used as discussed herein. In some embodiments,
the drug reservoir can be configured to hold a volume of the drug
between about 40 nanoliters and about 150 nanoliters, although
other volumes can be used as discussed herein.
[0025] The ocular implant can include one or more retention
features configured to anchor the ocular implant in ocular tissue.
The ocular implant can be configured to be positioned in the
supraciliary space. The ocular implant can be configured to be
positioned in the suprachoroidal space. The ocular implant can be
configured to be positioned in the supraciliary space and the
suprachoroidal space.
[0026] Several embodiments disclosed herein provide a drug delivery
ocular implant comprising an outer shell having a proximal end, a
distal end, the outer shell being shaped to define an interior
chamber (e.g., an interior lumen), at least a first active drug
positioned within the interior lumen, a cap configured for
reversible interaction with the proximal end of the outer shell, a
membrane positioned between the cap and the proximal end of the
outer shell, and a retention protrusion on the distal end of the
outer shell that is configured to anchor the ocular implant at a
target tissue site.
[0027] In several embodiments, the cap comprises at least one
aperture. In several embodiments a plurality of apertures are
provided. The overall surface area of the one or more apertures can
be selected in a particular embodiment, based on the desired rate
of elution of the first active drug from the implant.
[0028] In several embodiments, the placement of the cap over the
proximal end of the outer shell enables the retention of the
membrane between the cap and the proximal end of the outer shell.
In some embodiments the cap is a press-fit cap, while other
embodiments employ a crimp cap, screw cap or other type of cap. In
several embodiments, the membrane is permeable to the at least a
first active drug as well as to ocular fluid (and/or the water
component of ocular fluid). In several embodiments, the membrane
(once the cap is positioned) occludes the at least one aperture,
such that elution of the at least a first active drug occurs only
through the membrane (e.g., the compression of the membrane by the
cap also functions to seal the implant to other routes of
unintended drug release). In several embodiments, a distally
positioned seal is placed within the lumen to limit the fluid
communication between the interior lumen and the ocular space to
that occurring through the membrane. In several embodiments,
selected combinations of the membrane and the dimensions (e.g.,
surface area) of the aperture(s) are tailored to a specifically
desired elution rate of the first active agent.
[0029] In several embodiments, the membrane has a thickness of
between about 50 and about 100 microns. In such embodiments, such a
thickness results in drug elution from the implant for a period of
time ranging from about 12 to about 24 months. In several
embodiments, the membrane has a thickness of between about 90 and
about 200 microns. In such embodiments, such a thickness results in
drug elution from the implant for a period of time ranging from
about 24 to about 48 months.
[0030] In several embodiments, the outer shell further comprises at
least one fluid inflow pathway and one fluid outflow pathway, and
wherein the at least one fluid inflow pathway and one fluid outflow
pathway are configured to deliver ocular fluid to a physiological
outflow pathway. Thus, in several embodiments, the implant is
configured not only to provide a pharmaceutical therapy, but also a
physical therapy (e.g., drainage). In several embodiments, the
physiological outflow pathway is Schlemm's Canal. In several
embodiments, the at least one first active drug comprises a
prostaglandin, a prostaglandin analog, a prostaglandin inhibitor,
and/or combinations thereof. Additionally, in several embodiments,
a second agent may optionally be provided. In several embodiments,
the second (or third, etc.) agent results in synergistic effects
when combined with the first agent. In other embodiments, the
second agent reduces one or more side effects associated with the
first agent.
[0031] Additionally, there is provided, in several embodiments, a
drug delivery ocular implant comprising an elongate outer shell
having a proximal end, a distal end, the outer shell being shaped
to define an interior lumen, at least a first active drug
positioned within the interior lumen, at least one fluid flow
pathway running from a proximal region of the outer shell to a more
distal region of the outer shell, a valve positioned at the
distal-most end of the outer shell, wherein the valve is reversibly
openable to enable passage of the at least a first active drug from
the interior lumen to a target site external to the implant.
[0032] In several embodiments the at least one fluid flow pathway
is configured to deliver ocular fluid to a physiological outflow
pathway (e.g., supplementing the pharmacologic effects of the
active agent). In several embodiments, the first active drug
comprises a plurality of drug pellets, and the implant comprises at
least a second active agent. In several embodiments, the second
active agent is housed within a polymer configured to polymerize
and become solid or semi-solid at physiological temperature.
[0033] In several embodiments, the second active agent is housed
within a micelle or vesicular structure configured to release the
second active agent at a known rate. In several embodiments, the
second active agent is housed within a micelle or vesicular
structure configured to release the second active agent at a known
rate and wherein the micelle or vesicular structure is admixed with
a polymer configured to polymerize and become solid or semi-solid
at physiological temperature. Thus, in several such embodiments,
delivery of the second agent to the ocular target tissue results in
polymerization of the polymer upon exposure to the normal body
temperatures of the intraocular environment, thus reducing
migration of the second agent away from the target site (thereby
improving its therapeutic effects).
[0034] In several additional embodiments, there is provided a drug
delivery ocular implant comprising an elongate outer shell having a
proximal end, a distal end, the outer shell being shaped to define
an interior lumen with at least a first active drug positioned
within the interior lumen, wherein the outer shell comprises a
first thickness and wherein the outer shell comprises one or more
regions of drug release
[0035] In several embodiments, the elongate shell is formed by
extrusion. In several embodiments, the elongate shell comprises a
biodegradable polymer. In several embodiments, the outer shell is
permeable or semi-permeable to the first active drug, thereby
allowing at least about 5% of total the elution of the first active
drug to occur through the portions of the shell having the first
thickness.
[0036] In several embodiments, the outer shell comprises
polyurethane. In several embodiments, the polyurethane comprises a
polysiloxane-containing polyurethane elastomer.
[0037] In several embodiments, the regions of drug release are
configured to allow a different rate of drug elution as compared to
the elution through the outer shell. In several embodiments, the
overall rate of elution of the first active drug out of the implant
is greater in the distal region of the implant. In several
embodiments, there is a greater amount of the first active drug in
the distal half of the implant as compared to the proximal half of
the implant. In several other embodiments, the overall rate of
elution of the first active drug out of the implant is greater in
the proximal region of the implant. In several embodiments, there
is a greater amount of the first active drug in the proximal half
of the implant as compared to the distal half of the implant. In
several such embodiments, the implant is thus configured to treat
an anterior portion of the eye of a subject, while optionally
providing (depending on the embodiment) drainage of ocular fluid to
an outflow tract.
[0038] In several embodiments, the one or more regions of drug
release comprise one or more of regions of reduced thickness shell
material, one or more orifices passing through the outer shell, or
combinations thereof. In certain embodiments, the one or more
regions of drug release comprise orifices and wherein the orifices
are positioned along the long axis of the implant shell.
[0039] In several embodiments, the implant additionally comprises
one or more coatings that alter the rate of the first active agent
elution from the implant.
[0040] In several embodiments, at least the distal-most about 5 mm
to about 10 mm of the interior lumen houses the drug.
[0041] In several embodiments, the elution of the first active drug
from the implant continues for at least a period of at least one
year.
[0042] In several embodiments, the first active drug is present as
one or more micro-tablets, wherein the micro-tablets have a density
of about 0.7 g/cc to about 1.6 g/cc, an aspect ratio of length to
diameter of about 2.8 to 3.6, and/or minor axis of about 0.28 to
0.31 mm and a major axis of about 0.8 to 1.1 mm. In several
embodiments, the first active drug is present in an amount of at
least 70% by weight of a total weight of the one or more
micro-tablets. In several embodiments, the micro-tablets have a
surface area to volume ratio of about 13 to 17. In several
embodiments, the micro-tablets have dimensions allowing passage of
the micro-tablets through a conduit having an inner diameter of
about 23 to 25 gauge.
[0043] In several embodiments, the micro-tablets are formed by
utilizing one or more of processes selected from the group
consisting of tabletting, lyophilization, granulation (wet or dry),
flaking, direct compression, molding, and extrusion. In several
embodiments, the micro-tablets are configured to balance osmotic
pressure between the interior lumen and the ocular environment
external to an implant after implantation. In further embodiments,
the micro-tablets are optionally coated with a coating that
regulates the release of the first active drug from the
micro-tablet. In some embodiments, the coating is a polymeric
coating.
[0044] In several embodiments, the first active drug is an
anti-angiogenesis agent. In several embodiments, the first active
drug is selected from the group consisting of angiostatin,
anecortave acetate, thrombospondin, VEGF receptor tyrosine kinase
inhibitors and anti-vascular endothelial growth factor (anti-VEGF)
drugs. In several embodiments, the anti-VEGF drugs are selected
from the group consisting of ranibizumab, bevacizumab, pegaptanib,
sunitinib and sorafenib. In several embodiments, the first active
drug is bevacizumab.
[0045] In several embodiments, the first active drug is a
beta-adrenergic receptor antagonist. The beta-adrenergic receptor
antagonist may be either a selective beta-adrenergic antagonist, or
a non-selective beta-adrenergic receptor antagonist. In several
embodiments, the selective beta-adrenergic receptor antagonist is
selected from the group consisting of betaxolol and levobetaxolol,
and combinations thereof. In several embodiments the non-selective
beta-adrenergic antagonist is selected from the group consisting of
timolol, levobunolol, certeolol, and metipranolol, and combinations
thereof. In several embodiments, at least one active drug is used,
and in some embodiments that at least one first active drug is
timolol.
[0046] In several embodiments, the implants as described herein
optionally further comprise a lumen configured to transport ocular
fluid from a first location in an eye to one or more other
locations, thereby reducing intraocular pressure.
[0047] There is also provided herein methods for treating an ocular
condition or disorder in an intraocular target tissue comprising
making an opening in the temporal portion of an eye to access an
anterior chamber of the eye, advancing a delivery device associated
with a drug delivery ocular implant through the opening and across
the anterior chamber of the eye, inserting the drug delivery ocular
implant into eye tissue, positioning the implant such that at least
one of the one or more regions of drug release are located
proximate an intraocular target, and withdrawing the delivery
device from the eye, wherein drug elutes from the implant in
sufficient quantity to treat an ocular condition or disorder. In
some embodiments, a therapeutic effect is achieved for a period of
at least one year.
[0048] In several embodiments, the intraocular target is in the
posterior chamber of the eye. In some embodiments, the intraocular
target is selected from the group consisting of the macula, the
retina, the optic nerve, the ciliary body, and the intraocular
vasculature. In several other embodiments, the intraocular target
is in the anterior chamber of the eye.
[0049] In several embodiments, inserting the drug delivery ocular
implant into eye tissue comprises placing at least a portion of the
implant in a portion of the eye selected from the group consisting
of uveoscleral outflow pathway, suprachoroidal space, and Schlemm's
canal. In several embodiments, the drug delivery ocular implant is
delivered to the punctum.
[0050] As such, several embodiments provide for implants for
insertion into a punctum of the eye of a subject, comprising an
outer shell having a proximal end, a distal end, the outer shell
being shaped to define an interior lumen, the outer shell
dimensioned for insertion into the punctum of the eye of a subject,
at least a first active drug positioned within the interior lumen,
at least one region of drug release the proximal portion of outer
shell, and a distal occlusive member within the inner lumen, the
distal occlusive member preventing elution of the first active drug
from the distal end of the implant.
[0051] In several such embodiments, the first active drug elutes
from the lumen to the tear film of the eye of the subject by
passing through the at least one region of drug release. In some
embodiments, the implant is dimensioned to be implanted with the
distal end of the outer shell positioned in the lacrimal duct. In
some embodiments, the implant is dimensioned to be implanted with
the distal end of the outer shell positioned in the lacrimal sac.
In several embodiments, the implant is dimensioned to be implanted
with the distal end of the outer shell positioned in the
nasolacrimal duct.
[0052] In several embodiments, the at least one region of drug
release comprises at least one aperture. Additionally, in some
embodiments, the implant further comprises at least one membrane
that occludes the at least one aperture, wherein the membrane is
permeable to the at least a first active drug, wherein the membrane
allows elution of the at least a first active drug to occur only
through the at least one membrane.
[0053] In several embodiments, the at least one region of drug
release comprises a plurality of apertures through the outer shell
and positioned randomly or in a patterned array throughout the
proximal portion of the implant. As above, at least a portion of
the plurality of apertures is occluded by a membrane permeable to
the first active drug.
[0054] In several embodiments, the implant further comprises a cap
configured for reversible interaction with the proximal end of the
outer shell, wherein the cap comprises at least one aperture. In
some embodiments, the implant further comprises a membrane
positioned between the proximal end of the outer shell and the cap,
wherein the membrane occludes the at least one aperture, wherein
the membrane is permeable to the at least a first active drug, and
wherein the membrane allows elution of the at least a first active
drug to occur only through the at least one membrane.
[0055] Advantageously, in several embodiments, the at least one
membrane is dimensioned based on the permeability of the membrane
to the at least a first active drug and the desired duration of
elution of the first active drug, thereby creating a customized
elution profile. For example, in several embodiments, the membrane
has a thickness of between about 50 and about 100 microns. In some
such embodiments, the at least a first active drug elutes from the
ocular implant for a period of time ranging from about 12 to about
24 months. In some embodiments, the membrane has a thickness of
between about 90 and about 200 microns. In some such embodiments,
the at least a first active drug elutes from the ocular implant for
a period of time ranging from about 24 to about 48 months.
[0056] In several embodiments, the distal occlusive member
comprises a plug. In additional embodiments, the distal occlusive
member comprises a one-way valve allowing fluid flow from the
interior lumen to the distal end of the device. In some such
embodiments, the one-way valve is configured to remain closed until
exposed to elevated fluid pressure. For example, in several
embodiments the one-way valve is configured to open in response to
instilled fluid to allow flushing of the interior lumen to the
nasolacrimal duct. This may occur, for example if the concentration
or type of drug eluted from the implant is changed, or when the
implant is reloaded.
[0057] In several embodiments, the implant, being configured for
insertion into the punctum, has a length of between about 0.5 and
about 2.5 mm. For example, in several embodiments the implant has a
length of about 1.4 to about 1.6 mm. In several embodiments, the
implant has a diameter of about 0.2 to about 1.5 mm. For example,
in several embodiments the implant has a diameter of about 0.2 to
about 1.5 mm. In some embodiments, the implant has a diameter of
about 0.2 to about 0.6 mm. Advantageously, the length and diameter
of any of the implants disclosed herein can be adjusted to the
dimensions of a physiological space of a subject in which the
implant is to be positioned. In several embodiments, this ensures
that the implant is positioned, and remains positioned, at a
desired location.
[0058] In several embodiments, the first active drug is positioned
in the proximal portion of the lumen of the implant for placement
in the punctum. In several embodiments, the first active drug is
for the treatment of dry eye. For example, in several embodiments,
the first active drug is cyclosporine, cyclosporine A,
moxifloxacin, or combinations of those drugs (or with any of the
other drugs disclosed herein). In several embodiments, the first
active drug is an anti-glaucoma medication. In several embodiments,
the first active drug is a steroid. In several embodiments, the
first active drug facilitates tear production.
[0059] There is also provided for a composition for the treatment
of an ocular disorder, comprising a therapeutic agent having
anti-vascular endothelial growth factor (VEGF) effects, wherein the
anti-VEGF agent is formed into at least one micro-tablet. In
several embodiments, the anti-VEGF agent is lyophilized prior to
formation of the micro-tablets. In some embodiments, the anti-VEGF
agent comprises at least 70% by weight of the total weight of each
micro-tablet, and in some embodiments, each micro-tablet has a
density of about 0.7 g/cc to about 1.6 g/cc. In additional
embodiments, each of the micro-tablets has a minor axis of about
0.28 to 0.31 mm and a major axis of about 0.8 to 1.1 mm. In several
embodiments, each of the micro-tablets has an aspect ratio of
length to diameter of about 2.8 to 3.6.
[0060] In addition, there is provided a system for administering a
therapeutic agent to an damaged or diseased eye, comprising an
ocular implant delivery apparatus comprising a proximal end, a
distal end, and a cannula having an inner diameter of about 23 to
25 gauge, an ocular implant comprising an elongate outer shell
having a proximal end, a distal end, the outer shell being shaped
to define an interior lumen suitable for receiving one or more
micro-tablets and comprising at least a first thickness and
comprising one or more regions of drug release, and a therapeutic
agent formed in at least one micro-tablet, the agent having
anti-vascular endothelial growth factor (VEGF) effects. In several
embodiments, the anti-VEGF agent is lyophilized prior to formation
of the micro-tablets. In some embodiments, the anti-VEGF agent
comprises at least 70% by weight of the total weight of each
micro-tablet. In some embodiments, each micro-tablet has a density
of about 0.7 g/cc to about 1.6 g/cc. In additional embodiments, the
micro-tablets have an aspect ratio of length to diameter of about
2.8 to 3.6.
[0061] There is additionally provided for herein methods for the
intravitreal injection of an agent for the treatment of an ocular
disorder, comprising advancing to the surface of the sclera of an
eye a delivery apparatus comprising a proximal end, a distal end,
and a cannula having an inner diameter of about 23 to 25 gauge and
containing one or more micro-tablets comprising a therapeutic agent
having anti-vascular endothelial growth factor (VEGF) effects, an
activator that functions to expel the contents of the cannula from
the apparatus via passage through the proximal end, piercing the
scleral surface to create a hole in the sclera, further advancing
the delivery apparatus thru the hole such that the proximal end is
within the vitreal cavity of the eye, activating the activator to
expel the anti-VEGF micro-tablets; and withdrawing the apparatus
from the eye, thereby treating the disorder by the delivery of the
anti-VEGF micro-tablets.
[0062] In several embodiments, the micro-tablets have a minor axis
of about 0.28 to 0.31 mm and a major axis of about 0.8 to 1.1 mm.
In several embodiments, the micro-tablets have a density of about
0.7 g/cc to about 1.6 g/cc.
[0063] In several embodiments, the piercing of the sclera is
performed using an apparatus having a sharpened proximal end. In
several embodiments, the hole within the sclera is sufficiently
small to be self-healing.
[0064] In accordance with several embodiments there is provided a
drug delivery ocular implant comprising an elongate outer shell
having a proximal end, and a distal end, said outer shell being
shaped to define an interior lumen, and at least a first drug
positioned within said interior lumen. In certain embodiments, the
outer shell comprises a substantially uniform first thickness,
wherein said outer shell is permeable or semi-permeable to said
drug, thereby allowing at least about 5% of the total elution of
the drug to occur through the portions of the shell having said
first thickness, and wherein said outer shell comprises one or more
regions of drug release. In some embodiments, the one or more
regions of drug release comprise regions of greater or increased
elution or permeability to the drug than the portion of the outer
shell having the first thickness. Such regions of increased
permeability may comprise one or more of the outer shell having a
reduced thickness, one or more orifices, a different material than
the remainder of the outer shell and/or other means to provide
increased permeability or elution of the drug. In other
embodiments, the entirety of the elution of the drug is through the
outer shell, the entirety of which or one or more portions of which
may be considered to be a region of drug release.
[0065] In several embodiments, there is provided a drug delivery
ocular implant comprising an elongate outer shell having a proximal
end, a distal end, the outer shell being shaped to define an
interior lumen, and at least a first drug positioned within the
interior lumen. The outer shell preferably has a substantially
uniform first thickness that allows about 5 to 15% of the total
elution of the drug to occur through the shell having the first
thickness. The outer shell may comprise one or more regions of drug
release, wherein the regions of drug release are configured to
allow different rates of drug elution as compared to each other. In
some embodiments, the overall rate of elution of drug out of the
implant is optionally differential along the length of the
implant.
[0066] In some embodiments, there are provided implants having
regions of drug release that are configured or have one or more
regions that allow a greater rate of drug elution as compared to
the elution through other regions of the outer shell. In some
embodiments, the regions of greater drug release comprise one or
more of regions of reduced thickness shell material, one or more
orifices passing through the outer shell, or combinations thereof.
In some embodiments, the outer shell optionally comprises silicone
and/or may have one or more orifices passing through the outer
shell. In such embodiments, the orifices may be positioned along
the long axis of the implant shell or elsewhere. In other
embodiments, the outer shell optionally comprises siliconized
urethane and/or may comprise regions of reduced thickness, and may
or may not have any orifices passing through the outer shell.
[0067] In several embodiments disclosed herein, there is provided a
drug delivery ocular implant comprising an outer shell having a
proximal end, a distal end, and being shaped to define an interior
lumen, the outer shell having a substantially uniform first
thickness and having one or more regions of a second, reduced shell
thickness as compared to the first thickness, and a drug positioned
within the interior lumen, wherein the thickness of the outer shell
is inversely proportional to the rate of drug elution through the
shell. In some embodiments, the outer shell of the first thickness
is substantially impermeable to the drug. Release of the drug from
the interior lumen is controlled at least in part by the
permeability of the outer shell to the drug, with regions of
reduced shell thickness having a higher rate of release.
[0068] Also provided is a drug delivery ocular implant comprising
an outer shell having a proximal end, a distal end, and being
shaped to define an interior lumen and having one or more
partitions located within the interior lumen thereby creating two
or more sub-lumens, a drug positioned within each sub-lumen. In
some embodiments, at least a portion of the outer shell is
substantially impermeable to the drug, and the outer shell also
comprises one or more regions that are more permeable to the drug
relative to the remainder of the outer shell, and wherein release
of the drug from the interior lumen is controlled at least in part
by the permeability of the more permeable outer shell regions.
[0069] In several embodiments there is also provided a drug
delivery ocular implant comprising an outer shell having a proximal
end, a distal end, and being shaped to define an interior lumen, a
drug positioned within the interior lumen, wherein at least a
portion of the outer shell is substantially impermeable to the
drug, and the outer shell comprises one or more regions that are
more permeable to the drug relative to the remainder of the outer
shell.
[0070] In several embodiments disclosed herein, there is provided a
drug delivery ocular implant comprising an outer shell being shaped
to define an interior lumen, a drug positioned within the interior
lumen, wherein the outer shell is comprises a permeable material
that is capable of conveying both a solvent and the drug through
the outer shell, wherein release of the drug from the interior
lumen is initiated by the exposure of the outer shell to a suitable
solvent, such that the solvent is conveyed through the permeable
material to contact the drug, wherein after contact the solvent
contacts the drug, the drug is conveyed through the permeable
material to the exterior of the outer shell, and wherein the
conveyance of the drug is controlled at least in part by the
permeability of the permeable material. The outer shell may also
include one or more regions of substantially impermeable
material.
[0071] In several embodiments, there is provided a medical device
for the delivery of a therapeutic agent to a patient, comprising an
device dimensioned to be positioned at an area of a patient's body,
a therapeutic agent positioned on or in at least a portion of the
device, and wherein at least a portion of the device provides a
physical effect useful toward mitigation of an unwanted side effect
of the therapeutic agent.
[0072] In several embodiments, there is provided a drug delivery
ocular implant comprising an outer shell that has one or more
orifices therein, the shell being shaped to define an interior
lumen a drug positioned within the interior lumen one or more
coatings positioned on the interior surface of the shell, the outer
surface of the shell, and/or partially or fully enveloping the drug
positioned within the interior lumen. Embodiments may further
comprise one or more of the following optional features: the outer
shell comprises a material substantially impermeable to ocular
fluids, the outer shell is substantially impermeable to the drug,
at least one of the coatings at least partially defines the release
rate of the drug, and the implant is dimensioned such that the
distal end of the implant is positioned in the suprachoroidal space
and the proximal end of the implant is positioned fully within the
eye.
[0073] In several embodiments, there is provided a drug delivery
ocular implant comprising an outer shell that is optionally
substantially impermeable to ocular fluids and has one or more
orifices therein, the shell being shaped to define an interior
lumen, a drug positioned within the interior lumen, one or more
coatings positioned on the interior surface of the shell, the outer
surface of the shell, and/or partially or fully enveloping the drug
positioned within the interior lumen, and wherein the implant is
dimensioned such that the drug is released to a desired intraocular
target post-implantation.
[0074] In several embodiments, there is provided a drug delivery
ocular implant comprising a flexible material compounded or coated
with at least one drug, a flexible tether, wherein the flexible
material may be rolled or folded to form a tube shape, wherein the
tube shape is dimensioned to be placed within a delivery apparatus,
wherein the delivery apparatus deploys the drug delivery ocular
implant to an intraocular tissue, wherein the tube shape is
released upon withdrawal of the delivery apparatus, thereby
allowing the flexible material, which may be in the form of a sheet
or disc, to return substantially to its original shape or
configuration.
[0075] In several embodiments, there is provided a drug delivery
ocular implant comprising an outer shell shaped to define an
interior lumen or space with one open end, a cap dimensioned to fit
within or over the one open end and having one or more orifices
therein, and a drug positioned within the interior lumen. One or
more coatings are optionally positioned on the interior surface of
the cap, the outer surface of the cap, and/or between layers of
drug positioned within the interior lumen.
[0076] Any embodiments disclosed herein may optionally further
comprise a lumen, opening or shunt configured to transport ocular
fluid from a first, undesired location, to one or more other
locations, thereby reducing intraocular pressure.
[0077] The implants provided for herein optionally provide
differential elution along the length of the implant and in some
such embodiments, have a rate of elution that is greater at the
distal portion of the implant as compared more proximal regions of
the implant. In other embodiments, the implants have a rate of
elution that is greater at the proximal portion of the implant as
compared to more distal regions of the implant. Moreover, implants
may optionally additionally comprise one or more coatings on the
interior and/or exterior of the device and/or on the drug contained
therein, that alter the rate of drug elution from the implant, the
coatings optionally covering different portions of the implant.
[0078] In several embodiments, the distal-most about 5 mm to about
10 mm of the interior lumen houses the drug. In some embodiments,
the outer shell has a length between about 10 mm and about 20 mm,
an outer diameter between about 150 microns to about 500 microns,
and an interior lumen diameter of about 75 microns to about 475
microns.
[0079] Some embodiments provided for herein result in elution of
drug from the implant with zero-order or pseudo zero-order
kinetics.
[0080] Also provided for herein are methods for treating or
preventing an ocular condition in an intraocular target tissue
comprising making an incision in the cornea or limbus of an eye in
an advantageous position (e.g., temporal, nasal, superior,
inferior, and the like), advancing a delivery device associated
with a drug delivery implant according to several of the
embodiments disclosed herein through the cornea of the eye and
across the anterior chamber of the eye, inserting at least a
portion of the drug delivery implant into the suprachoroidal space
of the eye, positioning the implant such that the one or more
regions of drug release are located sufficiently near the
intraocular target to allow substantially all of the drug released
from the implant to reach the intraocular target, and withdrawing
the delivery device from the eye.
[0081] In some embodiments, the intraocular target is the posterior
chamber of the eye, the anterior chamber of the eye, both the
anterior chamber and posterior of the eye, or the macula, the
retina, the optic nerve, the ciliary body, and the intraocular
vasculature.
[0082] In several embodiments, the drug acts on the intraocular
target tissue to generate a therapeutic effect for an extended
period. In one embodiment, the drug comprises a steroid. In such
embodiments, the implant contains a total load of steroid ranging
from about 10 to about 1000 micrograms, steroid is released from
the implant at a rate ranging from about 0.05 to about 10
micrograms per day and/or the steroid acts on the diseased or
damaged target tissue at a concentration ranging from about 1 to
about 100 nanomolar. In some embodiments, the steroid additionally
generates side effects associated with accumulation of physiologic
fluid, and an optional shunt transports the accumulated fluid from
the first location to the remote second location (such as, for
example, from the anterior chamber to an existing physiological
outflow pathway, such as Schlemm's canal or the uveoscleral
pathway). The optional shunt is also used in other embodiments,
however, wherein side effects associated with the active drug do
not include accumulation of fluid. For example, several embodiments
relate to treatment of a region with a therapeutic drug in
combination with drainage (even in the absence of therapeutic
drug-induced increases in ocular fluid production).
[0083] Various embodiments of the implants disclosed herein may
comprise one or more of the following optional features: drug being
placed near the distal end of the shell, drug being placed near the
proximal end of the shell, one or more barriers placed within the
interior lumen to limit anterior (or, in some embodiments,
posterior) elution of the drug, and/or a barrier that comprises a
one-way valve positioned to allow fluid passage through the implant
in a proximal to distal direction. In some embodiments having one
or more barriers placed within the interior lumen, the one or more
barriers facilitate the simultaneous (or sequential) elution of one
or more drugs to the anterior and/or posterior chamber for targeted
effects.
[0084] In some embodiments disclosed herein, there are provided
coatings, preferably polymeric coatings, that are biodegradable. In
some embodiments, two or more polymeric coatings are positioned on
a surface of the outer shell and in some such embodiments, each
coating has a unique rate of biodegradation in ocular fluid
(including being substantially non-biodegradable), covers a
different portion of the shell including covering one or more
optional orifices in the shell, and/or permits ocular fluid to
contact the drug within the interior lumen by passing through an
increasing number of patent orifices in the shell over time that
are created by the degradation of the coating material. In some
embodiments, the coatings are optionally placed on the outer
surface of the shell, positioned between the drug and the interior
surface of outer shell, and/or positioned to envelop the drug
within the interior lumen. The drug may be in the form of one or
more pellets, beads, or tablets, oils, gels, emulsions, and the
like.
[0085] In several embodiments, biodegradation of the barriers or
coatings is triggered by an externally originating stimulus, such
as, for example, intraocular injection of a fluid that initiates
biodegradation of the barrier, application of heat, ultrasound, and
radio frequency, and the like. In some embodiments, the barriers
and/or coatings degrade faster than the drug, while in other
embodiments, the degradation rate of the drug is faster, or in
still other embodiments, in which the rate of degradation is unique
for each.
[0086] Any of the embodiments disclosed herein optionally further
comprise one or more anchor structures, one or more excipients
compounded with the drug, one or more orifices or openings in the
proximal portion of the device to allow drainage of ocular fluid
from the anterior chamber of the eye, and/or one or more wicks
passing through any outer shell of the implant.
[0087] Several embodiments optionally comprise a retention
protrusion configured to anchor the implant to an ocular tissue.
Such retention protrusions optionally comprise one or more of
ridges, claws, threads, flexible ribs, rivet-like shapes, flexible
barbs, barbed tips, expanding material (such as a hydrogel), and
biocompatible adhesives. In some embodiments, the expanding
material is placed on an exterior surface of the outer shell of the
implant and expands after contact with a solvent, such as, for
example, intraocular fluid.
[0088] Implants provided for herein are optionally anchored (e.g.,
any mechanism or element that allows an implant to become affixed
to, secured to or otherwise attached, either permanently or
transiently, to a suitable target intraocular tissue) to a
intraocular tissue, such as ciliary muscles, the ciliary tendons,
the ciliary fibrous band, the trabecular meshwork, the iris, the
iris root, the lens cortex, the lens epithelium, to or within the
lens capsule, the sclera, the scleral spur, the choroid, or to or
within Schlemm's canal. In certain embodiments comprising an
implant anchored within the lens capsule, such an implant is
preferably implanted concurrently, or after, removal of the native
lens (e.g., by cataract surgery).
[0089] In some embodiments, the devices comprise one or more
regions that are permeable to a drug or more permeable to a drug
than other regions of a device. The increased permeability may be
achieved by any means, including, but not limited to: use of
thinner or decreased thickness of material that has some degree of
permeability to the drug, whereby the decreased thickness increases
the rate of diffusion or transport of the drug; orifices or holes
wherein the orifices or holes may be of any suitable size or shape
to allow egress of drug and/or ingress of ocular fluids; use of a
second material that has increased permeability of a drug; use of a
coating which enhances transport of a drug from the interior of a
device to the exterior; and any combination of the foregoing.
[0090] Any of the implant embodiments described herein may also
further comprise a lumen or passageway to allow drainage of ocular
fluid from first location to a second location, such as, for
example, from the anterior chamber of the eye to a physiological
outflow pathway.
[0091] In any of the embodiments disclosed herein, the drug
preferably is released from the implant to act on a diseased or
damaged target tissue to generate a therapeutic effect. In some
embodiments, the drug additionally generates side effects
associated with accumulation of physiologic fluid and in such
embodiments the implant may further comprise a stent or passage to
transport the accumulated fluid from the first location to the
remote second location.
[0092] According the disclosure herein, any of the implants
described may comprise a shell of metal or polymeric material,
which includes homopolymers, polymer blends and copolymers, such as
random copolymers and block copolymers. In some embodiments, the
polymeric material comprises ethyl vinyl acetate, polyethylene,
Elasthane.TM., silicone, polyurethane, polyethersulfone, and/or
polyamide. In other embodiments, the polymeric material comprises
poly(carbonate urethane), poly(ether urethane), silicone
poly(carbonate urethane), silicone poly(ether urethane),
PurSil.TM., CarboSil.TM., or Bionate.TM..
[0093] In those embodiments having regions of reduced shell
thickness, such regions may be created by any suitable means,
including one or more of ablation, stretching, etching, grinding,
and molding. The region may be in any pattern on or around the
implant, including a spiral pattern, patches, rings and/or
bands.
[0094] Regions that are characterized by having an increased rate
of drug delivery, be it by reduced shell thickness, orifices,
permeable material or any other means or combination of means
described herein may be present at or in any portion or combination
of portions of the device. Preferably the regions are placed so as
to direct the drug to tissues in the eye which are the target of
treatment by the drug. In some embodiments, such regions (or a
single such region) are preferably concentrated towards the distal
end of an elongate device so as to target delivery of a drug to
tissues in the distal portions of the posterior chamber of the eye.
In some embodiments, such regions (or a single such region) are
preferably concentrated towards the proximal end of an elongated
device so as to target delivery of a drug to tissues in the
anterior chamber of the eye.
[0095] Implants as described herein may optionally be configured to
interact with a recharging device in order to recharge the implant
with an additional or supplementary dose of the drug. Such
rechargeable implants, optionally comprise a reversible coupling
between the proximal end of the implant and a clamping sleeve on
the recharging device. In certain embodiments, the clamping sleeve
houses flexible clamping grippers that create a secure coupling
between the implant and the recharging device. The secure coupling
optionally enables the recharging device to enable a flexible
pusher or filling tube incorporated into the recharging device to
be used to deliver a drug to a lumen of the implant. In several
embodiments, the secure coupling between the implant and the
recharging device enable a spring loaded flexible pusher tube
incorporated into the recharging device to be used to deliver drug
to a lumen of the implant. In some embodiments, there is a provided
a one-way passage that allows deposition of a drug to the lumen of
the implant, but prevents the drug from escaping the lumen through
the passage after the removal of the recharging device.
[0096] In some embodiments, implants are provided that further
comprise at least one partition within the interior lumen, thereby
creating at least two sub-lumens. In some embodiments having two or
more sub-lumens, each sub-lumen optionally houses a different drug
or a different concentration of the same drug as compared to the
other sub-lumens, optionally releases a drug to a different portion
of the eye. In some embodiments where the implant houses multiple
drugs one drug is therapeutically effective against an ocular
disorder and another drug ameliorates a side effect of
administration of the first drug.
[0097] In addition to sub-lumens, several embodiments are provided
for in which implants further comprise: distal regions of the shell
that are more permeable to the drugs as compared to more proximal
regions; proximal regions of the shell that are more permeable to
the drugs as compared to more distal regions; have partitions that
are positioned perpendicular to a long axis of the outer shell;
have partitions that are semi-permeable to a drug positioned within
the sub-lumens; wherein drug release from the sub-lumens occurs
first from the distal-most sub-lumen and last from the
proximal-most sub-lumen; and/or wherein drug release from the
sub-lumens occurs first from the proximal-most sub-lumen and last
from the distal-most sub-lumen.
[0098] In some such embodiments, the partitions are optionally
varied in permeability to the drugs within the sub-lumens such that
the overall elution profile includes periods of time where drug
release is reduced or eliminated.
[0099] Any of the embodiments disclosed herein comprising a lumen,
pathway or shunt in addition to drug elution in an implant may
optionally drain fluid to any existing physiological outflow
pathway, including the suprachoroidal space, the trabecular
meshwork, or Schlemm's canal, and may optionally target drug
delivery to the anterior chamber of the eye, the posterior chamber
of the eye, both the anterior chamber and posterior of the eye,
and/or specifically target the macula, the retina, the optic nerve,
the ciliary body, and/or the intraocular vasculature.
[0100] In several such embodiments, the implant comprises a
substantially straight, rigid, generally cylindrical shell or body.
In several embodiments, the implant, when implanted, extends into
the anterior chamber at its proximal end into the suprachoroidal
space at its distal end. For example, the body may be of a length
no greater than 7 mm, preferably not greater than about 5 mm, and
more preferably not greater than about 4 mm and not shorter than
about 2 mm. In several embodiments, the body has a tip that narrows
toward a distal end of the implant. In additional embodiments, the
body comprises a substantially flexible, generally cylindrical
shell or body, that may be of length approximately 25 mm, including
about 15 to about 18 mm, about 18 to about 21 mm, about 21 to about
23 mm, about 23 to about 25 mm, about 25 mm to about 27 mm, about
27 to about 30 mm, and overlapping ranges thereof.
[0101] In several embodiments, at least one opening located in or
near the proximal end of the implant communicates with at least one
interior lumen. The proximal opening can be located in the proximal
end of the implant and can be substantially perpendicular to a
longitudinal axis of the implant. In several embodiments, a first
active drug is positioned within the interior lumen. When
implanted, the drug can elute into the anterior chamber of the eye
of a subject via the proximal opening. Control of drug elution into
the anterior chamber is achieved, depending on the embodiment, for
example, by locating a membrane having a known permeability to the
drug over or around the proximal opening. In several embodiments,
the membrane is also permeable to aqueous humor or the water
component of aqueous humor (e.g., the membrane allows two-way flow,
aqueous humor or the water component of aqueous humor into the
device, and drug out of the device). By way of example, in some
embodiments, the implant can include a drug release element, for
example, as illustrated and discussed in connection with FIGS.
32-57. The drug release element can include features similar to or
the same as the drug release elements 530, 730, or 930, or other
drug release elements disclosed herein.
[0102] In embodiments comprising a shunt, the interior lumen
terminates at one or more openings located in or near the distal
end of the implant. In such embodiments, aqueous humor from the
anterior chamber drains through the proximal opening, into the
implant, and out of the distal opening into the suprachoroidal
space to reduce the intraocular pressure of the anterior chamber of
the eye.
[0103] Any of the embodiments disclosed herein may deliver a drug
and/or provide a therapeutic effect for several days, one to two
months, at least six months, at least a year, at least two years,
at least three years, at least four years, and/or at least five
years.
[0104] Any of the embodiments disclosed herein may be configured to
target a diseased or damaged target tissue that is characterized by
a limited ability to swell without loss or impairment of
physiological function.
[0105] In several embodiments, there is provided a method of
treating or preventing an ocular condition comprising: making an
incision in the eye, inserting at least a portion of a drug
delivery implant according to several embodiments disclosed herein
into the suprachoroidal space of the eye, and withdrawing the
delivery device from the eye.
[0106] In some embodiments, the implants are positioned such that
the regions of the implant from which drug is released are located
sufficiently near an intraocular target to allow substantially all
of the drug released from the implant to reach the intraocular
target
[0107] In several embodiments, the methods disclosed herein
optionally comprise one or more of making an incision in the cornea
or limbus of the eye in an advantageous position (e.g., temporal,
nasal, superior, inferior, and the like), advancing the delivery
device through the cornea of the eye and to the site of
implantation.
[0108] In several embodiments there is provided a method for
delivering an ocular implant comprising a stent according to
several embodiments disclosed herein that simultaneously treats an
ocular condition and limits treatment-associated side-effects,
particularly those associated with increased fluid accumulation in
the eye and/or increased intraocular pressure. In several
embodiments, an ocular implant having shunt works in conjunction
with elution of a first drug from the ocular implant to lower
intraocular pressure by providing a patent outflow pathway through
which aqueous humor can drain.
[0109] Other embodiments optionally comprise placing a peripheral
iridotomy adjacent to the implanted drug delivery device and
optionally maintaining the peripheral iridotomy as patent with a
stent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0110] 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. One of ordinary skill
in the art would readily appreciated that the features depicted in
the illustrative embodiments are capable of combination in manners
that are not explicitly depicted, but are both envisioned and
disclosed herein.
[0111] FIG. 1 illustrates a schematic cross sectional view of an
eye.
[0112] FIG. 2 illustrates a drug delivery device in accordance with
embodiments disclosed herein.
[0113] FIGS. 3A and 3B illustrate drug delivery devices in
accordance with embodiments disclosed herein.
[0114] FIG. 4 illustrates a drug delivery device in accordance with
embodiments disclosed herein.
[0115] FIG. 5 illustrates a drug delivery device in accordance with
embodiments disclosed herein.
[0116] FIGS. 6A-6I illustrate various aspects of a drug delivery
device in accordance with embodiments disclosed herein.
[0117] FIG. 7 illustrates a cross sectional view of drug delivery
implant in accordance with embodiments disclosed herein.
[0118] FIG. 8 illustrates the distal portion of a drug delivery
implant in accordance with embodiments disclosed herein.
[0119] FIG. 9 illustrates the distal portion of another drug
delivery implant in accordance with embodiments disclosed
herein.
[0120] FIGS. 10A-10G illustrate other drug delivery implants in
accordance with embodiments disclosed herein.
[0121] FIGS. 11A-11B illustrate various embodiments of implants as
disclosed herein that house one or more drug-containing pellets
within the implant.
[0122] FIG. 12A illustrates another drug delivery implant
incorporating a shunt in accordance with embodiments disclosed
herein.
[0123] FIG. 12B illustrates a further drug delivery implant
incorporating a shunt in accordance with embodiments disclosed
herein.
[0124] FIG. 12C illustrates a cross-sectional view of an embodiment
of retention features disposed on a drug delivery implant in
accordance with embodiments disclosed herein.
[0125] FIGS. 13A-13C illustrate drug delivery implants in
accordance with embodiments disclosed herein.
[0126] FIG. 14 illustrates a drug delivery implant in accordance
with embodiments disclosed herein.
[0127] FIG. 15 illustrates an illustrative embodiment of a drug
delivery implant and retention protrusion.
[0128] FIG. 16 illustrates an embodiment of a drug delivery implant
in accordance with embodiments disclosed herein.
[0129] FIG. 17 illustrates another embodiment of a drug delivery
implant in accordance with embodiments disclosed herein.
[0130] FIGS. 18A-18U illustrate various drug delivery devices in
accordance with embodiments disclosed herein.
[0131] FIGS. 19A-19Y illustrate various anchor elements used in
several embodiments disclosed herein.
[0132] FIGS. 20A-20C illustrate a rechargeable drug delivery device
in accordance with embodiments disclosed herein.
[0133] FIGS. 20D and 20E depict various features of elongate
delivery devices in accordance with several embodiments disclosed
herein.
[0134] FIG. 20F illustrates one embodiment of a delivery device in
accordance with embodiments disclosed herein.
[0135] FIGS. 20G-20I illustrate various implantation configurations
of drug delivery devices in accordance with embodiments disclosed
herein.
[0136] FIG. 20J illustrates an additional feature of the distal
portion of certain drug delivery devices in accordance with
embodiments disclosed herein.
[0137] FIG. 21 illustrates an apparatus for implanting a drug
delivery device in accordance with embodiments disclosed
herein.
[0138] FIG. 22 illustrates another apparatus for implanting a drug
delivery device in accordance with embodiments disclosed
herein.
[0139] FIG. 23 illustrates a schematic cross-sectional view of an
eye with a delivery device containing an implant being advanced
across the anterior chamber. The size of the implant is exaggerated
for illustration purposes.
[0140] FIG. 24 illustrates an additional implantation procedure
according to several embodiments disclosed herein. The size of the
implant is exaggerated for illustration purposes.
[0141] FIG. 25 illustrates a schematic cross-sectional view of an
eye with a delivery device being advanced adjacent the anterior
chamber angle. The size of the implant is exaggerated for
illustration purposes.
[0142] FIG. 26 illustrates a schematic cross-section view of an eye
with a delivery device implanting an implant that extends from the
anterior chamber through the suprachoroidal space and terminates in
close proximity to the macula.
[0143] FIGS. 27A-27D illustrate a cross-sectional view an eye
during the steps of one embodiment of a method for implanting drug
delivery devices as disclosed herein.
[0144] FIG. 28 illustrates a schematic cross-sectional view of an
eye with a delivery device being advanced across the eye targeting
the iris adjacent to the anterior chamber angle. The size of the
shunt is exaggerated for illustration purposes.
[0145] FIG. 29 illustrates a schematic cross-sectional view of an
eye with another embodiment of a delivery device targeting the iris
adjacent to the anterior chamber angle. The size of the shunt is
exaggerated for illustration purposes.
[0146] FIG. 30 illustrates a schematic cross-section view of an eye
with an implant anchored to the iris.
[0147] FIG. 31 illustrates a schematic cross-section view of an eye
with an implant implanted in the anterior chamber angle.
[0148] FIG. 32 is a distal perspective view of an example
embodiment of a drug delivery ocular implant.
[0149] FIG. 33 is a proximal perspective view of the implant of
FIG. 32.
[0150] FIG. 34 is a side view of the implant of FIG. 32.
[0151] FIG. 35 is a cross-sectional perspective view of an outer
shell of the implant of FIG. 32.
[0152] FIG. 36 is a cross-sectional perspective view of the implant
of FIG. 32.
[0153] FIG. 37 is a distal exploded perspective view of the implant
of FIG. 32.
[0154] FIG. 38 is a proximal exploded perspective view of the
implant of FIG. 32.
[0155] FIG. 39 is a distal exploded perspective view of a seal of
the implant of FIG. 32.
[0156] FIG. 40 is a proximal exploded perspective view of the seal
of FIG. 39.
[0157] FIG. 41 is a distal exploded perspective view of a drug
release element of the implant of FIG. 32.
[0158] FIG. 42 is a proximal exploded perspective view of the drug
release element of FIG. 41.
[0159] FIG. 43 is a cross-sectional view of the implant of FIG.
32.
[0160] FIG. 44 is a partial cross-sectional view of the implant of
FIG. 32.
[0161] FIG. 45 is a perspective view of an example embodiment of a
seal for use with a drug delivery ocular implant.
[0162] FIG. 46 is a perspective view of an example embodiment of a
proximal seal member for use with a drug delivery ocular
implant.
[0163] FIG. 47 is a distal perspective view of another example
embodiment of a drug delivery ocular implant.
[0164] FIG. 48 is a proximal perspective view of the implant of
FIG. 47.
[0165] FIG. 49 is a distal perspective view of another example
embodiment of a drug delivery ocular implant.
[0166] FIG. 50 is a proximal perspective view of the implant of
FIG. 49.
[0167] FIG. 51 is a cross-sectional view of the implant of FIG.
49.
[0168] FIG. 52 is a perspective view of an example embodiment of an
insertion tube for use with an ocular implant.
[0169] FIG. 53 is a perspective view of another example embodiment
of an insertion tube for use with an ocular implant.
[0170] FIG. 54 is a flowchart of an example embodiment of a method
for preparing a drug delivery ocular implant.
[0171] FIG. 55 shows a perspective view of an example embodiment of
an ocular implant.
[0172] FIG. 56 shows a side view of the example embodiment of an
ocular implant of FIG. 55.
[0173] FIG. 57 shows a cross-sectional view of the example
embodiment of an ocular implant of FIG. 55.
DETAILED DESCRIPTION
[0174] Achieving local ocular administration of a drug may require
direct injection or application, but could also include the use of
a drug eluting implant, a portion of which, could be positioned in
close proximity to the target site of action within the eye or
within the chamber of the eye where the target site is located
(e.g., anterior chamber, posterior chamber, or both
simultaneously). Use of a drug eluting implant could also allow the
targeted delivery of a drug to a specific ocular tissue, such as,
for example, the macula, the retina, the ciliary body, the optic
nerve, or the vascular supply to certain regions of the eye. Use of
a drug eluting implant could also provide the opportunity to
administer a controlled amount of drug for a desired amount of
time, depending on the pathology. For instance, some pathologies
may require drugs to be released at a constant rate for just a few
days, others may require drug release at a constant rate for up to
several months, still others may need periodic or varied release
rates over time, and even others may require periods of no release
(e.g., a "drug holiday"). Further, implants may serve additional
functions once the delivery of the drug is complete. Implants may
maintain the patency of a fluid flow passageway within an ocular
cavity, they may function as a reservoir for future administration
of the same or a different therapeutic agent, or may also function
to maintain the patency of a fluid flow pathway or passageway from
a first location to a second location, e.g. function as a stent.
Conversely, should a drug be required only acutely, an implant may
also be made completely biodegradable.
[0175] Implants according to the embodiments disclosed herein
preferably do not require an osmotic or ionic gradient to release
the drug(s), are implanted with a device that minimizes trauma to
the healthy tissues of the eye which thereby reduces ocular
morbidity, and/or may be used to deliver one or more drugs in a
targeted and controlled release fashion to treat multiple ocular
pathologies or a single pathology and its symptoms. However, in
certain embodiments, an osmotic or ionic gradient is used to
initiate, control (in whole or in part), or adjust the release of a
drug (or drugs) from an implant. In some embodiments, osmotic
pressure is balanced between the interior portion(s) of the implant
and the ocular fluid, resulting in no appreciable gradient (either
osmotic or ionic). In such embodiments, variable amounts of solute
are added to the drug within the device in order to balance the
pressures.
[0176] As used herein, "drug" refers generally to one or more drugs
that may be administered alone, in combination and/or compounded
with one or more pharmaceutically acceptable excipients (e.g.
binders, disintegrants, fillers, diluents, lubricants, drug release
control polymers or other agents, etc.), auxiliary agents or
compounds as may be housed within the implants as described herein.
The term "drug" is a broad term that may be used interchangeably
with "therapeutic agent" and "pharmaceutical" or "pharmacological
agent" and includes not only so-called small molecule drugs, but
also macromolecular drugs, and biologics, including but not limited
to proteins, nucleic acids, antibodies and the like, regardless of
whether such drug is natural, synthetic, or recombinant. Drug may
refer to the drug alone or in combination with the excipients
described above. "Drug" may also refer to an active drug itself or
a prodrug or salt of an active drug.
[0177] As used herein, "patient" shall be given its ordinary
meaning and shall also refer to mammals generally. The term
"mammal", in turn, includes, but is not limited to, humans, dogs,
cats, rabbits, rodents, swine, ovine, and primates, among others.
Additionally, throughout the specification ranges of values are
given along with lists of values for a particular parameter. In
these instances, it should be noted that such disclosure includes
not only the values listed, but also ranges of values that include
whole and fractional values between any two of the listed
values.
[0178] In several embodiments, a biocompatible drug delivery ocular
implant is provided that comprises an outer shell that is shaped to
define at least one interior lumen that houses a drug for release
into an ocular space. The outer shell is polymeric in some
embodiments, and in certain embodiments is substantially uniform in
thickness, with the exception of areas of reduced thickness,
through which the drug more readily passes from the interior lumen
to the target tissue. In other words, a region of drug release may
be created by virtue of the reduced thickness. In several other
embodiments the shell of the implant comprises one or more regions
of increased drug permeability (e.g., based on the differential
characteristics of portions of the shell such as materials,
orifices, etc.), thereby creating defined regions from which the
drug is preferentially released. In other embodiments, if the
material of the outer shell is substantially permeable to a drug,
the entire outer shell can be a region of drug release. In yet
another embodiment, portions of the outer shell that surround where
the drug is placed in the interior lumen or void of the device may
be considered a region of drug release. For example, if the drug is
loaded toward the distal end or in the distal portion of the device
(e.g. the distal half or distal 2/3 of the device), the distal
portion of the device will be a region of drug release as the drug
will likely elute preferentially through those portions of the
outer shell that are proximate to the drug. Therefore, as used
herein, the term "region of drug release" shall be given its
ordinary meaning and shall include the embodiments disclosed in
this paragraph, including a region of drug permeability or
increased drug permeability based on the characteristics of a
material and/or the thickness of the material, one or more orifices
or other passageways through the implant (also as described below),
regions of the device proximate to the drug and/or any of these
features in conjunction with one or more added layers of material
that are used to control release of the drug from the implant.
Depending on the context, these terms and phrases may be used
interchangeably or explicitly throughout the present
disclosure.
[0179] In some embodiments, the outer shell comprises one or more
orifices to allow ocular fluid to contact the drug within the lumen
(or lumens) of the implant and result in drug release. In some
embodiments, as discussed in more detail below, a layer or layers
of a permeable or semi-permeable material is used to cover the
implant (wholly or partially) and the orifice(s) (wholly or
partially), thereby allowing control of the rate of drug release
from the implant. Additionally, in some embodiments, combinations
of one or more orifices, a layer or layers covering the one or more
orifices, and areas of reduced thicknesses are used to tailor the
rate of drug release from the implant.
[0180] In still other embodiments, combinations of materials may be
used to construct the implant (e.g., polymeric portions of outer
shell bonded or otherwise connected, coupled, or attached to outer
shell comprising a different material).
[0181] In still other embodiments, the drug to be delivered is not
contained within an outer shell. In several embodiments, the drug
is formulated as a compressed pellet (or other form) that is
exposed to the environment in which the implant is deployed. For
example, a compressed pellet of drug is coupled to an implant body
which is then inserted into an ocular space (see e.g., FIG. 19T).
In some embodiments, the implant body comprises a fluid flow
pathway. In some embodiments, the implant optionally comprises a
retention feature. In some embodiments, the drug is encapsulated,
coated, or otherwise covered with a biodegradable coating, such
that the timing of initial release of the drug is controlled by the
rate of biodegradation of the coating. In some embodiments, such
implants are advantageous because they allow a variable amount of
drug to be introduced (e.g., not constrained by dimensions of an
implant shell) depending on the type and duration of therapy to be
administered. In some embodiments having a shunt feature the shunt
feature works in conjunction with the drug to treat one or more
symptoms of the disease or condition affecting the patient. For
example, in some embodiments, the shunt removes fluid from the
anterior chamber while the drug simultaneously reduces the
production of ocular fluid. In other embodiments, as discussed
herein, the shunt counteracts one or more side effects of
administration of a particular drug (e.g., the shunt drains ocular
fluid that was produced by the actions of the drug).
[0182] In some embodiments, biocompatible drug delivery implants
comprise a flexible sheet or disc flexibly optionally associated
with (e.g., tethered to) a retention protrusion (e.g., an anchoring
element, gripper, claw, or other mechanism to permanently or
transiently affix the sheet or disc to an intraocular tissue). In
certain of such embodiments, the therapeutic agent is compounded
with the sheet or disc and/or coated onto the sheet or disc. In
some embodiments, the flexible sheet or disc implants are
dimensioned such that they may be rolled or folded to be positioned
within the lumen of a delivery instrument, for example a small
diameter hollow needle.
[0183] Following implantation at the desired site within the eye,
drug is released from the implant in a targeted and controlled
fashion, based on the design of the various aspects of the implant,
preferably for an extended period of time. The implant and
associated methods disclosed herein may be used in the treatment of
pathologies requiring drug administration to the posterior chamber
of the eye, the anterior chamber of the eye, or to specific tissues
within the eye, such as the macula, the ciliary body or other
ocular target tissues.
[0184] 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 a
uveoscleral outflow pathway, which functions to remove a portion of
fluid from the anterior chamber, and a suprachoroidal space
positioned between the choroid 28 and the sclera 11. The eye also
includes the posterior region 30 of the eye which includes the
macula 32.
General
[0185] In some embodiments functioning as a drug delivery device
alone, the implant is configured to deliver one or more drugs to
anterior region of the eye in a controlled fashion while in other
embodiments the implant is configured to deliver one or more drugs
to the posterior region of the eye in a controlled fashion. In
still other embodiments, the implant is configured to
simultaneously deliver drugs to both the anterior and posterior
region of the eye in a controlled fashion. In yet other
embodiments, the configuration of the implant is such that drug is
released in a targeted fashion to a particular intraocular tissue,
for example, the macula or the ciliary body. In certain
embodiments, the implant delivers drug to the ciliary processes
and/or the posterior chamber. In certain other embodiments, the
implant delivers drug to one or more of the ciliary muscles and/or
tendons (or the fibrous band). In some embodiments, implants
deliver drug to one or more of Schlemm's canal, the trabecular
meshwork, the episcleral veins, the lens cortex, the lens
epithelium, the lens capsule, the sclera, the scleral spur, the
choroid, the suprachoroidal space, retinal arteries and veins, the
optic disc, the central retinal vein, the optic nerve, the macula,
the fovea, and/or the retina. In still other embodiments, the
delivery of drug from the implant is directed to an ocular chamber
generally. It will be appreciated that each of the embodiments
described herein may target one or more of these regions, and may
also optionally be combined with a shunt feature (described
below).
[0186] In several embodiments, the implant comprises an outer
shell. In some embodiments, the outer shell is tubular and/or
elongate, while in other embodiments, other shapes (e.g., round,
oval, cylindrical, etc.) are used. In certain embodiments, the
outer shell is not biodegradable, while in others, the shell is
optionally biodegradable. In several embodiments, the shell is
formed to have at least a first interior lumen. In certain
embodiments, the first interior lumen is positioned at or near the
distal end of the device. In other embodiments, a lumen may run the
entire length of the outer shell. In some embodiments, the lumen is
subdivided. In certain embodiments, the first interior lumen is
positioned at or near the proximal end of the device. In those
embodiments additionally functioning as a shunt, the shell may have
one or more additional lumens within the portion of the device
functioning as a shunt.
[0187] In several embodiments, the drug (or drugs) is positioned
within the interior lumen (or lumens) of the implant shell. In
several embodiments, the drug is preferentially positioned within
the more distal portion of the lumen. In some embodiments, the
distal-most 15 mm of the implant lumen (or lumens) house the drug
(or drugs) to be released. In some embodiments, the distal-most 10
mm, including 1, 2, 3, 4, 5, 6, 7, 8, and 9 mm of the interior
lumen(s) house the drug to be released. In several embodiments, the
drug is preferentially positioned within the more proximal portion
of the lumen.
[0188] In some embodiments, the drug diffuses through the shell and
into the intraocular environment. In several embodiments, the outer
shell material is permeable or semi-permeable to the drug (or
drugs) positioned within the interior lumen, and therefore, at
least some portion of the total elution of the drug occurs through
the shell itself, in addition to that occurring through any regions
of increased permeability, reduced thickness, orifices etc. In some
embodiments, about 1% to about 50% of the elution of the drug
occurs through the shell itself. In some embodiments, about 10% to
about 40%, or about 20% to about 30% of the elution of the drug
occurs through the shell itself. In some embodiments, about 5% to
about 15%, about 10% to about 25%, about 15% to about 30%, about
20% to about 35%, about 25% to about 40%, about 30% to about 45%,
or about 35% to about 50% of the elution of the drug occurs through
the shell itself. In certain embodiments, about 1% to 15%,
including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14% of the
total elution of the drug (or drugs) occurs through the shell. The
term "permeable" and related terms (e.g. "impermeable" or "semi
permeable") are used herein to refer to a material being permeable
to some degree (or not permeable) to one or more drugs or
therapeutic agents and/or ocular fluids. The term "impermeable"
does not necessarily mean that there is no elution or transmission
of a drug through a material, instead such elution or other
transmission is negligible or very slight, e.g. less than about 3%
of the total amount, including less than about 2% and less than
about 1%.
[0189] In some embodiments, the implant shell has one or more
regions of increased drug permeability through which the drug is
released to the target ocular tissue in a controlled fashion.
[0190] In some embodiments, the drug or drugs are positioned within
the interior lumen or lumens of an implant wherein the implant
shell comprises one or more orifices to allow ocular fluid to
contact the agent or agents and result in drug release. In some
embodiments, the implant comprises a polymeric coating on the
exterior surface of a shell. In other embodiments, the implant
comprises a polymeric coating on the interior surface of a shell.
In still other embodiments, polymeric coatings are on both the
interior and exterior surfaces. In yet other embodiments, the
polymeric coatings are biodegradable. Some embodiments comprise a
non-polymeric coating (e.g. heparin) in place of, or in addition to
the polymeric coatings. Additionally, in some embodiments,
combinations of one or more orifices, a layer or layers covering
the one or more orifices, and areas of reduced thicknesses are used
to tailor the rate of drug release from the implant.
[0191] In some embodiments, the interior lumen containing the
drug(s) are separated from the proximal portion of the implant by
way of an proximal barrier within the interior lumen that prevents
elution of the drug to the anterior portion of the eye. In some
embodiments, the interior lumen(s) containing the drug(s) are
separated from the proximal portion of the implant by way of a one
way valve within the interior lumen that prevents elution of the
drug to the anterior portion of the eye, but allows ocular fluid
from the anterior portion of the eye to reach the interior lumen(s)
containing the drug(s).
[0192] In some embodiments, the implant further comprises a
proximal portion structured for recharging/refilling the implant
with the same, or an additional therapeutic drug, multiple drugs,
or adjuvant compound, or compounds.
[0193] In some embodiments comprising a shunt, the shunt portion,
following implantation at an implantation site, drains fluid from
an ocular chamber into a physiologic outflow space to reduce
intraocular pressure. In some embodiments, the implant is
dimensioned such that when either the proximal or distal end of the
implant is at an implantation site near a tissue targeted for drug
delivery, the outflow ports of the implant will drain ocular fluid
to a remote region and/or a physiological outflow pathway.
[0194] For example, in some embodiments, the implant is dimensioned
such that, following implantation, the distal end of the implant is
located sufficiently close to the macula that the drug delivered by
the implant reaches the macula. In some embodiments incorporating a
shunt feature, the implant is dimensioned such that when the distal
end of the implant is positioned sufficiently near the macula, the
proximal end of the implant extends into the anterior chamber of
the eye. In those embodiments, outflow ports in the implant,
described in more detail below, are positioned such that the
aqueous humor will be drained into the uveoscleral outflow pathway
or other physiological outflow pathway.
[0195] In still other embodiments, combination drug delivery-shunt
implants may be positioned in any physiological location that
necessitates simultaneous drug delivery and transport of fluid from
a first physiologic site to a second site (which may be physiologic
or external to a patient). In some embodiments, the shunt feature
works in conjunction with the drug delivery function to potentiate
the therapeutic effects of the delivered agent. In other
embodiments, the therapeutic effects of the delivered agent may be
associated with unwanted side effects, such as fluid accumulation
or swelling. In some embodiments, the shunt feature functions
ameliorate the side effects of the delivered agent. It shall be
appreciated that the dimensions and features of the implants
disclosed herein may be tailored to attain targeted and/or
controlled delivery to various regions of the eye while still
allowing communication with a physiological outflow pathway.
[0196] For example, in some embodiments, the implant is dimensioned
such that following implantation 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 of the eye. In several
embodiments, the drug eluted from the implant elutes from the
proximal end of the implant into the anterior chamber. In some
embodiments incorporating a shunt feature, one or more outflow
ports in the implant are positioned such that aqueous humor will
drain into the uveoscleral pathway. In several embodiments, aqueous
humor will drain from the anterior chamber to the suprachoroidal
space.
[0197] 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 may be used to place the implant into a desired
position, such as the inferior portion of the iris, the
suprachoroidal space near the macula, in a position extending from
the anterior chamber to the suprachoroidal space, or other
intraocular region, 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, such as for example, injection
of dye and/or viscoelastic fluid, dissection, or use as a
guidewire. As used herein, the term "incision" shall be given its
ordinary meaning and may also refer to a cut, opening, slit, notch,
puncture or the like.
[0198] In certain embodiments the drug delivery implant may contain
one or more drugs which may or may not be compounded with a
bioerodible polymer or a bioerodible polymer and at least one
additional agent. In still other embodiments, the drug delivery
implant is used to sequentially deliver multiple drugs.
Additionally, certain embodiments are constructed using different
outer shell materials, and/or materials of varied permeability to
generate a tailored drug elution profile. Certain embodiments are
constructed using different numbers, dimensions and/or locations of
orifices in the implant shell to generate a tailored drug elution
profile. Certain embodiments are constructed using different
polymer coatings and different coating locations on the implant to
generate a tailored drug elution profile. Some embodiments elute
drug at a constant rate, others yield a zero-order release profile.
Yet other embodiments yield variable elution profiles. Still other
embodiments are designed to stop elution completely or nearly
completely for a predetermined period of time (e.g., a "drug
holiday") and later resume elution at the same or a different
elution rate or elution concentration. Some such embodiments elute
the same therapeutic agent before and after the drug holiday while
other embodiments elute different therapeutic agents before and
after the drug holiday.
Drug Delivery Implants
[0199] The present disclosure relates to ophthalmic drug delivery
implants which, following implantation at an implantation site,
provide controlled release of one or more drugs to a desired target
region within the eye, the controlled release being for an
extended, period of time. Various embodiments of the implants are
shown in FIGS. 2-20 and will be referred to herein.
[0200] FIG. 2 depicts a cross sectional schematic of one embodiment
of an implant in accordance with the description herein. The
implant comprises an outer shell 54 made of one or more
biocompatible materials. The outer shell of the implant is
manufactured by extrusion, drawing, injection molding, sintering,
micro machining, laser machining, and/or electrical discharge
machining, or any combination thereof. Other suitable manufacturing
and assembly methods known in the art may also be used. In several
embodiments, the outer shell is tubular in shape, and comprises at
least one interior lumen 58. In some embodiments the interior lumen
is defined by the outer shell and a partition 64. In some
embodiments, the partition is impermeable, while in other
embodiments the partition is permeable or semi-permeable. In some
embodiments, the partition allows for the recharging of the implant
with a new dose of drug(s). In some other embodiments, other shell
shapes are used, yet still produce at least one interior lumen. In
several embodiments the outer shell of the implant 54 is
manufactured such that the implant has a distal portion 50 and a
proximal portion 52. In several embodiments, the thickness of the
outer shell 54 is substantially uniform. In other embodiments the
thickness varies in certain regions of the shell. Depending on the
desired site of implantation within the eye, thicker regions of the
outer shell 54 are positioned where needed to maintain the
structural integrity of the implant.
[0201] In some embodiments, the implant is made of a flexible
material. In other embodiments, a portion of the implant is made
from flexible material while another portion of the implant is made
from rigid material. In some embodiments, the implant comprises one
or more flexures (e.g., hinges). In some embodiments, the drug
delivery implant is pre-flexed, yet flexible enough to be contained
within the straight lumen of a delivery device.
[0202] In other embodiments, at least a portion of the implant
(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 implant has a preformed
shape. In other embodiments, at least a portion of the implant is
made of a superelastic material. In some embodiments, at least a
portion of the implant is made up of nitinol. In other embodiments,
at least a portion of the implant is made of a deformable
material.
[0203] In several embodiments the majority of the surface of the
outer shell of the implant is substantially impermeable to ocular
fluids. In several embodiments, the majority of the surface of the
outer shell of the implant is also substantially impermeable to the
drug 62 housed within the interior lumen of the implant (discussed
below). In other embodiments, the outer shell is semi-permeable to
drug and/or ocular fluid and certain regions of the implant are
made less or more permeable by way of coatings or layers or
impermeable (or less permeable) material placed within or on the
outer shell.
[0204] In several embodiments, the outer shell also has one or more
regions of drug release 56. In some embodiments the regions of drug
release are of reduced thickness compared to the adjacent and
surrounding thickness of the outer shell. In some embodiments, the
regions of reduced thickness are formed by one or more of ablation,
stretching, etching, grinding, molding and other similar techniques
that remove material from the outer shell. In other embodiments the
regions of drug release are of a different thickness (e.g., some
embodiments are thinner and other embodiments are thicker) as
compared to the surrounding outer shell, but are manufactured with
an increased permeability to one or more of the drug 62 and ocular
fluid. In still other embodiments, the outer shell is uniform or
substantially uniform in thickness but constructed with materials
that vary in permeability to ocular fluid and drugs within the
lumen. As such, these embodiments have defined regions of drug
release from the implant.
[0205] The regions of drug release may be of any shape needed to
accomplish sufficient delivery of the drug to a particular target
tissue of the eye. For example, in FIG. 2, the regions 56 are
depicted as defined areas of thinner material. FIG. 3A depicts the
regions of drug release used in other embodiments, namely a spiral
shape of reduced thickness 56. In some embodiments, the spiral is
located substantially at the distal end of the implant, while in
other embodiments, the spiral may run the length of the interior
lumen. In still other embodiments, the spiral region of drug
release is located on the proximal portion of the implant. In some
embodiments, the spiral is on the interior of the implant shell
(i.e., the shell is rifled; see FIG. 3A). In other embodiments,
spiral is on the exterior of the shell (see FIG. 3B). In other
embodiments, the region of drug release is shaped as
circumferential bands around the implant shell.
[0206] FIG. 4 depicts another embodiment, wherein a region of drug
release is located at the distal-most portion of the implant.
Certain such embodiments are used when more posterior regions of
the eye are to be treated. Alternatively, or in conjunction with
the embodiment of FIG. 4, the proximal portion of the implant may
also have a region of drug release at or near the proximal-most
portion. In other embodiments, the regions of drug release are
uniformly or substantially uniformly distributed along the distal
and/or proximal portions of the implant. In some embodiments, the
regions of drug release are located at or near the distal end of
the implant or, in alternative embodiments at or near the proximal
end of the implant (or in still additional embodiments, at or near
both the proximal and distal ends). In certain embodiments, the
implants (based on the regions of drug release (based on
thickness/permeability, orifices, layers etc.) are strategically
placed to create a differential pattern of drug elution from the
implant, depending on the target tissue to be treated after
implantation. In some embodiments, the regions of drug release are
configured to preferentially elute drug from the distal end of the
implant. In some such embodiments, the regions of drug release are
strategically located at or near a target tissue in the more
posterior region of the eye after the implantation procedure is
complete. In some embodiments, the regions of drug release are
configured to preferentially elute drug from the proximal end of
the implant. In some such embodiments, the regions of drug release
are strategically located at or near a target tissue in the
anterior chamber of the eye after the implantation procedure is
complete. As discussed in more detail below, in several
embodiments, the regions of drug release comprises one (or more)
orifices that allow communication between an interior lumen of the
implant and the environment in which the implant is implanted. It
shall also be appreciated from the disclosure herein that, in
certain embodiments, combinations of regions of drug release (as
described above) may be combined with one or more orifices and/or
coatings (below) in order to tailor the drug release profile.
Similarly, the embodiments described above and depicted in FIGS.
2-4 can be adapted to be implanted into the punctum of a subject,
as described in more detail herein.
[0207] The implant in some embodiments includes a distal portion
located at the distal end of the implant. In some embodiments, the
distal portion is sufficiently sharp to pierce eye tissue near the
scleral spur of the eye. The distal portion can be sufficiently
blunt so as not to substantially penetrate scleral tissue of the
eye. In some embodiments, the implant has a generally sharpened
forward end and is 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 taper angle of the sharpened end is, for example,
about 30.degree..+-.15.degree. in some embodiments. In some
embodiments, the radius of the tip of the distal end is about 70
microns to about 200 microns. In embodiments comprising a shunt,
discussed further herein, an outlet opening is formed at the distal
end of the shunt and the distal portion gradually increases in
cross-sectional size in the proximal direction, preferably at a
generally constant taper or radius, or in a parabolic manner.
[0208] In some embodiments, the body of the implant includes 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
comprise barbs or other projections, which can extend from the
outer surface of the implant to inhibit migration of the implant
from its implanted position. In some embodiments, the projections
comprise external ribbing to resist displacement of the implant.
The surface irregularity in some embodiments interacts with the
tissue of the interior wall of the sclera and/or with the tissue of
the ciliary attachment tissue. In some embodiments, the implant is
anchored by mechanical interlock between tissue and an irregular
surface and/or by friction fit. In several embodiments, as
discussed in more detail herein, the surface irregularities
function to prevent growth of host tissue into or onto the implant
(e.g., fibrotic growth) that could, depending on the embodiment,
reduce the efficiency of drug elution.
[0209] In some embodiments, the implant incorporates fixation
features, such as flexible radial (i.e., outwardly-extending)
extensions. The extensions may be separate pieces attached to the
implant, may be formed integrally with the implant, or may be
formed by slitting the implant 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 implant, or both, to
prevent extrusion of the implant from its intended location. In
several embodiments, the extensions are longitudinally spaced along
the implant. Spacing between the extensions may be regular or
irregular. The flexibility of the fixation features will facilitate
entry through the corneal incision, and also through the ciliary
muscle attachment tissue.
[0210] In some embodiments, the implant has a cap or tip at one or
both ends. A distal end cap can include a tissue-piercing end. In
some embodiments the cap has a conically shaped tip. 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 can also 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 embodiments comprising a shunt,
the distal end cap has one or more outlet openings to allow fluid
flow. Each of the one or more outlet openings can communicate with
at least one of the one or more lumens.
[0211] In some embodiments, the implant has a proximal end cap. For
example, an O-ring cap with a region of drug release (as discussed
more fully herein and with reference to FIGS. 18K and 18M) can be
located over the proximal end of the implant to allow for drug
elution into the anterior chamber of the eye. In other embodiments,
a crimp cap comprising a region of drug release (as discussed more
fully herein and with reference to FIGS. 18L and 18N) is located
over the proximal end of the implant. Regions of the crimp cap can
be compressible such that the cap can be securely placed on, and
sealed to, the body of the implant. In some embodiments, the cap
comprises one or more orifices or layers in place of, or in
addition to, regions of drug release based on thickness and/or
permeability of the cap material. In some embodiments, a coating is
placed within the cap to cover an orifice therein. The coating may
comprise a membrane or layer of semi-permeable polymer. In some
embodiments, the coating has a defined thickness, and thus a
defined and known permeability to various drugs and ocular fluid.
In some embodiments, the coating is placed in other locations,
including on the exterior of the cap, within the orifice, or
combinations thereof. In several embodiments, the embodiments
described above are adapted for implantation of the implant into
the punctum of a subject, as described in more detail herein.
[0212] In some embodiments, the implant has an outer diameter that
will permit the implant to fit within a 23-gauge needle during
implantation. The implant can also have a diameter that is designed
for insertion with larger needles. For example, the implant can
also be delivered with 18-, 19-, or 20-gauge needles. In other
embodiments, smaller gauge applicators, such as 23-gauge or
smaller, are used. In some embodiments, the implant has a
substantially constant cross-sectional shape through most of its
length. Alternatively, the implant can have portions of reduced or
enlarged cross-sectional size (e.g., diameter) along its length. In
some embodiments, the distal end of the implant has 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 distal 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 30-gauge
to about 23-gauge, and preferably about 25-gauge.
[0213] In several embodiments, lumens are present in both the
proximal and distal portions of the implant (see FIGS. 5; 58a and
58, respectively). In such embodiments both the proximal 52 and the
distal portion 50 of the implant have one or more regions of drug
release. In some such embodiments the proximal and distal portions
of the implant house two different drugs 62a (proximal) and 62
(distal) in the lumens. See FIG. 5. In other embodiments, the
proximal and distal portion of the implant may house the same
drugs, or the same drug at different concentrations or combined
with alternate excipients. It will be appreciated that the
placement of the regions of drug release, whether within the
proximal portion, distal portion, or both portions of the implant,
are useful to specifically target certain intraocular tissues. For
example, placement of the region of drug release at the distal most
portion of the implant, is useful, in some embodiments, for
specifically targeting drug release to particular intraocular
regions, such as the macula. In other embodiments, the regions of
drug release are placed to specifically release drug to other
target tissues, such as the ciliary body, the retina, the
vasculature of the eye, or any of the ocular targets discussed
above or known in the art. In some embodiments, the specific
targeting of tissue by way of specific placement of the region of
drug release reduces the amount of drug needed to achieve a
therapeutic effect. In some embodiments, the specific targeting of
tissue by way of specific placement of the region of drug release
reduces non-specific side effects of an eluted drug. In some
embodiments, the specific targeting of tissue by way of specific
placement of the region of drug release increases the overall
potential duration of drug delivery from the implant.
[0214] Regardless of their shape and location(s) on the outer shell
of the implant, the regions of drug release are of a defined and
known area. The defined area assists in calculating the rate of
drug elution from the implant (described below). The regions of
drug release are formed in several embodiments by reducing the
thickness of the outer shell in certain defined areas and/or
controlling the permeability of a certain region of the outer
shell. FIGS. 6A-I represent certain embodiments of the region of
drug release. FIGS. 6A and B depict overlapping regions of a
thicker 54 and thinner 54a portion of the outer shell material with
the resulting formation of an effectively thinner region of
material, the region of drug release 56. FIGS. 6C and 6D depict
joinder of thicker 54 with thinner 54a portions of the outer shell
material. The resulting thinner region of material is the region of
drug release 56. It will be appreciated that the joining of the
thicker and thinner regions may be accomplished by, for example,
butt-welding, gluing or otherwise adhering with a biocompatible
adhesive, casting the shell as a single unit with varying
thickness, heat welding, heat fusing, fusing by compression, or
fusing the regions by a combination of heat and pressure. Other
suitable joining methods known in the art may also be used.
[0215] FIG. 6E depicts a thicker sleeve of outer shell material
overlapping at least in part with a thinner shell material. The
thinner, non-overlapped area, 56, is the region of drug release. It
will be appreciated that the degree of overlap of the material is
controllable such that the region of non-overlapped shell is of a
desired area for a desired elution profile.
[0216] FIG. 6F illustrates an outer shell material with a thin area
56 formed by one or more of ablation, stretching, etching,
grinding, molding and other similar techniques that remove material
from the outer shell.
[0217] FIG. 6G depicts a "tube within a tube" design, wherein a
tube with a first thickness 54 is encased in a second tube with a
second thickness 54a. The first tube has one or more breaks or gaps
in the shell, such that the overlaid thinner shell 54a covers the
break or gap, thereby forming the region of drug release. In the
embodiment shown in FIG. 6G, and in certain other embodiments, the
break or gap in the shell with a first thickness 54, does not
communicate directly with the external environment.
[0218] FIG. 6H depicts an embodiment wherein the region of drug
release is bordered both by the outer shell 54 and by a
substantially impermeable matrix material 55 having a communicating
particulate matter 57 dispersed within the impermeable matrix. In
several embodiments, the communicating particulate matter is
compounded with the impermeable matrix material during implant
manufacturing. The implant may then be contacted with a solvent,
which is subsequently carried through the communicating particulate
matter and reaches the drug housed within the lumen of the implant.
Preferred solvents include water, saline, or ocular fluid, or
biocompatible solvents that would not affect the structure or
permeability characteristics of the impermeable matrix.
[0219] As the drug in the lumen is dissolved into the solvent, it
travels through the communicating particulate matter from the lumen
of the implant to the ocular target tissue. In some embodiments,
the implant is exposed to a solvent prior to implantation in the
eye, such that drug is ready for immediate release during or soon
after implantation. In other embodiments, the implant is exposed
only to ocular fluid, such that there is a short period of no drug
release from the implant while the ocular fluid moves through the
communicating particulate matter into the lumen of the implant.
[0220] In some such embodiments, the communicating particulate
matter comprises hydrogel particles, for example, polyacrylamide,
cross-linked polymers, poly2-hydroxyethylmethacrylate (HEMA)
polyethylene oxide, polyAMPS and polyvinylpyrrolidone, or naturally
derived hydrogels such as agarose, methylcellulose, hyaluronan.
Other hydrogels known in the art may also be used. In some
embodiments, the impermeable material is silicone. In other
embodiments, the impermeable material may be Teflon.RTM., flexible
graphite, silicone rubber, silicone rubber with fiberglass
reinforcement, Neoprene.RTM., fiberglass, cloth inserted rubber,
vinyl, nitrile, butyl, natural gum rubber, urethane, carbon fiber,
fluoroelastomer, and or other such impermeable or substantially
impermeable materials known in the art. In this and other
embodiments disclosed herein, terms like "substantially
impermeable" or "impermeable" should be interpreted as relating to
a material's relative impermeability with regard to the drug of
interest. This is because the permeability of a material to a
particular drug depends upon characteristics of the material (e.g.
crystallinity, hydrophilicity, hydrophobicity, water content,
porosity) and also to characteristics of the drug.
[0221] FIG. 6I depicts another embodiment wherein the region of
drug release is bordered both by the outer shell 54 and by an
impermeable matrix material 55, such as silicone having a
communicating particulate matter 57 dispersed within the
impermeable matrix. In other embodiments, the impermeable material
may be Teflon.RTM., flexible graphite, polydimethylsiloxane and
other silicone elastomers, Neoprene.RTM., fiberglass, cloth
inserted rubber, vinyl, nitrile, butyl, natural gum rubber,
urethane, carbon fiber, fluoroelastomer, and or other such
impermeable or substantially impermeable materials known in the
art. In several embodiments, the communicating particulate matter
is compounded with the impermeable matrix material during implant
manufacturing. The resultant matrix is impermeable until placed in
a solvent that causes the communicating particulate matter to
dissolve. In several embodiments, the communicating particles are
salt crystals (for example, sodium bicarbonate crystals or sodium
chloride crystals). In other embodiments, other soluble and
biocompatible materials may be used as the communicating
particulate matter. Preferred communicating particulate matter is
soluble in a solvent such as water, saline, ocular fluid, or
another biocompatible solvent that would not affect the structure
or permeability characteristics of the impermeable matrix. It will
be appreciated that certain embodiments, the impermeable matrix
material compounded with a communicating particulate matter has
sufficient structural integrity to form the outer shell of the
implant (i.e., no additional shell material is necessary).
[0222] In certain embodiments, the communicating particles are
extracted with a solvent prior to implantation. The extraction of
the communicating particles thus creates a communicating passageway
within the impermeable material. Pores (or other passages) in the
impermeable material allow ocular fluid to pass into the particles,
which communicate the fluid into the lumen of implant. Likewise,
the particles communicate the drug out of the lumen of the implant
and into the target ocular tissue.
[0223] In contrast to a traditional pore or orifice (described in
more detail below), embodiments such as those depicted in FIGS. 6H
and 6I communicate drug from the lumen of the implant to the ocular
tissue through the communicating particles or through the resultant
vacancy in the impermeable matrix after dissolution of the
particle. These embodiments therefore create an indirect passage
from the lumen of the implant to the eye (i.e. a circuitous route
or tortuous path of passage). Thus, purposeful design of the
particulate material, its rate of communication of fluids or rate
of dissolution in solvent, allows further control of the rate and
kinetics of drug release. In several embodiments, the regions of
drug release are employed on implants adapted to be implanted into
the punctum of a subject, as described in more detail herein. For
example, in several implant embodiments configured for treatment of
glaucoma, the punctal implant has regions of drug release
positioned along the proximal portion of the implant, but not at
the proximal end. This advantageously allows release of the
therapeutic agent from the implant, but prevents the drainage of
tears from washing the drug down the nasolacrimal duct. See also,
FIGS. 7-9.
[0224] In several embodiments, the region of drug release comprises
one or more orifices. It shall be appreciated that certain
embodiments utilize regions of drug release that are not orifices,
either alone or in combination with one or more orifices in order
to achieve a controlled and targeted drug release profile that is
appropriate for the envisioned therapy. FIG. 7 shows a cross
sectional schematic of one embodiment of an implant in accordance
with the description herein. As discussed above, the implant
comprises a distal portion 50, a proximal portion 52, an outer
shell 54 made of one or more biocompatible materials, and one or
more orifices that pass through the shell 56a. In some embodiments
the outer shell of the implant is substantially impermeable to
ocular fluids. In several embodiments, the implant houses a drug 62
within the interior lumen 58 of the implant.
[0225] As discussed in more detail below, in some embodiments, the
drug comprises a therapeutically effective drug against a
particular ocular pathology as well as any additional compounds
needed to prepare the therapeutic agent in a form with which the
drug is compatible. In some embodiments the therapeutic agent is in
the form of a drug-containing pellet. Some embodiments of
therapeutic agent comprise a drug compounded with a polymer
formulation. In certain embodiments, the polymer formulation
comprises a poly(lactic-co-glycolic acid) or PLGA co-polymer or
other biodegradable or bioerodible polymer. While the drug is
represented as being placed within the lumen 58 in FIG. 7, it has
been omitted from several other Figures, so as to allow clarity of
other features of those embodiments. It should be understood,
however, that all embodiments herein optionally include one or more
drugs.
[0226] In several embodiments, the implant further comprises a
coating 60 which may be positioned in various locations in or on
the implant as described below. In some embodiments, the coating 60
is a polymeric coating. FIG. 8 depicts an implant wherein the
coating 60 is positioned inside the implant, but enveloping the
therapeutic agent housed within the lumen, while FIG. 9 depicts the
coating 60 on the exterior of the shell 54. Some other embodiments
may comprise implants with non-polymeric coatings in place of, or
in addition to a polymeric coating. The coating is optionally
biodegradable. Some other embodiments may comprise an implant made
entirely of a biodegradable material, such that the entire implant
is degraded over time. In some embodiments, the coating is placed
over the entire implant (e.g., enveloping the implant) while in
other embodiments only a portion of the implant is covered. In some
embodiments, the coating is on the exterior surface of the implant.
In some embodiments, the coating is placed on the luminal wall
within the implant. Similarly, in some embodiments in which the
coating is positioned inside the implant, the coating covers the
entire inner surface of the lumen, while in other embodiments, only
a portion of the inner surface is covered. It shall be appreciated
that, in addition to the regions of drug release described above,
implants according to several embodiments, disclosed herein combine
regions of drug release with one or more coatings in order to
control drug release characteristics.
[0227] In several embodiments, one or more orifices 56a traversing
the thickness of the outer shell 54 provide communication passages
between the environment outside the implant and the interior lumen
58 of the implant (FIGS. 7-9). The one or more orifices are created
through the implant shell by way of drilling through the various
shells of a particular implant or any other technique known in the
art. The orifices may be of any shape, such as spherical, cubical,
ellipsoid, and the like. The number, location, size, and shape of
the orifices created in a given implant determine the ratio of
orifice to implant surface area. This ratio may be varied depending
on the desired release profile of the drug to be delivered by a
particular embodiment of the implant, as described below. In some
embodiments, the orifice to implant surface area ratio is greater
than about 1:100. In some embodiments, the orifice to implant
surface area ratio ranges from about 1:10 to about 1:50, from about
1:30 to about 1:90, from about 1:20 to about 1:70, from about 1:30
to about 1:60, from about 1:40 to about 1:50. In some embodiments,
the orifice to implant surface area ratio ranges from about 1:60
top about 1:100, including about 1:70, 1:80 and 1:90.
[0228] In other embodiments, the outer shell may contain one or
more orifice(s) 56b in the distal tip of the implant, as shown in
FIGS. 10A and 10B. In other embodiments, the outer shell contains
one or more orifice(s) in the proximal tip of the implant, such as
for example drug elution and/or fluid influx (e.g., for dissolution
of drug housed within the implant and/or for shunting of fluid to a
fluid outflow pathway). The shape and size of the orifice(s) can be
selected based on the desired elution profile. Still other
embodiments comprise a combination of a distal orifice and multiple
orifices placed more proximally on the outer shell. Additional
embodiments comprise combinations of distal orifices, proximal
orifices on the outer shell and/or regions of drug release as
described above (and optionally one or more coatings). Additional
embodiments have a closed distal end. In such embodiment the
regions of drug release (based on thickness/permeability of the
shell, orifices, coatings, placement of the drug, etc.) are
arranged along the long axis of the implant. Such a configuration
is advantageous in order to reduce the amount of tissue damage
caused by the advancing distal end that occurs during the several
embodiments of the implantation procedures disclosed herein.
[0229] In some embodiments, the distal orifice comprises a
biodegradable or bioerodible plug 61 with a plurality of orifice(s)
56b that maintain drug elution from the implant, should one or more
orifices become plugged with tissue during the
insertion/implantation. In other embodiments, the orifice(s) can
comprise permeable or semi-permeable membranes, porous films or
sheets, or the like. In some such embodiments, the permeable or
semi-permeable membranes, films, or sheets may lie outside the
shell and cover the orifices, inside the shell to cover the
orifices or both. The permeability of the material will partially
define the release rate of the drug from the implant, which is
described in further detail below. Such membranes, sheets, or films
are useful in those embodiments having elongated orifices in the
outer shell. Arrows in FIG. 10B depict flow of drug out of the
implant.
[0230] In several embodiments, an additional structure or
structures within the interior of the lumen partially controls the
elution of the drug from the implant. In some embodiments, a
proximal barrier 64a is positioned proximally relative to the drug
62 (FIGS. 7 and 10C). An optional shunt feature may also be
included which comprises outflow apertures 66 in communication with
a proximal inflow lumen 68 located in the proximal region 52 of the
implant. In addition to the layer or layers of permeable or
semi-permeable material may be used to envelope the drug discussed
above, FIG. 10C depicts an internal plug 210 that is be located
between the drug 62 and the various orifices 56a and 56b in certain
embodiments. In such embodiments, the internal plug need not
completely surround the drug. In some embodiments, the material of
the internal plug 210 differs from that of the shell 54, while in
some embodiments the material of the internal plug 210 is the same
material as that of the shell 54. Suitable materials for the
internal plug include, but are not limited to, agarose or hydrogels
such as polyacrylamide, polymethyl methacrylate, or HEMA
(hydroxyethyl methacrylate). In additional any material disclosed
herein for use in the shell or other portion of the implant may be
suitable for the internal plug, in certain embodiments.
[0231] In such embodiments where the material is the same, the
physical characteristics of the material used to construct 210 are
optionally different than that of the shell 54. For example, the
size, density, porosity, or permeability of the material of 210 may
differ from that of the shell 54. In some embodiments, the internal
plug is formed in place (i.e. within the interior lumen of the
implant), for example by polymerization, molding, or solidification
in situ of a dispensed liquid, powder, or gel. In other
embodiments, the internal plug is preformed external to the shell
placed within the shell prior to implantation. In such embodiments,
tailored implants are constructed in that the selection of a
pre-formed internal plug may be optimized based on a particular
drug, patient, implant, or disease to be treated. In several
embodiments, the internal plug is biodegradable or bioerodible,
while in some other embodiments, the internal plug is durable
(e.g., not biodegradable or bioerodible).
[0232] In several embodiments, the internal plug may be closely fit
or bonded to the inner wall of shell. In such embodiments, the
internal plug is preferably permeable to the drug, thereby allowing
passage of the drug through the plug, through the orifices and to
the target tissue. In some embodiments, the internal plug is also
permeable to body fluids, such that fluids from outside the implant
may reach the drug. The overall release rate of drug from the
device in this case may be controlled by the physical
characteristics of several aspects of the implant components,
including, but not limited to, the area and volume of the orifices,
the surface area of any regions of drug release, the size and
position of the internal plug with respect to both the drug and the
orifices and/or regions of drug release, and the permeability of
the internal plug to the drug and bodily fluids. In addition, in
several embodiments, the internal plug increases path length
between the drug and the orifices and/or regions of drug release,
thereby providing an additional point of control for the release
rate of drug.
[0233] In several other embodiments, the internal plug 210 may be
more loosely fit into the interior lumen of the shell which may
allow flow or transport of the drug around the plug. See FIG. 10D.
In still other embodiments, the internal plug may comprise two or
more pieces or fragments. See FIG. 10E. In such embodiments with a
looser fitting or fragmented plug, the drug may elute from the
implant by passing through the gap between the internal plug and
the interior wall of shell. The drug may also elute from the
implant by passing through the gaps between pieces or fragments of
the internal plug. The drug may also elute from the implant by
passing through the permeable inner plug. Similarly, bodily fluids
may pass from the external portion of the implant into the implant
and reach the drug by any of these, or other, pathways. It shall be
appreciated that elution of the drug can occur as a result of a
combination of any of these routes of passage or permeability.
[0234] In several embodiments, the orifices 56a are covered (wholly
or partially) with one or more elution membranes 100 that provide a
barrier to the release of drug 62 from the interior lumen 58 of the
implant shell 54. See FIG. 10F. In several embodiments, the elution
membrane is permeable to the therapeutic agent, to bodily fluids or
to both. In some embodiments the membrane is elastomeric and
comprises silicone. In other embodiments, the membrane is fully or
partially coated with a biodegradable or bioerodible material,
allowing for control of the inception of entry of bodily fluid, or
egress of therapeutic agent from the implant. In certain
embodiments, the membrane is impregnated with additional agents
that are advantageous, for example an anti-fibrotic agent, a
vasodilator, an anti-thrombotic agent, or a permeability control
agent. In addition, in certain embodiments, the membrane comprises
one or more layers 100a, 100b, and 100c in FIG. 10G, for example,
allowing a specific permeability to be developed.
[0235] Similar to the internal plug and regions of drug release
described above, the characteristics of the elution membrane at
least partially define the release rate of the therapeutic agent
from the implant. Thus, the overall release rate of drug from the
implant may be controlled by the physical characteristics of the
implant, including, but not limited to, the area and volume of the
orifices, the surface area of any regions of drug release, the size
and position of any internal plug with respect to both the drug and
the orifices and/or regions of drug release, and the permeability
of any layers overlaying any orifices or regions of drug release to
the drug and bodily fluids.
[0236] In some embodiments, multiple pellets 62 of single or
multiple drug(s) are placed end to end within the interior lumen of
the implant (FIG. 11A). In some such embodiments, the orifices 56a
(or regions of drug release) are positioned at a more distal
location on the implant shell. In other such embodiments, the
orifices 56a (or regions of drug release) are positioned at a more
proximal location on the implant shell, depending on the ocular
tissue being targeted. In some other embodiments a partition 64 is
employed to seal therapeutic agents from one another when contained
within the same implant inner lumen. In some embodiments, the
partition 64 bioerodes at a specified rate. In some embodiments,
the partition 64 is incorporated into the drug pellet and creates a
seal against the inner dimension of the shell of the implant 54 in
order to prevent drug elution in an unwanted direction. In certain
embodiments further comprising a shunt, a partition may be
positioned distal to the shunt outlet holes, which are described in
more detail below.
[0237] In certain alternative embodiments, the orifices or regions
of drug release may be positioned along a portion of or
substantially the entire length of the outer shell that surrounds
the interior lumen and one or more partitions may separate the
drugs to be delivered.
[0238] An additional non-limiting additional embodiment of a drug
pellet-containing implant is shown in FIG. 11B (in cross section).
In certain embodiments, the pellets are micro-pellets 62' (e.g.,
micro-tablets) with characteristics described more fully below. In
some embodiments, such one or more such micro-pellets are housed
within a polymer tube having walls 54' of a desired thickness. In
some embodiments, the polymer tube is extruded and optionally has a
circular cross-section. In other embodiments, other shapes (e.g.,
oval, rectangular, octagonal etc.) are formed. In some embodiments,
the polymer is a biodegradable polymer, such as those discussed
more fully below. Regardless of the material or the shape, several
embodiments of the implant are dimensioned for implantation into
the eye of a subject (e.g., sized to pass through a 21 gauge, 23
gauge, 25 gauge, 27 gauge, or smaller needle).
[0239] Within that context, the dimensions of several embodiments
of such a device may be varied in order to provide a desired
release time for the therapeutic agent in the micro-pellets. For
example, the wall thickness of a polymer tube can be adjusted to
alter the permeability of the polymer tube to the therapeutic
agent. Moreover, in the case of biodegradable polymers, the wall
thickness can also be altered in order to control the overall rate
of degradation of the device. In combination with other variables
more fully described herein, e.g., the polymer chemistry and the
molecular weight of the polymers used, elution of the therapeutic
agent from the implant is highly controllable.
[0240] As shown generally in FIG. 11B, the micro-pellet 62' can be
housed within a compartment defined by endpieces or partitions 64'.
In some embodiments, the endpieces 64' defining each lumen or
compartment are thermoformed from the same material as tubing 54'.
In other embodiments, they may be formed of sections of polymer
filaments. In still other embodiments, the endpieces are formed
within the interior of the tube by injecting or otherwise applying
small volumes of thermosetting polymers, adhesives, polymer
solutions in volatile solvents, and the like. Alternatively,
endpieces may be machined from hard polymers, metals or other
materials, and positioned and retained within the tube using
solvent or adhesive bonding. In those embodiments wherein the
endpieces are polymers, some embodiments employ biodegradable
polymers, which may be designed to degrade before, at the time of,
or after the micro-pelleted therapeutic agent is released.
Moreover, polymeric endpieces may comprise the same polymer as the
extruded polymeric tube 54', or may be a different polymer.
[0241] While shown in FIG. 11B as dimensioned to hold one
micro-tablet of therapeutic agent 62', it shall be appreciated
that, in some embodiments, the lumen 58' may be dimensioned to hold
a plurality of micro-tablets comprising the same or differing
therapeutic agents. Advantageously, such embodiments employed an
extruded shell and one or more micro-pellets allow the release of
the therapeutic agents from the implant, in a controlled fashion,
without the therapeutic agent being exposed to the elevated
temperatures that are often required for extrusion. Rather, the
shell may first be extruded and then loaded with micro-pellets once
temperatures are normalized.
[0242] As discussed in more detail herein, each tablet comprises a
therapeutic agent (also referred to herein as an active
pharmaceutical ingredient (API)) optionally combined with one or
more excipients. Excipients may include, among others, freely water
soluble small molecules (e.g., salts) in order to create an osmotic
pressure gradient across the wall of tubing 54'. In some
embodiments, such a gradient increases stress on the wall, and
decreases the time to release drug.
[0243] The in vivo environment into which several embodiments of
the implants disclosed herein are positions may be comprised of a
water-based solution (such as aqueous humor or blood plasma) or gel
(such as vitreous humor). Water from the surrounding in vivo
environment may, in some embodiments, diffuse through semipermeable
or fenestrated stent walls into the drug reservoir (e.g., one or
more of the interior lumens, depending on the embodiment). Water
collecting within the drug-containing interior lumen then begins
dissolving a small amount of the tablet or drug-excipient powder.
The dissolution process continues until a solution is formed within
the lumen that is in osmotic equilibrium with the in vivo
environment.
[0244] In additional embodiments, osmotic agents such as
saccharides or salts are added to the drug to facilitate ingress of
water and formation of the isosmotic solution. With relatively
insoluble drugs, for example corticosteroids, the isosmotic
solution may become saturated with respect to the drug in certain
embodiments. In certain such embodiments, saturation can be
maintained until the drug supply is almost exhausted. In several
embodiments, maintaining a saturated condition is particularly
advantageous because the elution rate will tend to be essentially
constant, according to Fick's Law.
[0245] Implants such as those depicted generally in FIG. 11B may be
implanted singularly (e.g., a single implant) or optionally as a
plurality of multiple devices. In some embodiments, the plurality
of implants may be joined together (e.g., end to end) to form a
single, larger implant. As discussed above, and in greater detail
below, such implants may be generated having different drug release
times, for example, by varying the time or -degradation properties
of extruded tubing 54'. Implantation of a plurality of varied
devices having different release times, a desired overall drug
release profile can be obtained based on the serial (or concurrent)
release of drug from the plurality of implants a given time period.
For example, release times can be designed such that a first period
of drug release occurs, and is then followed by a drug "holiday"
prior a second period of drug release.
[0246] Several embodiments of the implant may also comprise a shunt
in addition to functioning as a drug delivery device. 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 the portion of the
implant defining one or more fluid passages for transport of fluid
from a first, often undesired location, to one or more other
locations. 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 an outflow pathway to reduce
intraocular pressure, such as is depicted generally in FIG. 12A. In
other embodiments the shunt can be configured to provide a fluid
flow path for draining aqueous humor to an outflow pathway. Still
other embodiments can be configured to drain ocular fluid or
interstitial fluid from the area in and around the eye to a remote
location. Yet other combination drug delivery-shunt implants may be
configured to drain physiological fluid from a first physiologic
site to a second site (which may be physiologic or external to a
patient). In still additional embodiments, the shunt additionally
(or alternatively) functions to provide a bulk fluid environment to
facilitate the dilution and/or elution of the drug.
[0247] The shunt portion of the implant can have an inflow portion
68 and one or more outflow portions 66. As described above, the
outflow portion may be disposed at or near the proximal end 52 of
the implant. While not illustrated, in some embodiments a shunt
outflow portion may be disposed at or near the distal end of the
implant with the inflow portion residing a different location (or
locations) on the implant. In some embodiments, when the implant is
deployed, 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 supraciliary or
suprachoroidal space. In some embodiments, the outflow portion may
be sized and configured to reside in the supraciliary region of the
uveoscleral outflow pathway, the suprachoroidal space, other part
of the eye, or within other physiological spaces amenable to fluid
deposition.
[0248] In some embodiments, at least one lumen extends through the
shunt portion of the implant. In some embodiments, there is at
least one lumen that operates to conduct the fluid through the
shunt portion of the implant. In certain embodiments, each lumen
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.
[0249] In implants additionally comprising a shunt in the proximal
portion of the device, the first (most proximal) outflow orifice on
the implant is positioned between 1 and 10 mm from the anterior
chamber of the subject. In some embodiments additionally comprising
a shunt in the proximal portion of the device, the first (most
proximal) outflow orifice on the implant is positioned preferably
between 2 and 5 mm from the anterior chamber of the subject.
Additional outflow orifices may be positioned in more distal
locations, up to or beyond the point where the interior lumen
housing the drug or therapeutic agent begins.
[0250] In some embodiments comprising a shunt, a shunt inflow
portion preferably is disposed at or near a proximal end of the
implant and a shunt outflow portion preferably is disposed at or
near a distal end of the shunt. When implanted, in several
embodiments, the shunt inflow portion is sized and configured to
reside in the anterior chamber of the eye and the shunt outflow
portion is sized and configured to reside in the uveoscleral
outflow pathway. In some embodiments, the shunt outflow portion is
sized and configured to reside in the supraciliary region of the
uveoscleral outflow pathway or in the suprachoroidal space.
Multiple outflow points may be used in a single device, depending
on the embodiment.
[0251] In some embodiments, the flow path through the implant is
configured to regulate the flow rate to 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
mm Hg, 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 intraocular pressure may be maintained
between about 8 mm Hg 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.
[0252] For example, the Hagen-Poisseuille equation suggests that a
4 mm-long shunt at a flow rate of 2.5 .mu.L/min should have an
inner diameter of 52 micrometers to create a pressure gradient of 5
mm Hg above the pressure in the suprachoroidal space.
[0253] FIG. 12B illustrates another embodiment of a drug eluting
implant 430 comprising a shunt that is operable to drain fluid from
the anterior chamber to the uveoscleral outflow pathway (e.g., the
suprachoroidal space). The drug eluting implant 430 can comprise at
least one interior lumen 436 extending therethrough, wherein at
least a first active drug can be placed. The interior lumen 436 of
the implant 430 can communicate with an inflow portion 432 and an
outflow portion 434. When implanted, the inflow portion 432 is
sized and configured to reside in the anterior chamber of the eye
and the outflow portion 434 is sized and configured to reside in
the uveoscleral outflow pathway. The first active drug can elute
from the inflow portion 432 into the anterior chamber to treat a
target ocular tissue. As the first active drug elutes from the
interior lumen 436 into the anterior chamber, fluid can be
conducted through the interior lumen 436 if the implant.
[0254] The implant 430 preferably has an outer diameter that will
permit the implant 430 to fit within a 21-gauge or 23-gauge needle
or hollow instrument during implantation; however, larger or
smaller gauge instruments may also be used. The implant 430 can
also have a diameter that is designed for delivery with larger
needles. For example, the implant 430 can also be delivered with
18-, 19- or 20-gauge needles. The implant 430 can have a constant
diameter through most of its length. In some embodiments, the
implant 430 comprises retention features 446 that operate to
mechanically lock or anchor the implant 430 in place when
implanted. In some embodiments, the retention features 446 comprise
portions of reduced diameter, e.g., annular grooves, between the
proximal end 438 and the distal end 440. In some embodiments, the
retention features 446 comprise barbs or other projections, which
extend from the outer surface of the implant 430, to inhibit
migration of the implant 430 from its implanted position, as
described above.
[0255] As shown in FIG. 12C, for example, some embodiments of an
implant 430 have a plurality of annular ribs 448 formed on an
exterior surface of the implant 430. The annular ribs 448 can be
spaced longitudinally along the implant 430 between the proximal
end 438 and the distal end 440. Spacing between the annular ribs
448 can be regular or irregular.
[0256] The outflow portion 434 of the implant 430 preferably is
disposed at or near the distal end 440 of the implant 430. In the
embodiment illustrated in FIG. 12B, the outflow portion 434 has a
tapered portion 444; however, it may also have other shapes (e.g.
semi-sphere, a paraboloid, a hyperboloid) with a continually
decreasing radial dimension with respect to the lumen axis 442
along the length of the axis 442. The tapered portion 444
preferably terminates with a smaller radial dimension at the
outflow end 440. During implantation, the tapered portion 444 can
operate to form, dilate, and/or increase the size of, an incision
or puncture created in the tissue. For example, the distal end 440
can operate as a trocar to puncture or create an incision in the
tissue. Following advancement of the distal end 440 of the implant
430, the tapered portion 444 can be advanced through the puncture
or incision. The tapered portion 444 will operate to stretch or
expand the tissue around the puncture or incision to accommodate
the increasing size of the tapered portion 444 as it is advanced
through the tissue.
[0257] The tapered portion 444 can also facilitate proper location
of the implant 430 into the supraciliary or suprachoroidal spaces.
For example, the implant 430 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 430. The implant 430 can be advanced through this tissue
and abut against the sclera once the implant 430 extends into the
uveoscleral outflow pathway. As the implant 430 abuts against the
sclera, the tapered portion 444 preferably provides a generally
rounded edge or surface that facilitates sliding of the implant 430
within the suprachoroidal space along the interior wall of the
sclera. For example, as the implant 430 is advanced into the
uveoscleral outflow pathway and against the sclera, the implant 430
will likely be oriented at an angle with respect to the interior
wall of the sclera. As the tip of the implant 430 engages the
sclera, the tip preferably has a radius that will permit the
implant 430 to slide along the sclera instead of piercing or
substantially penetrating the sclera. As the implant 430 slides
along the sclera, the tapered portion 444 will provide an edge
against which the implant 430 can abut against the sclera and
reduce the likelihood that the implant 430 will pierce the
sclera.
[0258] Once the implant 430 is implanted in position with the
inflow portion 432 residing in the anterior chamber and the outflow
portion 434 residing in the uveoscleral outflow pathway, the first
active drug can elute from the lumen 436 of the implant 430 into
the anterior chamber and aqueous humor can flow from the anterior
chamber to the uveoscleral outflow pathway through the lumen 436 of
the implant 430. The flow of fluid is preferably restricted by the
size of the lumen 436, 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. The flow of fluid through the
implant 430 is preferably configured to be restricted to a flow
rate 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 implants 430 can be used in a
single eye to elute at least a first drug into the anterior chamber
and to conduct fluid from the anterior chamber to the uveoscleral
outflow pathway. In such applications, the cumulative flow rate
through the implants 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 implants can be significantly less than about 2.5 .mu.L/min.
For example, if an application called for implantation of five
implants, then each implant 430 can be configured to have a flow
rate of about 0.5 .mu.L/min.
[0259] While the lumen 436 is depicted in FIG. 4 as extending
substantially through the longitudinal center of the implant 430,
in some embodiments, the lumen can be offset from the longitudinal
center of the shunt. For example, while FIG. 4 depicts the implant
430 as having a tapered portion 444 that terminates substantially
where the tapered portion 444 meets the lumen 436, the lumen 436
can be offset from the center of the implant 430 such that lumen
436 opens along one of the sides of the tapered portion 444.
Accordingly, the tapered portion 444 can terminate at a location
offset from the lumen axis 442 and can extend beyond the point at
which the interior lumen 436 and the exterior tapered portion 444
meet. Additionally, the lumen 436 can vary in direction along its
length.
[0260] In some embodiments, the implant comprises one or more
lumens or sub-lumens, as described further herein. In some
embodiments, at least a first active drug is placed in at least one
sub-lumen. The sub-lumen can have a closed distal end or can have
an outlet located in or near the distal end to allow fluid to flow
from the anterior chamber to the uveoscleral outflow pathway. In
some embodiments, at least one sub-lumen does not contain any
active drugs and is configured exclusively to allow fluid to drain
from the anterior chamber to the uveoscleral outflow pathway.
[0261] The implant 430 preferably comprises any of the materials
described herein. The implant 430 can be fabricated through
conventional micro machining techniques or through procedures
commonly used for fabricating optical fibers. For example, in some
embodiments, the implant 430 is drawn with a bore, or lumen,
extending therethrough. In some embodiments, the tapered portion
444 at the outflow portion 434 can be constructed by shearing off
an end tubular body. This can create a tapered portion 444 that can
be used to puncture or incise the tissue during implantation and
dilate the puncture or incision during advancement of the implant
430. Other materials can be used for the implant 430 of FIG. 4, and
other methods of manufacturing the implant 430 can also be used.
For example, the implant 430 can be constructed of metals or
plastics, and the implants can be machined with a bore that is
drilled as described above.
[0262] The implant 430 of FIG. 4 represents an implant having a
construction that provides for the opportunity to vary the size of
the implant 430 or the lumen 436. The implant 430 also need not
have a unitary configuration; that is, be formed of the same piece
of material. For example, a proximal portion of the implant can be
formed of glass drawn to have at least one small diameter lumen. A
distal portion of the implant can be a cap formed of a different
material. The cap can include a tissue-piercing end and one or more
outlet openings. Each of the one or more outlet openings
communicates with at least one of the one or more lumens in the
proximal portion. In one preferred mode, the cap has a conically
shaped tip with a plurality of outlet openings disposed proximal of
the tip's distal end.
[0263] In some embodiments, the implant has a proximal end cap. For
example, an O-ring cap with a region of drug release (as discussed
more fully herein and with reference to FIGS. 18K and 18M) can be
located over the proximal end of the implant to allow for drug
elution into the anterior chamber of the eye. In other embodiments,
a crimp cap comprising a region of drug release (as discussed more
fully herein and with reference to FIGS. 18L and 18N) is located
over the proximal end of the implant. Regions of the crimp cap can
be compressible such that the cap can be securely placed on, and
sealed to, the body of the implant. The regions of drug release are
further permeable to aqueous humor to allow for drainage of aqueous
humor from the anterior chamber and through the lumen of the
implant. In some embodiments, the cap comprises one or more
orifices or layers in place of, or in addition to, regions of drug
release based on thickness and/or permeability of the cap material.
The one or more orifices or layers can be permeable to aqueous
humor to allow for drainage from the anterior chamber. In some
embodiments, a coating is placed within the cap to cover an orifice
therein. The coating may comprise a membrane or layer of
semi-permeable polymer. In some embodiments, the coating has a
defined thickness, and thus a defined and known permeability to
various drugs and ocular fluid. In some embodiments, the coating is
placed in other locations, including on the exterior of the cap,
within the orifice, or combinations thereof.
[0264] In some embodiments, the implant is formed with one or more
dividers positioned longitudinally within the outer shell, creating
multiple additional sub-lumens within the interior lumen of the
shell. The divider(s) can be of any shape (e.g. rectangular,
cylindrical) or size that fits within the implant so as to form two
or more sub-lumens, and may be made of the same material or a
different material than the outer shell, including one or more
polymers, copolymers, metal, or combinations thereof. In one
embodiment, a divider is made from a biodegradable or bioerodible
material. The multiple sub-lumens may be in any configuration with
respect to one another. In some embodiments, a single divider may
be used to form two sub-lumens within the implant shell. See e.g.,
FIG. 13A. In some embodiments, the two sub-lumens are of equal
dimension. In other embodiments the divider may be used to create
sub-lumens that are of non-equivalent dimensions. In still other
embodiments, multiple dividers may be used to create two or more
sub-lumens within the interior of the shell. In some embodiments
the lumens may be of equal dimension. See, e.g. FIG. 13B.
Alternatively, the dividers may be positioned such that the
sub-lumens are not of equivalent dimension.
[0265] In some embodiments, one or more of the sub-lumens formed by
the dividers may traverse the entire length of the implant. In some
embodiments, one or more of the sub-lumens may be defined of
blocked off by a transversely, or diagonally placed divider or
partition. The blocked off sub-lumens may be formed with any
dimensions as required to accommodate a particular dose or
concentration of drug.
[0266] In some embodiments comprising a shunt, one or more lumens
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.
[0267] In other embodiments, the implant is formed as a combination
of one or more tubular shell structures 54 that are substantially
impermeable to ocular fluids that are nested within one another to
form a "tube within a tube" design, as shown in FIG. 13C. In
alternative embodiments, a cylindrical divider is used to partition
the interior of the implant into nested "tubes." In such
embodiments, a coating 60, which can optionally be polymer based,
can be located in or on the tubular implant. In such embodiments,
at least a first interior lumen 58 is formed as well as an ocular
fluid flow lumen 70. In some embodiments, the ocular fluid flow
lumen 70 is centrally located. In other embodiments, it may be
biased to be located more closely to the implant shell. In still
other embodiments, additional shell structures are added to create
additional lumens within the implant. Drugs 62 may be positioned
within one or more of said created lumens. Orifices or regions of
drug release may be placed as necessary to allow ocular fluid to
contact the therapeutic agent. In certain embodiments the coating
is placed on the outer surface of the outer shell. In certain
embodiments, two or more biodegradable coatings are used on a
single implant, with each coating covering a separate or
overlapping portion of the implant. In those embodiments employing
biodegradable coatings, each coating optionally has a unique rate
of biodegradation in ocular fluid.
[0268] In some embodiments, a wick 82 is included in the implant
(FIG. 14). The wick may take any form that assists in transporting
ocular fluid from the external side of the device to an interior
lumen more rapidly than would be achieved through the orifices of
regions of drug release alone. While FIG. 14 depicts a wick passing
through an orifice, it shall be appreciated that an implant having
only regions of drug release are also capable of employing a wick.
In such embodiments a wick may be positioned to pass through the
outer shell during the manufacture of the implant such that an
orifice is not created. In some embodiments, a fiber is positioned
in an orifice or through the outer shell such a portion of the wick
lies adjacent to the drug within the lumen of the implant. In other
embodiments, the drug is formed around the wick, so that ocular
fluid is delivered directly to an interior portion of the agent. In
still other embodiments, one or more wicks are used as described
above, thus allowing dissolution of the agent from the exterior and
interior portions of the pellet or mass of drug.
[0269] FIG. 15 shows a cross sectional schematic of one embodiment
of an implant in accordance with the description herein and further
comprising a retention protrusion 359 for anchoring the implant to
ocular tissue. While depicted in FIG. 15, and other Figures, as
having the distal portion being the implant end and the proximal
portion being the retention protrusion 359 end, in some
embodiments, depending on the site and orientation of implantation,
the distal portion and proximal portion may be reversed relative to
the orientation in FIG. 15. Additionally, while the illustrated
implant depicts the presence of orifices that pass through the
outer shell, it shall be appreciated that embodiments of the
implants comprising regions of drug release based on thickness
and/or permeability of the shell material can also be used in
conjunction with a retention feature. Moreover, implants comprising
combinations of one or more orifices, one or more layers of
permeable and/or semi-permeable material, and one or more areas of
drug release based on thickness and/or permeability of the shell
material are used in several embodiments.
[0270] In several embodiments, implants comprise a sheet 400 and a
retention protrusion 359. See FIG. 16. In some embodiments, the
sheet is not joined to a retention protrusion. The sheet can be
made of any biocompatible material, including but not limited to,
polymers, fibers, or composite materials. In some embodiments, the
sheet is compounded with one or more therapeutic agent(s). In some
embodiments, the sheet is coated with a material that is compounded
with one or more therapeutic agents. In other embodiments, a sheet
compounded with a first therapeutic agent is coated with a material
compounded with a second therapeutic agent, a different
concentration of the first therapeutic agent, or an auxiliary
agent. In some embodiments the sheet is biodegradable, while in
others it is not. In other embodiments, a disc 402 (FIG. 17) is
used in place of a sheet. In several embodiments, the sheet or disc
is flexible.
[0271] For delivery of some embodiments of the sheet or disc
implants, the sheets or discs are dimensioned such that they can be
rolled, folded, or otherwise packaged within a delivery instrument.
In some embodiments, the entire implant is flexible. In some
embodiments, the implant is pre-curved or pre-bent, yet still
flexible enough to be placed within a non-curved lumen of a
delivery apparatus. In some embodiments the flexible sheets or
discs have thicknesses ranging from about 0.01 mm to about 1.0 mm.
Preferably, the delivery instrument has a sufficiently small cross
section such that the insertion site self seals without suturing
upon withdrawal of the instrument from the eye, for example an
outer dimension preferably no greater than about 18 gauge and is
not smaller than about 27 or 30 gauge. In such embodiments, the
rolled or folded sheets or discs can return to substantially their
original dimensions after attachment to the ocular tissue and
withdrawal of the delivery instrument. In certain embodiments,
thicknesses of about 25 to 250 microns, including about 50 to 200
microns, about 100 to 150 microns, about 25 to 100 microns, and
about 100 to 250 microns are used.
[0272] The implant is dimensioned, in some embodiments, to be
affixed (e.g., tethered) to the iris and float within the aqueous
of the anterior chamber. In this context, the term "float" is not
meant to refer to buoyancy of the implant, but rather that the
sheet surface of the implant is movable within ocular fluid of the
anterior chamber to the extent allowed by the retention protrusion.
In certain embodiments, such implants are not tethered to an
intraocular tissue and are free floating within the eye. In certain
embodiments, the implant can be adhesively fixed to the iris with a
biocompatible adhesive. In some embodiments, a biocompatible
adhesive may be pre-activated, while in others, contact with ocular
fluid may activate the adhesive. Still other embodiments may
involve activation of the adhesive by an external stimulus, after
placement of the implant, but prior to withdrawal of the delivery
apparatus. Examples of external stimuli include, but are not
limited to heat, ultrasound, and radio frequency, or laser energy.
In certain embodiments, affixation of the implant to the iris is
preferable due to the large surface area of the iris. In other
embodiments, the implant is flexible with respect to a retention
protrusion affixed to the iris, but is not free floating.
Embodiments as disclosed herein are affixed to the iris in a manner
that allows normal light passage through the pupil.
[0273] As discussed above, several embodiments disclosed herein
employ multiple materials of varying permeability to control the
rate of drug release from an implant. FIGS. 18A-18Q depict
additional implant embodiments employing materials with varied
permeability to control the rate of drug release from the implant.
FIG. 18A shows a top view of the implant body 53 depicted in FIG.
18B. The implant body 53 comprises the outer shell 54 and retention
protrusion 359. While not explicitly illustrated, it shall be
appreciated that in several embodiments, implants comprising a body
and a cap are also constructed without a retentions protrusion.
FIG. 18C depicts an implant cap 53a, which, in some embodiments, is
made of the same material as the outer shell 54. In other
embodiments, the cap 53 is made of a different material from the
outer shell. A region of drug release 56 is formed in the cap
through the use of a material with permeability different from that
of the shell 54. It shall also be appreciated that implants
comprising a body and a cap (and optionally a retention protrusion)
may be constructed with orifices through the body or the cap, may
be constructed with layers or coatings of permeable or
semi-permeable material covering all or a portion of any orifices,
and may also be constructed with combinations of the above and
regions of drug release based on thickness and/or permeability of
the shell material. See 18E-18F.
[0274] FIGS. 18G-18J depict assembled implants according to several
embodiments disclosed herein. The implant body 53 is joined with
the implant cap 53a, thereby creating a lumen 58 which is filled
with a drug 62. In some embodiments, the material of the implant
body 54 differs from that of the cap 54a. Thus, the assembly of a
cap and body of differing materials creates a region of drug
release 56.
[0275] Additional non-limiting embodiments of caps are shown in
FIGS. 18K and 18L. In FIG. 18K, an O-ring cap 53a with a region of
drug release 56 is shown in cross-section. In other embodiments
there may be one or more regions of drug release in the cap. An
o-ring 99 (or other sealing mechanism) is placed around the cap
such that a fluid impermeable seal is made between the cap and the
body of the implant when assembled. In FIG. 18L, a crimp cap is
shown. The outer shell of the cap comprises regions that are
compressible 98 such that the cap is securely placed on, and sealed
to, the body of the implant. As discussed above, certain
embodiments employ orifices and layers in place of, or in addition
to regions of drug release based on thickness and/or permeability
of the shell material. FIG. 18M depicts an O-ring cap 53a shown in
cross-section. A coating 60 is placed within the outer shell 54 of
the cap and covering an orifice 56a. In other embodiments there may
be one or more orifices in the cap. In some embodiments, the
coating 60 comprises a membrane or layer of semi-permeable polymer.
In some embodiments, the coating 60 has a defined thickness, and
thus a defined and known permeability to various drugs and ocular
fluid. In FIG. 18N, a crimp cap comprising an orifice and a coating
is shown. While the coatings are shown positioned within the caps,
it shall be appreciated that other locations are used in some
embodiments, including on the exterior of the cap, within the
orifice, or combinations thereof (See FIG. 18O).
[0276] Additionally, as shown in FIGS. 18P and 18Q, in certain
embodiments, coatings are employed within the drug material such
that layers are formed. Coatings can separate different drugs 62a,
62b, 62c, 62d within the lumen (FIG. 18P). In certain embodiments,
coatings are used to separate different concentration of the same
drug (FIG. 18Q). It shall be appreciated that such internal layers
are also useful in embodiments comprising regions of drug release
(either alone or in combination with other drug release elements
disclosed herein, e.g., orifices). In certain embodiments, the
layers create a particularly desired drug elution profile. For
example, use of slow-eroding layers is used to create periods of
reduced drug release or drug "holidays." Alternatively, layers may
be formulated to create zero order (or other kinetic profiles) as
discussed in more detail below.
[0277] In each of the embodiments depicted in the Figures, as well
as other embodiments, the coatings or outer layers of shell
material may be formed by spraying, dipping, or added by some other
equivalent means known in the art. Thus, in some embodiments, the
permeability of the region of drug release or layer(s) covering an
orifice (and hence the elution rate) will be at least partially
defined by the materials used in manufacturing the implant, the
coatings (if any) on the implant, and the effective thickness of
implant outer shell.
[0278] Additionally, in several embodiments, one or more portions
of the implant are manufactured separately, then combined for a
final implant that is ready for insertion to a target site (e.g.,
an assembled cap and implant shell). As shown, for example, in FIG.
18R, the implant 53, in several embodiments, comprises an implant
shell 54, a separate cap 54a (which is shown for clarity in a
different shade, but is optionally constructed of the same or of
different material as compared to the implant shell). Any of the
various cap configurations can be used with any of the implant
shells (adjusting, of course, for dimensions that allow interaction
between the components). As shown in FIG. 18R, the cap 54a
comprises a central aperture, thereby creating a region of drug
release 56. In several embodiments, the assembly of certain such
embodiments exploit the elastic or semi-elastic characteristics of
the membrane 60 through which the drug (or drugs) housed within the
implant will elute. Advantageously, in several embodiments, the
elastic properties of the membrane 60 allow the cap of an implant
to be press fit onto the implant shell, and then retained by the
pressure provided against the cap by the elastic rebound of the
membrane (e.g., a "self-lock" feature). Thus, the membrane 60, in
several embodiments, not only serves to define the release rate of
the drug (or drugs), it also functions as a gasket to seal the
interior portions of the implant from the outer environment, thus
limiting the fluid communication between interior and exterior
portions to that occurring through the membrane 60. As discussed in
more detail below with respect to the possible materials from which
the outer shell is constructed, the membrane 60 is (depending on
the embodiment) constructed of similar materials, or combinations
thereof. For example, the membrane 60, in one embodiment, comprises
ethylene vinyl acetate, while in another embodiment, the membrane
comprises silicone or other partially or semi-permeable materials
material, homopolymers, polymer blends and copolymers, such as
random copolymers and block copolymers, polyethylene, polyurethane,
polyethersulfone, polyamide, poly(carbonate urethane), poly(ether
urethane), silicone poly(carbonate urethane), silicone poly(ether
urethane), PurSil.TM., Elasthane.TM., CarboSil.TM. and/or
Bionate.TM.. The selection of the membrane material and its
dimensions (e.g., its thickness) are derived, at least in part, by
the therapeutic agent of choice.
[0279] FIG. 18S depicts an exploded view of one embodiment of the
implants disclosed herein. The implant 53 comprises, for example, a
retention protraction 359 at one end in order to anchor the implant
into a target tissue. The implant comprises at least one internal
lumen 58 to house a therapeutic agent (or agents). As discussed
above, the implant further comprises a cap 54a and an membrane 60,
which when assembled together create a region of drug release 56
that is tailored (based on the membrane) to a particular
therapeutic drug (or drugs) of interest.
[0280] In various embodiments, the thickness of the membrane 60
(taken in conjunction with the particular therapeutic agent or
agents of choice) ranges from about 30 to about 200 .mu.m in
thickness, including about 30 to about 200 .mu.m, about 50 to about
200 .mu.m, about 70 to about 200 .mu.m, about 90 to about 200
.mu.m, about 30 to about 100 .mu.m, about 30 to about 115 .mu.m,
about 50 to about 125 .mu.m, about 63 to about 125 .mu.m, about 84
to about 110 .mu.m, about 57 to about 119 .mu.m, and overlapping
ranges thereof. In several embodiments, the thickness of the
membrane 60 also defines, at least in part, the elution rate of the
drug (or drugs) of interest.
[0281] As discussed herein, the elution rate of the drug is
controlled, depending on the embodiment, to allow drug release over
a desired time frame. For example, in several embodiments, the
duration of drug release, depending on the embodiment, ranges from
several months to several years, e.g., about 6 to about 12 months,
about 12 to about 18 months, about 18 to about 24 months, about 24
to about 30 months, about 30 to about 36 months, etc.
[0282] FIG. 18T depicts another embodiment in which the implant 53
further comprises at least one inflow pathway 38k and at least one
fluid outflow pathway 56k. Other fluid inflow/outflow
configurations are described in detail elsewhere here (e.g., see
FIGS. 19R-19Y). As shown in FIG. 18T, a retention protrusion 359
anchors the implant in the ocular tissue such that the implant
rests at or near the trabecular meshwork 23 and the fluid outflow
pathway 56k allows ocular fluid to be directed through the implant
(via fluid inflow pathway 38k) and to a physiological outflow
space, shown here as Schlemm's canal 22. Similar to those
embodiments described above, there is a region of drug release 56
which allows drug elution to a target tissue(s) of interest). It
shall be appreciated that any of the various fluid inflow/outflow
configurations can readily be adapted for use with any of the
variety of implant bodies disclosed herein. Likewise, any of the
retention protrusions are ready configurable for use with any of
the implant shells, depending on the target tissue, the drug to be
delivered, the desired drug delivery duration, and the like. For
example, while the implant shown in FIG. 18T is depicted as having
a spike-like or barb-like retention protrusion, the implant can
also be configured with, for example, a threaded region as depicted
in FIG. 19C.
[0283] FIG. 18U depicts a cross sectional view of one embodiment of
an implant having fluid inflow 38K and fluid outflow pathways 56k.
As shown, the implant comprises a lumen 58 for containing drug to
be delivered to a target tissue via elution through a membrane 60
and out of the implant via the region of drug release 56. One
embodiment of a cap structure 53a is shown, into which the membrane
60 is integrated. To ensure that ocular fluid passes into the
implant to dissolve drug (and drug flows out of the implant) only
through the membrane 60 (which ensures controlled release) the cap
53 comprises a seal 99. Similarly, to prevent intrusion of ocular
fluid into the implant from the portion adjacent to the inflow
pathway 38k, an additional lower seal 99a is placed distal to the
drug containing lumen 58. In several embodiments, the various
features that allow for controlled release of a therapeutic agent
(or agents) from the implant can be adapted to be implanted into
the punctum of a subject, as described in more detail herein.
[0284] During manufacture of the implants of certain embodiments,
one or more interior lumen 58 is formed within the outer shell of
the implant. In some embodiments, an interior lumen is localized
within the proximal portion of the implant, while in other
embodiments, an interior lumen runs the entire length or any
intermediate length of the implant. Some embodiments consist of a
single interior lumen, while others comprise two or more interior
lumens. In some embodiments, one or more of the internal lumens may
communicate with an ocular chamber or region, e.g., the anterior
chamber. In some embodiments, implants are dimensioned to
communicate with more than one ocular chamber or region. In some
embodiments, both the proximal and the distal end of the implant
are positioned within a single ocular chamber or region, while in
other embodiments, the ends of the implant are positioned in
different ocular chambers or regions.
[0285] A drug 62 is housed within the interior lumen 58 of the
implant. The drug 62 comprises a therapeutically effective agent
against a particular ocular pathology as well as any additional
compounds needed to prepare the drug in a form with which the drug
is compatible. In some embodiments, one or more of the internal
lumens may contain a different drug or concentration of drug, which
may be delivered simultaneously (combination therapy) or
separately. In some preferred embodiments, an interior lumen is
sized in proportion to a desired amount of drug to be positioned
within the implant. The ultimate dimensions of an interior lumen of
a given embodiment are dictated by the type, amount, and desired
release profile of the drug or drugs to be delivered and the
composition of the drug(s).
[0286] In some embodiments, the drug is in the form of a
drug-containing pellet, while in other embodiments, the drug is a
liquid, a slurry, micro-pellets (e.g., micro-tablets) or powder. In
certain such embodiments, the form of the drug allows the implant
to be flexible. In some embodiments the drug is compounded with a
polymer formulation. In some embodiments, the drug positioned in
the lumen is pure drug. In certain embodiments, the polymer
formulation comprises a poly(lactic-co-glycolic acid) or PLGA
co-polymer or other biodegradable or bioerodible polymer. In still
other embodiments, the interior lumen contains only drug.
[0287] In some embodiments, multiple pellets 62 of single or
multiple drug(s) are placed within an interior lumen of the
implant. In some embodiments an impermeable partition 64 is used to
seal drug(s) within the lumen, such that the sole route of exit
from the implant is through the region of drug release. In some
embodiments, the impermeable partition 64 may bioerode at a
specified rate. In some embodiments, the impermeable partition 64
is incorporated into the drug pellet and creates a seal against the
inner dimension of the shell of the implant 54. In other
embodiments, more than one impermeable partition is used within a
lumen, thereby creating sub-lumens, which may contain different
drugs, the same drug at a different concentration, or the same or
another drug compounded with different excipients etc. In such
embodiments, sequential drug release or release of two agents that
are inert within the implant and active when co-mingled outside
their respective sub-lumens may be achieved.
[0288] In some embodiments, the therapeutic agent is formulated as
micro-pellets or micro-tablets. Additionally, in some embodiments,
micro-tablets allow a greater amount of the therapeutic agent to be
used in an implant. This is because, in some embodiments,
tabletting achieves a greater density in a pellet than can be
achieved by packing a device. Greater amounts of drug in a given
volume may also be achieved by decreasing the amount of excipient
used as a percentage by weight of the whole tablet, which has been
found by the inventors to be possible when creating tablets of a
very small size while retaining the integrity of the tablet. In
some embodiments, the percentage of active therapeutic (by weight)
is about 70% or higher. As discussed herein, the therapeutic agent
can be combined with excipients or binders that are known in the
art. In some embodiments, the percentage of therapeutic agent
ranges from about 70% to about 95%, from about 75 to 85%, from
about 75 to 90%, from about 70 to 75%, from about 75% to about 80%
from about 80% to about 85%, from about 85% to about 90%, from
about 90% to about 95%, from about 95% to about 99%, from about 99%
to about 99.9%, and overlapping ranges thereof. In some
embodiments, the percentage of therapeutic agent ranges from about
80% to about 85%, including 81, 82, 83, and 84% by weight.
[0289] In several embodiments, micro-tablets provide an advantage
with respect to the amount of an agent that can be packed, tamped,
or otherwise placed into an implant disclosed herein. The resultant
implant comprising micro-tablets, in some embodiments, thus
comprises therapeutic agent at a higher density than can be
achieved with non-micro-tablet forms. For example, in some
embodiments, the density of the micro-pellet form of an agent
within an implant ranges from about 0.7 g/cc to about 1.6 g/cc. In
some embodiments, the density used in an implant ranges from about
0.7 g/cc to about 0.9 g/cc, from about 0.9 g/cc to about 1.1 g/cc,
from about 1.1 g/cc to about 1.3 g/cc, from about 1.1 g/cc to about
1.5 g./cc, from about 1.3 g/cc to about 1.5 g/cc, from about 1.5
g/cc to about 1.6 g/cc, and overlapping ranges thereof. In some
embodiments, densities of therapeutic agent that are greater than
1.6 g/cc are used.
[0290] As described herein, some embodiments of the devices
disclosed herein are rechargeable, and as such, the size of
micro-tablets is advantageous. In some embodiments, the loading
and/or recharging of a device is accomplished with a
syringe/needle, through which the therapeutic agent is delivered.
In some embodiments, micro-tablets are delivered through a needle
of about 23 gauge to about 32 gauge, including 23-25 gauge, 25 to
27 gauge, 27-29 gauge, 29-30 gauge, 30-32 gauge, and overlapping
ranges thereof. In some embodiments, the needle is 23, 25, 27, 30,
or 32 gauge. In some embodiments, the micro-tablets may be
introduced into the eye directly, such as into the vitreous cavity,
using a syringe or cannula.
[0291] In one embodiment, micro-tablets with the above properties,
or any combination thereof, are made using known techniques in the
art including tableting, lyophilization, granulation (wet or dry),
flaking, direct compression, molding, extrusion, and the like.
Moreover, as discussed below, alterations in the above-discussed
characteristics can be used to tailor the release profile of the
micro-tableted therapeutic agent from an implant.
[0292] In several embodiments, lyophilization of a therapeutic
agent is used prior to the micro-pelleting process. In some
embodiments, lyophilization improves the stability of the
therapeutic agent once incorporated into a micro-tablet. In some
embodiments, lyophilization allows for a greater concentration of
therapeutic to be obtained prior to micro-pelleting, thereby
enhancing the ability to achieve the high percentages of active
therapeutic agents that are desirable in some embodiments. For
example, many commercially available therapeutic agents useful to
treat ocular diseases are developed as first-line agents for other
diseases. As such, their original formulation may not be suitable
or ideal for micro-pelleting or for administration to an ocular
target via an ocular implant such as those disclosed herein. For
example, several anti-VEGF compounds are supplied as sterile liquid
in single use vials meant to be administered intravenously (e.g.,
bevacizumab). As a result, such a liquid formulation is less
preferred for formation of micro-pellets as compared to a solid,
though a liquid therapeutic agent may optionally be used in some
embodiments. To achieve micro-pelleting at high percentages of
therapeutic agent, such liquid formulations may be frozen (e.g.,
stored at temperatures between -20 and -80 C for 16 to 24 hours or
longer) and then subject to lyophilization until dry.
Alternatively, air spraying, crystallization, or other means may
optionally be used to dry the therapeutic agent.
[0293] Once dry, the lyophilized (or otherwise dried) therapeutic
agent is optionally tested for purity. In some embodiments,
solvents may be added to a liquid (or solid) formulation in order
to dissolve and remove (via evaporation) non-therapeutic components
(e.g., excipients or inert binding agents). In some embodiments, a
therapeutic agent is purified by conventional methods (e.g.,
antibody-based chromatography, HPLC, etc.) prior to lyophilization.
In such embodiments, lyophilization often functions to increase the
concentration of the therapeutic agent in the recovered purified
sample.
[0294] In some embodiments, the dried therapeutic agent (which, for
efficiency purposes is optionally dried in bulk) is ground, sieved,
macerated, freeze-fractured, or subdivided into known quantities by
other means, and then micro-pelleted.
[0295] After lyophilization and or subdivision, the therapeutic
agent is fed into a micro-pelleting process. In some embodiments,
standard techniques (e.g., compression, extrusion, molding, or
other means) are used. However, in several embodiments employing
high percentages of active therapeutic agent, more specialized
techniques are used.
[0296] In several embodiments, the therapeutic agent is a protein,
and in such embodiments, drying and/or tabletization should be
completed under conditions (e.g., temperature, acid/base, etc.)
that do not adversely affect the biological activity of the
therapeutic agent. To assist in maintenance of biological activity
of micro-pelleted therapeutic agents, in some embodiments, protein
therapeutics are formulated with a stabilizing agent (e.g.,
mannitol, trehalose, starch, or other poly-hydroxy polymer) to
maintain the structure (and therefore activity) of the therapeutic
protein.
Punctal Implants
[0297] In several embodiments, the implants are configured
specifically for use (e.g., implantation) in the punctum of the eye
of a subject (e.g., the upper and/or lower punctum of the upper
and/or lower canaliculus, respectively). The puncta function to
collect tears that are released onto the surface of the eye by the
lacrimal glands. However, in some individuals tear production is
reduced, blocked, decreased, or otherwise insufficient to maintain
an adequate level of moisture on the eye (or eyes). Damage to the
corneal surface of the eye can result if the moisture on the eye
remains reduced. When functioning normally (e.g., in a patient with
normal tear production), the puncta convey the tear fluid to the
lacrimal sac, which then allows it to drain through the
nasolacrimal duct to the inner nose. One treatment for dry eye or
similar syndromes is implantation of punctual plugs. Once implanted
the plugs function to block the drainage of tear fluid, thereby
increasing the retention of tear fluid on the eye. However, several
of the implant embodiments disclosed herein advantageously allow
the supplementation of the physical blockage of tear drainage with
the delivery of one or more therapeutic agents to the eye in order
to treat one or more aspects of reduced tear production. Thus, in
several embodiments, one or more therapeutic agents are positioned
in the implant in order to increase tear production and/or treat a
symptom of dry eye, including, but not limited to, reduction in
swelling, irritation of the eye and surrounding tissues and/or
inflammation. Additional symptoms that are reduced, ameliorated,
and in some cases eliminated include stinging or burning of the
eye, a sandy or gritty feeling as if something is in the eye,
episodes of excess tears following very dry eye periods, a stringy
discharge from the eye, pain and redness of the eye, temporary or
extended episodes of blurred vision, heavy eyelids, reduced ability
to cry, discomfort when wearing contact lenses, decreased tolerance
of reading, working on the computer, or any activity that requires
sustained visual attention, and eye fatigue.
[0298] In several embodiments, the implants advantageously obviate
the need for additional topical agents (e.g., ointments, artificial
tears, etc.). In several embodiments, however, the implants are
configured (e.g., have a particular drug release profile) to work
synergistically with one or more of such agents. For example, in
several embodiments, the implant is configured to deliver a
constant dosage of a therapeutic agent over time to treat a damaged
or diseased eye, and a subject with them implants in place can also
use artificial tears, for example, to further enhance the efficacy
of the agent delivered from the implant.
[0299] In several embodiments, the agents delivered from the
implant are used for treatment of another ocular disorder, such as
glaucoma, ocular hypertension, and/or elevated intraocular
pressure.
[0300] Advantageously, as discussed herein, several embodiments of
the implants configured for punctual placement allows metered
delivery of one or more therapeutic agents; that is, delivery at a
constant rate, thereby reducing the peaks and valleys of
therapeutic agent concentration as occurs with topical
administration (e.g., via eyedrop).
[0301] Any of the relevant features disclosed herein can be applied
to the embodiments configured for use in the punctum. For example,
the dimensions of the implants, their shape, their drug release
characteristics, and the like can be configured for use in the
punctum. In several embodiments, the plugs can be tailored to the
punctal dimensions of a particular subject. Moreover, the plugs can
be configured to be removable or, in several embodiments, permanent
(e.g., capable of being recharged). In several embodiments, the
punctal implants comprise at least a first active agent that is
loaded, at least in part, preferentially in the proximal region of
the implant (e.g., such that the agent is released to the tear film
of the subject) with the distal region of the implant positioned
within the within the lacrimal ducts. In several such embodiments,
the implant is specifically adapted to prevent unintended release
of the active agent (or agents) from the distal portion of the
implant. In some such embodiments, a plug (e.g., an impermeable
occlusive member), a membrane (e.g., a membrane with little to no
permeability to the active agent/agents), and/or a valve (e.g., a
one-way valve) prevent elution in a distal region of the
device.
[0302] In several embodiments, the use of a valve or plug enables
flushing of the implant. For example, if there is a need to replace
the therapeutic agent (e.g., with a different agent or a different
dose of the same agent) it may be beneficial to substantially
remove any remaining agent within the implant. In such instances,
the plug can be removed and the implant flushed from a proximal to
distal direction, allowing the therapeutic agent remaining in the
implant to be flushed down the nasolacrimal duct. Thereafter the
implant can be reloaded with another dose, another agent, and the
like. Similarly, flushing the implant can be performed when a valve
is positioned in the distal region of the implant, the valve being
opened by pressure exerted on it from the flushing procedure and
preventing backflow of the flushed agent into the implant.
[0303] In several embodiments, an implant and method for treating
an eye with latanoprost or other therapeutic agent(s) is provided,
the method comprising inserting a distal end of an implant into at
least one punctum of the eye and positioning the implant such that
the proximal portion of the implant delivers latanoprost or other
therapeutic agent(s) to the tear fluid adjacent the eye. In several
embodiments, delivery of the latanoprost or other therapeutic
agent(s) is inhibited distally of the proximal end.
[0304] FIGS. 19A-19W illustrate embodiments of drug various
embodiments of retention protrusions. As used herein, retention
protrusion is to be given its ordinary meaning and may also refer
to any mechanism or anchor element that allows an implant to become
affixed, anchored, or otherwise attached, either permanently or
transiently, to a suitable target intraocular tissue (represented
generally as 15 in FIGS. 19A-19G). For example, a portion of an
implant that comprises a biocompatible adhesive may be considered a
retention protrusion, as may barbs, barbs with holes, screw-like
elements, knurled elements, and the like. In some embodiments,
implants are sutured to a target tissue. For example, in some
embodiments, implants are sutured to the iris, preferably the
inferior portion. It should be understood that any retention means
may be used with any illustrated (and/or described) implant (even
if not explicitly illustrated or described as such). In some
embodiments, implants as described herein are wedged or trapped
(permanently or transiently) based on their shape and/or size in a
particular desirable ocular space. For example, in some
embodiments, an implant (e.g., a suprachoroidal stent) is wedged
within an ocular space (e.g., the suprachoroidal space) based on
the outer dimensions of the implant providing a sufficient amount
of friction against the ocular tissue to hold the implant in
place.
[0305] Intraocular targets for anchoring of implants include, but
are not limited to the fibrous tissues of the eye. In some
embodiments, implants are anchored to the ciliary muscles and/or
tendons (or the fibrous band). In some embodiments, implants are
anchored into Schlemm's canal, the trabecular meshwork, the
episcleral veins, the iris, the iris root, the lens cortex, the
lens epithelium, the lens capsule, the sclera, the scleral spur,
the choroid, the suprachoroidal space, the anterior chamber wall,
or disposed within the anterior chamber angle. As used herein, the
term "suprachoroidal space" shall be given its ordinary meaning and
it will be appreciated that other potential ocular spaces exist in
various regions of the eye that may be encompassed by the term
"suprachoroidal space." For example, the suprachoroidal space
located in the anterior region of the eye is also known as the
supraciliary space, and thus, in certain contexts herein, use of
"suprachoroidal space" shall be meant to encompass the supraciliary
space.
[0306] The retention protrusions may be formulated of the same
biocompatible material as the outer shell. In some embodiments the
biodegradable retention protrusions are used. In alternate
embodiments, one or more of the retention protrusions may be formed
of a different material than the outer shell. Different types of
retention protrusions may also be included in a single device.
[0307] In some embodiments, see for example FIG. 19A, the retention
protrusion 359 may comprise a ridged pin 126 comprising a ridge 128
or series of ridges formed on the surface of a base portion 130.
Such ridges may be formed in any direction on the surface of the
implant including, but not limited to, biased from the long axis of
the implant, spiraling around the implant, or encircling the
implant (see, e.g. FIG. 19B). Likewise, the ridges may be distinct
or contiguous with one another. Other anchoring elements may also
be used, such as raised bumps; cylinders; deep threads 134, as
shown in FIG. 19C; ribs 140, as shown in FIG. 19D; a rivet shaped
base portion 146, as shown in FIG. 19E; biocompatible adhesive 150
encircling the retention element 359 where it passes through an
ocular tissue, as shown in FIG. 19F; or barbs 170, as shown in FIG.
19G. In some embodiments, the retention protrusion is positioned
within a pre-existing intraocular cavity or space, shown generally
as 20. For example, as depicted in FIG. 19H, an elongated blade 34
resides within Schlemm's canal 22 and is attached to a base portion
130 that traverses the trabecular meshwork 21. In other
embodiments, as depicted in FIG. 19I, based on the dimensions of
intraocular spaces, which are well-known in the art, a shorter base
130a is used and attached to the elongated blade 34 residing within
Schlemm's canal 22.
[0308] In certain embodiments, an expandable material 100 is used
in conjunction with or in place of a physical retention protrusion.
For example, in FIG. 19J, the base 130 is covered, in particular
areas, with an expandable material 100. Upon contact with an
appropriate solvent, which includes ocular fluid, the material
expands (as depicted by the arrows), thus exerting pressure on the
surrounding tissue, for example the trabecular meshwork 21 and base
of Schlemm's canal 22 in FIG. 19J.
[0309] In some embodiments, an external stimulus is used to induce
the expansion of the expandable material 100. As depicted in FIG.
19K, the base 130 is covered, in particular areas, with an
expandable material 100. Upon stimulation by an external stimuli
hv, the material expands (as depicted by the arrows), thus exerting
pressure on the surrounding tissue, for example the trabecular
meshwork 21 and base of Schlemm's canal 22 in FIG. 19K. Suitable
external stimuli include, but are not limited to, light energy,
electromagnetic energy, heat, ultrasound, radio frequency, or laser
energy.
[0310] In several other embodiments, the expandable material 100,
is coated or layered on the outer shell 54, which expands in
response to contact with a solvent. See FIGS. 19L-19Q. In some
embodiments, once the implant is fully positioned within the
desired intraocular space, contact with bodily fluid causes the
expandable material to swell, solidify or gel, or otherwise expand.
(Compare dimension D to D.sub.1 in FIGS. 19L-19Q). As a result, the
expanded material exerts pressure on the surrounding ocular tissue,
which secures in the implant in position. In several embodiments,
such expandable materials (or other retention mechanisms) are
employed on implants adapted to be implanted into the punctum of a
subject, as described in more detail herein.
[0311] In some embodiments, the expanding material fills any voids
between the implant shell and the surrounding intraocular tissue.
In some such embodiments, the expanded material seals one portion
of the implant off fills or otherwise seals the volume around the
implant outer shell such that fluid is prevented from flowing
around the implant, and must flow through the implant.
[0312] In other embodiments, such as those schematically depicted
in FIGS. 19P and 19Q, the expandable material 100 is positioned on
selected areas of the implant shell 54, such that the expanded
material exerts pressure on the surrounding ocular tissue, but also
maintains the patency of a natural ocular fluid passageway by the
creation of zones of fluid flow 102 around the implant shell and
expandable material. In still other embodiments, the expandable
material can be positioned within the lumen of the implant, such
that the expansion of the material assists or causes the lumen to
be maintained in a patent state.
[0313] The expandable material can be positioned on the implant by
dipping, molding, coating, spraying, or other suitable process
known in the art.
[0314] In some embodiments, the expandable material is a hydrogel
or similar material. Hydrogel is a three-dimensional network of
cross-linked, hydrophilic polymer chains. The hydrophilicity of the
polymer chains causes the hydrogel to swell in the presence of
sufficient quantities of fluid. In other embodiments, the
expandable material is foam, collagen, or any other similar
biocompatible material that swells, solidifies or gels, or
otherwise expands. In some embodiments, the expandable material
begins to expand immediately on contact with an appropriate
solvent. In other embodiments, expansion occurs after passage of a
short period of time, such that the implant can be fully positioned
in the desired target site prior to expansion of the material.
Preferred solvents that induce expansion include water, saline,
ocular fluid, aqueous humor, or another biocompatible solvents that
would not affect the structure or permeability characteristics of
the outer shell.
[0315] The expansion of the expandable material is varied in
several embodiments. In some embodiments, as described above, the
material is positioned on the outer shell of implant such that the
expanded material exerts pressure on the surrounding ocular tissue,
thereby securing the implant in position. In other embodiments, the
expandable material may be placed adjacent to, surrounding, or
under another anchoring element (such as those described above),
such that the expansion of the expandable material causes the
anchoring element to move from a first, retracted state to a
second, expanded state wherein the anchoring element anchors the
implant against an ocular structure in the expanded state. In some
embodiments, the expandable material is designed to expand only in
two dimensions, while in other embodiments, the material expands in
three dimensions.
[0316] Although FIGS. 19L and 19M depict the expandable material as
rectangular in cross-section, it will be appreciated that the
cross-sectional shape can vary and may include circular, oval,
irregular, and other shapes in certain embodiments. The relative
expansion (change from dimension D to D.sub.1) of the material is
also controlled in several embodiments. In certain embodiments the
D to D.sub.1 change is greater than in other embodiments, while in
some embodiments, a smaller D to D.sub.1 change is realized upon
expansion of the material.
[0317] FIGS. 19P and 19Q show side views of an implant having
expandable anchoring elements 100 comprising projections extending
radially outward from the body of the implant. In some such
embodiments, the anchoring elements are individually connected to
the implant body, while in other embodiments, they are
interconnected by a sheath region that mounts over the implant
body.
[0318] In selected embodiments, the implant and/or the retention
protrusion additionally includes a shunt feature. 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 the portion of the implant defining
one or more fluid passages for transport of fluid from a first,
often undesired location, to one or more other locations. The term
"stent" may also be used to refer to a shunt. 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 an
outflow pathway to reduce intraocular pressure, for example, as in
FIGS. 19R-19T. In still other embodiments, the shunt feature of the
implant may be positioned in any physiological location that
necessitates simultaneous drug delivery and transport of fluid from
a first physiologic site to a second site (which may be physiologic
or external to a patient).
[0319] The shunt portion of the implant can have an inflow portion
38k and one or more outflow portions 56k. In some embodiments, the
inflow and outflow portions are positioned at various locations on
the implant depending on the physiological space in which they are
to be located. As shown in FIG. 19R, the outflow portion may be
disposed at or near the proximal end 52 of the implant. When the
implant is deployed, 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 within the trabecular
meshwork 23 or Schlemm's canal 22. In other embodiments, the
outflow portion may be sized and configured to reside in the
supraciliary region of the uveoscleral outflow pathway, the
suprachoroidal space, other part of the eye, or within other
physiological spaces amenable to fluid deposition.
[0320] At least one lumen can extend through the shunt portion of
the implant. In some embodiments, there is at least one lumen that
operates to conduct the fluid through the shunt portion of the
implant. In certain embodiments, each lumen 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.
[0321] As discussed above, in some embodiments, a compressed pellet
of drug not coated by an outer shell 62 is attached or otherwise
coupled to an implant comprising a shunt and a retention feature.
As depicted in FIG. 19T, the shunt portion of the implant comprises
one or more inflow portions 38k and one or more outflow portions
56k. In some embodiments, the inflow portions are positioned in a
physiological space that is distinct from the outflow portions. In
some embodiments, such a positioning allows for fluid transport
from a first location to a second location. For example, in some
embodiments, when deployed intraocularly, the inflow portions are
located in the anterior chamber and the outflow portions are
located in Schlemm's canal 22. In this manner, ocular fluid that
accumulates in the anterior chamber is drained from the anterior
chamber into Schlemm's canal, thereby reducing fluid pressure in
the anterior chamber. In other embodiments, the outflow portion may
be sized and configured to reside in the supraciliary region of the
uveoscleral outflow pathway, the suprachoroidal space, other part
of the eye, or within other physiological spaces amenable to fluid
deposition.
[0322] Additional embodiments comprising a shunt may be used to
drain ocular fluid from a first location to different location. As
depicted in FIG. 19U, a shunt 30p directs aqueous from the anterior
chamber 20 directly into a collector channel 29 which empties into
aqueous veins. The shunt 30p has a distal end 160 that rests
against the back wall of Schlemm's canal. A removable alignment pin
158 is utilized to align the shunt lumen 42p with the collector
channel 29. In use, the pin 158 extends through the implant lumen
and the shunt lumen 42p and protrudes through the base 160 and
extends into the collector channel 29 to center and/or align the
shunt 30p over the collector channel 29. The shunt 30p is then
pressed firmly against the back wall 92 of Schlemm's canal 22. A
permanent bio-glue 162 is used between the shunt base and the back
wall 92 of Schlemm's canal 22 to seat and securely hold the shunt
30p in place. Once positioned, the pin 158 is withdrawn from the
shunt and implant lumens 42p to allow the aqueous to flow from the
anterior chamber 20 through the implant, through the shunt, and
into the collector duct 29. The collector ducts are nominally 20 to
100 micrometers in diameter and are visualized with a suitable
microscopy method (such as ultrasound biomicroscopy (UBM)) or laser
imaging to provide guidance for placement of the shunt 30p. In
another embodiment, the pin 158 is biodegradable in ocular fluid,
such that it need not be manually removed from the implant.
[0323] In some embodiments, the shunt 30p is inserted through a
previously made incision in the trabecular meshwork 23. In other
embodiments, the shunt 30p may be formed with blade configuration
to provide self-trephining capability. In these cases, the incision
through the trabecular meshwork 23 is made by the self-trephining
shunt device which has a blade at its base or proximate to the
base.
[0324] As shown in FIG. 19V, a shunt extending between an anterior
chamber 20 of an eye, through the trabecular meshwork 23, and into
Schlemm's canal 22 of an eye can be configured to be axisymmetric
with respect to the flow of aqueous therethrough. For example, as
shown in FIG. 19V, the shunt 229A comprises an inlet end 230
configured to be disposed in the anterior chamber 20 and associated
with a drug delivery implant in accordance with embodiments
disclosed herein. For clarity of the shunt feature, the implant is
not shown. The second end 231 of the shunt 229A is configured to be
disposed in Schlemm's canal 22. At least one lumen 239 extends
through the shunt 229A between the inlet and outlet ends 230, 232.
The lumen 239 defines an opening 232 at the inlet end 230 as well
as an outlet 233 at the outlet end 231.
[0325] In the illustrated embodiment, an exterior surface 238 of
the shunt 229A is cone-shaped. Thus, a circumference of the
exterior surface 238 adjacent to the inlet end 230 is smaller than
the circumference of the outer surface 238 at the outlet end
231.
[0326] With the shunt 229A extending through the trabecular
meshwork 23, the tissue of the trabecular meshwork 23 provides
additional anchoring force for retaining the shunt 229A with its
inlet end 230 in the anterior chamber and its outlet end 231 in
Schlemm's canal. For example, the trabecular meshwork 23 would
naturally tend to close an aperture occupied by the shunt 229A. As
such, the trabecular meshwork 23 would tend to squeeze the shunt
229A. Because the exterior surface 238 is conical, the squeezing
force applied by the trabecular meshwork 23 would tend to draw the
shunt 229A towards Schlemm's canal 22. In the illustrated
embodiment, the shunt 229A is sized such that a portion 234 of the
shunt 229 adjacent to the inlet end 230 remains in the anterior
chamber 20 while a portion 235 of the shunt 229 adjacent to the
outlet end 231 remains in Schlemm's canal 22.
[0327] In the illustrated embodiment, the outer surface 238 of the
shunt 229A is smooth. Alternatively, the outer surface 238 can have
other contours such as, for example, but without limitation curved
or stepped. In one embodiment, the outer surface 238 can be curved
in a concave manner so as to produce a trumpet-like shape.
Alternatively, the outer surface 238 can be convex.
[0328] In certain embodiments, the shunt 229A preferably includes
one or plurality of posts or legs 236 configured to maintain a
space between the outlet opening 233 and a wall of Schlemm's canal
22. As such, the legs 236 prevent a wall of Schlemm's canal from
completely closing off the outlet opening 233 of the shunt 229A. In
the illustrated embodiment, the legs 236 are coupled to the
distal-most surface of the shunt 229A and are substantially
parallel to an implant axis extending through the shunt 229A and
between the anterior chamber 20 and Schlemm's canal 22.
[0329] This arrangement of the legs 236 and the outlet 233 imparts
an axisymmetric flow characteristic to the shunt 229A. For example,
aqueous can flow from the outlet 233 in any direction. Thus, the
shunt 229A can be implanted into Schlemm's canal at any angular
position relative to its implant axis. Thus, it is not necessary to
determine the angular orientation of the shunt 229A prior to
implantation, nor is it necessary to preserve a particular
orientation during an implantation procedure.
[0330] FIG. 19W illustrates a modification of the shunt 229A,
identified generally by the reference numeral 229B. In this
embodiment, the shunt 229B includes a flange 237 extending radially
from the portion 234. Preferably, the flange 237 is configured to
retain the first portion 234 within the anterior chamber 20. It is
to be recognized that although generally, aqueous will flow from
the anterior chamber 20 towards Schlemm's canal 22, the shunt 229A,
229B or any of the above-described shunts as well as other shunts
described below, can provide for omni-directional flow of
aqueous.
[0331] FIG. 19X illustrates another modification of the shunt 229A,
identified generally by the reference numeral 229C. In this
embodiment, the outer surface 238C is not conical. Rather, the
outer surface 238C is cylindrical. The shunt 229C includes a flange
240 that can be the same size and shape as the flange 237. The legs
236C extend from the flange 240.
[0332] Constructed as such, the natural tendency of the tissue of
the trabecular meshwork 21 to close the hole in which the shunt
229C is disposed, aids in anchoring the shunt 229C in place.
Additionally, the legs 236C aid in preventing the walls of
Schlemm's canal from completely closing the outlet 233C of the
lumen 239C.
[0333] With reference to FIG. 19Y, another embodiment of an
axisymmetric trabecular shunting device is illustrated therein and
identified generally by the reference numeral 229F.
[0334] The shunt 229F comprises an inlet (proximal) section having
a first flange 240F, an outlet (distal) section having a second
flange 237F and a middle section 284 connecting the inlet section
and the outlet section. A lumen 239F of the device 229F is
configured to transport aqueous, liquid, or therapeutic agents
between the inlet section and the outlet section.
[0335] The inlet section of the shunt 229F has at least one inlet
opening 286 and the outlet section comprises at least one outlet
opening 287. In some embodiments, the inlet opening 286 is directly
associated with the proximal end of an implant, such that ocular
fluid flowing through a lumen of the implant passes into the lumen
239F of the shunt. In other embodiments, the shunt is joined or
associated with an implant in a manner where the inlet opening 286
receives ocular fluid directly from an ocular cavity, without
having first passed through the implant. In still other
embodiments, the shunt carries fluid from both sources (e.g., from
the eye and from the implant lumen).
[0336] A further advantage of such embodiments is provided where
the outlet section 237F includes at least one opening 287, 288
suitably located for discharging substantially axisymmetrically the
aqueous, liquid or therapeutic agents, wherein the opening 287, 288
is in fluid communication with the lumen 285 of the device 281. In
the illustrated embodiment, the openings 288 extend radially from
the lumen 285 and open at the outwardly facing surface around the
periphery of the outlet flange 237F.
[0337] It should be understood that all such anchoring elements and
retention protrusions may also be made flexible. It should also be
understood that other suitable shapes can be used and that this
list is not limiting. It should further be understood the devices
may be flexible, even though several of the devices as illustrated
in the Figures may not appear to be flexible. In those embodiments
involving a rechargeable device, the retention protrusions not only
serve to anchor the implant, but provide resistance to movement to
allow the implant to have greater positional stability within the
eye during recharging.
[0338] For the sake of clarity, only a small number of the possible
embodiments of the implant have been shown with the various
retention projections. It should be understood that any implant
embodiment may be readily combined with any of the retention
projections disclosed herein, and vice versa.
[0339] It will further be appreciated that, while several
embodiments described above are shown, in some cases as being
anchored within or to particular intraocular tissues, that each
embodiment may be readily adapted to be anchored or deployed into
or onto any of the target intraocular tissues disclosed herein or
to other ocular tissues known in the art.
[0340] Additionally, while embodiments described both above and
below include discussion of retention projections, it will be
appreciated that several embodiments of the implants disclosed
herein need not include a specific retention projection. Such
embodiments are used to deliver drug to ocular targets which do not
require a specific anchor point, and implants may simply be
deployed to a desired intraocular space. Such targets include the
vitreous humor, the ciliary muscle, ciliary tendons, the ciliary
fibrous band, Schlemm's canal, the trabecular meshwork, the
episcleral veins, the anterior chamber and the anterior chamber
angle, the lens cortex, lens epithelium, and lens capsule, the
ciliary processes, the posterior chamber, the choroid, and the
suprachoroidal space. For example, in some embodiments, an implant
according to several embodiments described herein is injected (via
needle or other penetrating delivery device) through the sclera at
a particular anatomical site (e.g., the pars plana) into the
vitreous humor. Such embodiments need not be constructed with a
retention protrusion, thus it will be appreciated that in certain
embodiments, the use of a retention protrusion is optional for a
particular target tissue.
[0341] Some embodiments disclosed herein are dimensioned to be
wholly contained within the eye of the subject, the dimensions of
which can be obtained on a subject to subject basis by standard
ophthalmologic techniques. Upon completion of the implantation
procedure, in several embodiments, the proximal end of the device
may be positioned in or near the anterior chamber of the eye. The
distal end of the implant may be positioned anywhere within the
suprachoroidal space. In some embodiments, the distal end of the
implant is near the limbus. In other embodiments, the distal end of
the implant is positioned near the macula in the posterior region
of the eye. In other embodiments, the proximal end of the device
may be positioned in or near other regions of the eye. In some such
embodiments, the distal end of the device may also be positioned in
or near other regions of the eye. As used herein, the term "near"
is used at times to as synonymous with "at," while other uses
contextually indicate a distance sufficiently adjacent to allow a
drug to diffuse from the implant to the target tissue. In still
other embodiments, implants are dimensioned to span a distance
between a first non-ocular physiologic space and a second
non-ocular physiologic space.
[0342] In one embodiment, the drug delivery implant is positioned
in the suprachoroidal space by advancement through the ciliary
attachment tissue, which lies to the posterior of the scleral spur.
The ciliary attachment tissue is typically fibrous or porous, and
relatively easy to pierce, cut, or separate from the scleral spur
with the delivery instruments disclosed herein, or other surgical
devices. In such embodiments, the implant is advanced through this
tissue and lies adjacent to or abuts the sclera once the implant
extends into the uveoscleral outflow pathway. The implant is
advanced within the uveoscleral outflow pathway along the interior
wall of the sclera until the desired implantation site within the
posterior portion of the uveoscleral outflow pathway is
reached.
[0343] In some embodiments the total length of the implant is
between 1 and 30 mm in length. In some embodiments, the implant
length is between 2 and 25 mm, between 6 and 25 mm, between 8 and
25 mm, between 10 and 30 mm, between 15 and 25 mm or between 15 and
18 mm. In some embodiments the length of the implant is about 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25
mm so that that the delivery device containing an implant can be
inserted and advanced through the cornea to the iris and produce
only a self-sealing puncture in the cornea, in some embodiments,
the outer diameter of the implants are between about 100 and 600
microns. In some embodiments, the implant diameter is between about
150-500 microns, between about 125-550 microns, or about 175-475
microns. In some embodiments the diameter of the implant is about
100, 125, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325,
350, 375, 400, 425, 450, 460, 470, 475, 480, 490, or 500 microns.
In some embodiments, the inner diameter of the implant is from
about between 50-500 microns. In some embodiments, the inner
diameter is between about 100-450 microns, 150-500 microns, or
75-475 microns. In some embodiments, the inner diameter is about
80, 90, 100, 110, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350,
375, 400, 410, 420, 425, 430, 440, or 450 microns. In some
embodiments, including but not limited to those in which the device
is disc or wafer-shaped, the thickness is from about 25 to 250
microns, including about 50 to 200 microns, about 100 to 150
microns, about 25 to 100 microns, and about 100 to 250 microns. In
several embodiments configured for implantation into the punctum,
the implant ranges between about 0.5 and about 2.5 mm long (e.g.,
from the proximal end to the distal end). The length of the
implant, in some embodiments, ranges from about 0.5 mm to about 0.7
mm, about 0.7 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm,
about 1.0 mm to about 1.1 mm, about 1.1 mm to about 1.2 mm, about
1.2 mm to about 1.3 mm, about 1.3 mm to about 1.35 mm, about 1.35
mm to about 1.4 mm, about 1.4 mm to about 1.45 mm, about 1.45 mm to
about 1.5 mm, about 1.5 mm to about 1.55 mm, about 1.55 mm to about
1.6 mm, about 1.6 mm to about 1.65 mm, about 1.65 mm to about 1.7
mm, about 1.7 mm to about 1.9 mm, about 1.9 mm to about 2.1 mm,
about 2.1 mm to about 2.3 mm, about 2.3 mm to about 2.5 mm, or
lengths in between these ranges. In several embodiments, implants
configured for implantation into the punctum have a diameter
between about 0.2 mm and 2.0 mm, including about 0.2 mm to about
0.3 mm, about 0.3 mm to about 0.4 mm, about 0.4 mm to about 0.5 mm,
about 0.5 mm to about 0.6 mm, about 0.5 mm to about 0.6 mm, about
0.6 mm to about 0.7 mm, about 0.7 mm to about 0.8 mm, about 0.8 mm
to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to
about 1.1 mm, about 1.1 mm to about 1.2 mm, about 1.2 mm to about
1.3 mm, about 1.3 mm to about 1.4 mm, about 1.4 mm to about 1.5 mm,
about 1.5 mm to about 1.6 mm, about 1.6 mm to about 1.7 mm, about
1.7 mm to about 1.8 mm, about 1.8 mm to about 1.9 mm, about 1.9 mm
to about 2.0 mm and diameters in between these ranges.
[0344] In further embodiments, any or all of the interior lumens
formed during the manufacture of the implants may be coated with a
layer of hydrophilic material, thereby increasing the rate of
contact of ocular fluid with the therapeutic agent or agents
positioned within the lumen. In one embodiment, the hydrophilic
material is permeable to ocular fluid and/or the drug. Conversely,
any or all of the interior lumens may be coated with a layer of
hydrophobic material, to coordinately reduce the contact of ocular
fluid with the therapeutic agent or agents positioned within the
lumen. In one embodiment, the hydrophobic material is permeable to
ocular fluid and/or the drug.
[0345] Selected embodiments of the drug delivery implants described
herein allow for recharging of the implant, i.e. refilling the
implant with additional (same or different) therapeutic agent. In
the embodiments shown in FIGS. 20A-20C, the proximal end 52 of the
implant is open and interacts with a recharging device 80. The
recharging device 80 comprises a clamping sleeve 72 that houses
flexible clamping grippers 74 that interacts with the proximal end
52 of the implant. A flexible pusher tube 76 that may be spring
loaded contains a small internal recess 78 that holds the new
therapeutic agent 62 for delivery to the implant lumen 58. In FIG.
20A, a new dose of agent, coated in a shell and capped with
proximal barrier is inserted into the lumen of the implant. FIGS.
20B and 20C depict recharging the implant with multiple drug
pellets. In such embodiments, a one-way passage 70 allows the
insertion of a recharging device carrying a drug pellet into the
lumen of the implant, but upon removal of the recharging device,
the passage closes to prevent the drug from escaping the lumen. In
addition to providing the ability to renew dose of drug in the
implant, recharging an implant with multiple pellets may provide
one or more other benefits. In some embodiments, the pellets are
sized to allow an increased surface area of drug that is exposed to
ocular fluids (as compared to an implant packed with a solid drug
core). As the exposure to ocular fluid is one variable in the
overall elution rate of a drug, in such embodiments, the size of
the pellets may be adjusted as needed to provide a particular
desired release rate. Moreover, in certain embodiments, the size of
the multiple pellets is adjusted to provide a greater rate or
capacity for fluid to flow through the lumen of the implant, even
when a full drug load is present. Furthermore, one or more of the
multiple pellets, in certain embodiments, is coated in order to
regulate the dissolution or elution of the drug. It shall be
appreciated that, as discussed for coatings in relation to the
implant itself, the pellets may be coated with coatings of various
thickness, compositions, with or without apertures, etc., in order
to control the rate of drug release from the pellet itself. In some
embodiments, coated pellets are used in a non-coated device, while
in other embodiments, combinations of coated and uncoated pellets
are used with coated devices. For example, if an ocular condition
is known to require drug therapy in addition to removal/diversion
of ocular fluid, the pellets can be sized to deliver a sufficient
quantity of drug to provide a therapeutic effect and simultaneously
allow ocular fluid to flow through the lumen of the implant from a
first location to a second location. Additionally, the presence of
multiple pellets, or a plurality of particles, as opposed to a
single solid core of drug, allows, in certain embodiments, the
implant to be flexible. In such embodiments, the shape of the
pellets may be designed to provide space around the periphery of
the pellets such that the implant is able to articulate as needed
to fit within or adjacent to a desired physiological space without
inhibition of this articulation from pellet to pellet contact. It
shall be appreciated that in such embodiments, the pellets may
contact one another to some degree, still allowing for a high
degree of efficiency in packing the implant with drug. It shall
also be appreciated that in certain embodiments where flexibility
of the implant is unnecessary or undesirable, the pellets may be
shaped to contact one another more fully, thereby supplementing the
rigidity of an implant.
[0346] As schematically shown in FIGS. 20D and 20E, elongate
implants can comprise a plurality of the features disclosed herein.
For example, FIG. 20D depicts an elongate implant with a proximal
52 and distal end 50, containing a plurality of pellets of
therapeutic agent 62. As discussed in more detail herein, the
therapeutic agent, depending on the embodiment, may be in a variety
of forms, such as pellets, micropellets, vesicles, micelles, or
other membrane-like bound structures, oils, emulsions, gels,
slurries, etc. The implant comprises a region of drug release 56.
Moreover, the embodiments depicted in FIGS. 20D and 20E comprise
fluid inflow 38k and outflow 56k pathways, thus allowing the
combination of delivery of a therapeutic agent as well as directing
fluid to an ocular fluid outflow pathway (e.g., Schlemm's
canal).
[0347] FIG. 20G schematically depicts an eye with one embodiment of
an elongate implant positioned in accordance with several
embodiments disclosed herein. As shown the proximal end of the
implant 52 resides near the anterior portion of the eye, while the
distal end of the implant 50 resides in a more posterior position.
The implant can be implanted in the suprachoroidal space, in one
embodiment, and positioned such that the region of drug release 56
allows the therapeutic agent 58 to elute from the implant in a
posterior region of the eye. While not expressly depicted here, it
shall be appreciated that the implant may, optionally, include the
fluid inflow and outflow pathway described herein.
[0348] FIG. 20H depicts an additional configuration that is used in
several embodiments. For example, in one embodiment the implant is
positioned (e.g., via use of a custom inserter 1000) in the eye
with the distal end 50 in a posterior portion of the eye and the
proximal end 52 in a more anterior region. The implant depicted,
and described in more detail elsewhere herein, comprises a
plurality of regions of drug release, indicated as 56 and 56a, and
a plurality of types of therapeutic agent, namely 58 and 58a in
FIG. 20H. Several embodiments of such an implant are used when, for
example, it is beneficial to provide a loading or bolus dose of a
therapeutic agent (58a) for acute or relatively short term effects
(perhaps, for example to reduce inflammation or risk of infection).
Thereafter, a more long term formulation of the therapeutic agent
(e.g., a pellet; 58) provides controlled drug release for a period
of time beyond the acute effect. In several embodiments, such a
configuration reduces complications with insertion of the device
and reduces the time from insertion to reduction in one or more
symptoms associated with the disease or disorder being treated.
[0349] FIG. 20I depicts yet another embodiment of an elongate
device with an alternative drug elution strategy. Again the implant
is positioned with the distal portion 50 in the posterior region of
the eye. In the depicted embodiment, the regions of drug release 56
and 56a are positioned at or near the very distal end of the
implant. The distal end is configured such that pellets of
therapeutic agent 58, and or therapeutic agent in a different form
(e.g., micropellets, vesicles, gel) or a different therapeutic
agent (e.g., one that reduces or prevents a side effect due to the
first therapeutic agent) are capable of being flushed out of the
distal end of the implant. One schematic of such an implant is
shown in FIG. 20J, wherein the distal end of the implant 50
comprises a region of drug release 56 that is generated by virtue
of a one-way valve 70. In several embodiments, the valve comprises
two or more flaps 70, open at the proximal end and reversibly
closed at the distal end. The pressure provided on the proximal
portion of the flaps induces the flaps to open and the drugs 58 and
58a are expelled (partially or completely) from the implant. In
several embodiments, the flaps return to their closed (or
substantially closed) position such that a seal is created to
prevent backflow of ocular fluid (which may include expelled
therapeutic agent) into the implant. In other embodiments, however,
a fluid-tight seal is not formed. Other flap or sealing mechanisms
are used, depending on the embodiment.
[0350] Such embodiments, are used, in several embodiments, during
an initial implantation surgery. In such cases, flushing out the
therapeutic agents 58 allows the agent 58 to be to fully exposed to
the intraocular environment, which may hasten the therapeutic
effects of the agent. Additionally, with the initial therapeutic
agent 58 flushed out of the implant, the distal portion of the
implant is open (e.g., not blocked with agent) for the delivery of
a second therapeutic agent 58a. The flushing of the initial agent
58 from the device helps to ensure that the second agent (which,
again, may reduce or prevent a side effect of the first agent)
reaches the desired anatomical target tissue. If the device were
not flushed and still contained the therapeutic agent 58, the
second agent 58a would either have to move around the first agent
within the implant or be eluted/flushed from the implant through
side ports (which are more proximal, and thus farther from the
posterior target tissue). Either approach may result in the second
agent 58a failing to reach (at least in therapeutically effective
concentrations) the desired target in the posterior region of the
eye.
[0351] In additional embodiments, devices that are configured to
allow flushing of their therapeutic drug contents out the distal
end of the device are useful when assessing the efficacy and/or
functionality of the device post-implantation. At such a time, it
may be advantageous to be able to deliver a second agent (perhaps
to ameliorate side effects) or a different concentration of an
agent. This can thus be accomplished by flushing the implant with
the second agent or a new concentration of a first agent.
[0352] In several embodiments, the agents 58a that are delivered
secondarily and/or in conjunction with a flush of the first
therapeutic agent 58 are in a fluid, semi-fluid, or fluid-like
form. In several embodiments, microparticles that behave like a
fluid (e.g., they have liquid-like flow properties) are used. In
some embodiments, the secondary agent 58a is configured to have its
own desired elution profile. In such cases, the secondary agent 58a
is optionally housed or contained within a structure that allows
for controlled release. In several embodiments, this comprises
admixing the therapeutic agent with one or more polymers (e.g.,
creating a "matrix) that allows release of the therapeutic agent
from the admixture with a known rate of elution. In several
embodiments, the one or more polymers are selected such that they
are readily intercovertible between a liquid or semi-liquid state
and a solid or semi-solid state. In several embodiments, the
interconversion is due to externally applied stimuli (e.g., radio
frequency, light, etc.). In several embodiments, the
interconversion is temperature or pressure induced. For example, in
several embodiments, the polymers are liquid or semi-liquid at room
temperature, but upon exposure to increased temperatures (e.g.,
physiological temperatures) become solid or semi-solid. In such a
manner, the polymer matrix can be used to hold the therapeutic
agent at a desired target site, thereby improving the accuracy of
delivery and reduction of wash-out due to ocular fluid flow. In
several embodiments, optionally, the polymers are biodegradable
(such that repeated administration does not result in build-up of
polymer at the delivery site). In several embodiments, the polymers
are mixtures of polymers that are configured to mimic a membrane
bound structure (e.g., a micelle or vesicle). In several such
embodiments, the drug is intermixed with those polymers such that
it is incorporated into the micelle or vesicle, and (based on the
known characteristics of the polymers) elutes at a certain rate.
Similarly, such micelles or vesicles are optionally mixed with a
polymeric matrix that is readily intercovertible between a liquid
or semi-liquid state and a solid or semi-solid state.
[0353] FIG. 32 shows a distal perspective view of an example
embodiment of a drug delivery ocular implant 500. FIG. 33 shows a
proximal perspective view of the implant 500. FIG. 34 shows a side
view of the implant 500. The implant 500 can include various
features as described in connection with FIGS. 18R-18U, as well as
features described in connection with other embodiments disclosed
herein. The implant 500 can have a distal end 502 and a proximal
end 504. The implant can include an outer shell 506, which can
define an interior chamber 508 (e.g., an interior lumen) for
holding a drug, as described herein. FIG. 35 shows a
cross-sectional perspective view of an example embodiment of a
shell 506 for the implant 500. The interior chamber 508 can be
generally cylindrical in shape, although other cross-sectional
shapes (e.g., square, rectangular, oval, polygonal) can be used.
The implant 500 can have a total longitudinal length of less than
or equal to about 5 mm, less than or equal to about 3 mm, less than
or equal to about 2 mm, less than or equal to about 1.75 mm, less
than or equal to about 1.5 mm, less than or equal to about 1.25 mm,
less than or equal to about 1.0 mm, at least about 0.5 mm, at least
about 0.75 mm, at least about 1.0 mm, at least about 1.25 mm, at
least about 1.5 mm, at least about 1.75 mm, and/or at least about
2.0 mm, although the implant 500 may have a length outside of these
ranges, in some embodiments. The total longitudinal length of the
implant 500 can be between about 1.0 mm and about 2.5 mm, between
about 1.5 mm and about 2.0 mm, or between about 1.7 mm and about
1.9 mm.
[0354] The implant 500 can include an anchor mechanism 510 (e.g., a
retention protrusion) configured to anchor the implant 500 to
ocular tissue as described herein (e.g., at or near the trabecular
meshwork 23). The anchor mechanism 510 can include a barbed end
portion to facilitate retention of the implant 500 after
implantation, although various other retention mechanisms can be
used, as described herein. For example, the anchor mechanism 510
can include ribs, expandable material, threading, etc. In some
embodiments, the anchor mechanism 510 can include a tissue ingress
orifice (see orifice 401 in FIG. 18R), which can be configured such
that ocular tissue (e.g., scleral tissue) can fill the orifice upon
implantation to facilitate retention of the implant. By way of
example, the retention protrusion can pass through the trabecular
meshwork, through Schlemm's canal, and into the sclera. The barbed
end portion can be a scleral anchor.
[0355] In some embodiments, the implant 500 can be configured to
facilitate drainage of fluid from the anterior chamber 20 of the
eye, as discussed herein. The implant 500 can include one or more
inlets (e.g., inflow pathway 512), which can be positioned in the
anterior chamber 20 upon implantation, and one or more outlets
(e.g., outflow pathway 514), which can be positioned in a
physiological outflow space, such as Schlemm's canal 22, upon
implantation. In some embodiments, the inflow pathway 512 can
extend through the implant 500 (e.g., laterally) and can include
two inlets positioned on generally opposing sides of the implant
500. Similarly, in some embodiments, the outflow pathway 514 can
extend through the implant 500 (e.g., laterally) and can include
two outlets positioned on generally opposing sides of the implant
500. As can be seen in FIG. 35, a pathway 516 can extend (e.g.,
longitudinally) between the inflow pathway 512 and the outflow
pathway 514 to provide fluid communication between the inlet(s) and
the outlet(s). The outflow pathway 514 can be on the retention
protrusion 510 at a location that is configured to position the
outflow pathway 514 in Schlemm's canal 22 upon implantation. In
some embodiments, the outflow pathway 514 can be elongate in the
longitudinal direction to compensate for small differences in the
anatomy of different patients and for different implant techniques,
to thereby facilitate reliable placement of at least part of the
outflow pathway 514 into Schlemm's canal 22. In some embodiments,
the inflow pathway 512 can be spaced (e.g., longitudinally) from
the outflow pathway 514 by a distance 513. The distance 513 can be
less than or equal to about 1.0 mm, less than or equal to about 0.5
mm, less than or equal to about 0.2 mm, less than or equal to about
0.1 mm, less than or equal to about 0.075 mm, less than or equal to
about 0.05 mm, at least about 0.025 mm, at least about 0.05 mm, at
least about 0.075 mm, at least about 0.1 mm, at least about 0.2 mm,
and/or at least about 0.5 mm, although values outside these ranges
may also be used in some embodiments. The distance 513 can be
between about 0.05 mm and about 0.15 mm or between about 0.075 mm
and about 0.125 mm.
[0356] Many variations are possible. For example, in some
embodiments, the implant 500 can include a single inlet and a
single outlet. In some embodiments, a single, curved, and/or
U-shaped fluid channel can connect an inlet to an outlet to provide
a drainage fluid pathway through the implant 500. The one or more
inlets and the one or more outlets can be positioned at locations
other than those shown in illustrated examples, depending on the
desired location of implantation and/or the desired source and
destination of the drained fluid.
[0357] The implant 500 can include one or more standoffs 518 to
prevent the implant from compressing Schlemm's canal 22 (or other
physiological outflow space). The standoffs 518 can extend distally
and can be spaced laterally away from the retention protrusion 510.
Force applied to the implant 500 in the distal direction (e.g.,
force from pressing on the implant 500 distally during implantation
and/or the distal force from the retention protrusion holding the
implant 500 in place) can cause the one or more standoff 518 to
press against ocular tissue (e.g., at or near the trabecular
meshwork 23) at one or more locations that are spaced away from the
outflow space (e.g., Schlemm's canal 22). Accordingly, the
standoffs 518 can facilitate sufficiently firm placement of the
implant 500 while preventing or reducing compression of the outflow
space (e.g., Schlemm's canal 22) to facilitate drainage, as
described herein. The standoffs 518 can extend distally beyond the
surface 519 between the standoffs 518 and the retention protrusion
510 by a distance of at least about 20 microns, at least about 30
microns, at least about 40 microns, at least about 50 microns, less
than or equal to about 100 microns, less than or equal to about 70
microns, less than or equal to about 50 microns, less than or equal
to about 40 microns, and/or less than or equal to about 30 microns,
although values outside of these ranges can be used in some
embodiments. The implant 500 can include two standoffs 518 that are
spaced laterally apart by a distance 511, which can be configured
such that the two standoffs 518 are positioned on opposing sides of
Schlemm's canal 22 upon implantation, such that the standoffs 518
prevent or reduce compression of Schlemm's canal 22 when distal
force is applied during implantation and/or during use. The
distance 511 can be at least about 0.1 mm, at least about 0.2 mm,
at least about 0.3 mm, at least about 0.4 mm, at least about 0.5
mm, less than or equal to about 1.0 mm, less than or equal to about
0.75 mm, less than or equal to about 0.5 mm, less than or equal to
about 0.4 mm, and/or less than or equal to about 0.3 mm, although
values outside these ranges can be used in some embodiments. The
lateral distance 511 can be between about 0.2 mm and about 0.5 mm
or between about 0.3 mm and about 0.4 mm.
[0358] The longitudinal distance 515 between the surface (e.g.,
distal surfaces of the standoffs 518) that abuts against the ocular
tissue (e.g., at or near the trabecular meshwork 23) and the center
of the outflow pathway 514 can be configured to position the
outflow pathway 514 in Schlemm's canal 22. For example, the
distance 515 can be less than or equal to about 150 microns, less
than or equal to about 100 microns, less than or equal to about 75
microns, less than or equal to about 50 microns, at least about 25
microns, at least about 50 microns, at least about 75 microns,
and/or at least about 100 microns, although values outside these
ranges may be used in some embodiments. The longitudinal distance
515 can be between about 40 microns and about 90 microns or between
about 60 microns and about 70 microns.
[0359] The implant 500 can include a flange 520 to impede tissue
from covering the inflow pathway 512. In some instances, pressing
the implant into ocular tissue during implantation can cause the
tissue under the implant 500 to compress. If the inflow pathway 512
is positioned adjacent to the tissue being compressed, the
surrounding tissue that is less compressed could block part or all
of the inflow pathway 512 and impede drainage through the implant
500. Also, in some instances, tissue can grow around the implant
500, especially for implants that are intended to remain implanted
for several years. In some instances, tissue that grows around the
implant 500 could block part or all of the inflow pathway 512 and
impeded drainage through the implant 500. The flange 520 can be
disposed between the inflow pathway 512 and the abutting surface
(e.g., the distally facing surfaces of the standoffs 518 or the
distally facing surface adjacent to the retention protrusion 510)
that is configured to abut against the ocular tissue (e.g., the
trabecular meshwork 23) when the implant 500 is implanted. In some
embodiments, the flange 520 can extend laterally outward from the
inflow pathway 512 by a distance 522 (as shown in FIG. 35) to is
configured to prevent tissue from blocking the inflow pathway 512,
as discussed herein. The distance 522 can be less than or equal to
about 150 microns, less than or equal to about 125 microns, less
than or equal to about 100 microns, less than or equal to about 90
microns, less than or equal to about 80 microns, less than or equal
to about 70 microns, less than or equal to about 60 microns, at
least about 40 microns, at least about 50 microns, at least about
60 microns, at least about 70 microns, at least about 80 microns,
at least about 90 microns, at least about 100 microns, although
values outside these ranges may be used in some embodiments. The
distance 522 can be between about 50 microns and about 100 microns
or between about 70 and 90 microns.
[0360] In some embodiments, the inflow pathway 512 is spaced
longitudinally away from the abutting surface (e.g., the distal
ends of the standoffs 518) that abuts against the ocular tissue
(e.g., at or near the trabecular meshwork 23) by a distance 524
that impedes surrounding tissue from blocking the inflow pathway
512. For example, the distance 524 between the distal ends of the
standoffs 518 and the distal end of the inflow pathway can be at
least about 50 microns, at least about 75 microns, at least about
90 microns, at least about 100 microns, at least about 110 microns,
at least about 125 microns, less than or equal to about 150
microns, less than or equal to about 125 microns, less than or
equal to about 110 microns, less than or equal to about 100
microns, less than or equal to about 90 microns, and/or less than
or equal to about 80 microns, although values outside these ranges
may be sued in some embodiments. The distance 524 can be between
about 50 microns and about 150 microns, between about 75 microns
and about 125 microns, or between about 90 microns and about 100
microns. Various features of the implant 500 can cooperate to
facilitate drainage of the fluid through the inflow pathway 512 and
outflow pathway 514. For example, in some instances in which the
inflow pathway 512 is positioned further from the standoffs 518, a
smaller flange 520 can be used, or the flange 520 can be omitted
altogether.
[0361] In some embodiments, the inflow pathway 512 and the outflow
pathway 514 can extend parallel or substantially parallel through
the implant 500. The inlets and outlets can be aligned such that a
plane intersecting the central longitudinal axis 525 of the implant
500 (e.g., the plane of the cross-section of FIG. 35) can also
intersect the inlets and outlets. The inflow pathway 512 and the
outflow pathway 514 can be positioned such that when the outflow
pathway 514 is positioned to be in fluid communication with
Schlemm's canal 22, the inflow pathway 512 is positioned to be in
fluid communication with the anterior chamber 20 of the eye. When
implanting the implant 500, the rotational orientation of the
implant 500 about the longitudinal axis 525 can be positioned such
that inflow pathway 512 can access the anterior chamber 20 and such
that the outflow pathway 514 can access Schlemm's canal 22, so that
fluid can drain through the implant 500. In some embodiments,
misalignment of the implant 500 can interfere with the drainage.
For example, if the implant 500 were oriented 90 degrees offset
about the longitudinal axis 525 from the desired position, the
cornea 12 and/or the iris 13 could block the inflow pathway 512
and/or the outflow pathway 514 could be misaligned with Schlemm's
canal 23 such that drainage is impeded or reduced.
[0362] In some embodiments, the implant 500 can include a
positioning element 526 (e.g., a protrusion) to facilitate proper
orientation about the longitudinal axis 525 of the implant 500. In
FIGS. 32 and 33, for example, the positioning element 526 is offset
by about 90 degrees from the inlets (e.g., of the inflow pathway
512) and the outlets (e.g., of the outflow pathway 514). By
orienting the implant 500 with the positioning element 526 facing
towards the front of the eye (e.g., towards the cornea 12), the
medical practitioner can orient the inlets and outlets at the
desired positions, as discussed above. Although the positioning
element 526 is shown as a protrusion, various other positioning
elements 526 can be used, such as an indentation, a visible marker,
etc. In some embodiments, the positioning element 526 (e.g., the
protrusion) can interface with a corresponding feature on an
implanting tool configured to enable a medical practitioner to
rotate the implant 500 about its longitudinal axis 525 to achieve
the desired orientation during implantation, as discussed in
connection with FIGS. 52 and 53. In some embodiments, the
protrusion 526 extends laterally outward from the longitudinal axis
525 by less than or equal to the lateral extension of the flange
520.
[0363] In some embodiments, the implant 500 can include inlets that
are rotationally offset from each other and/or outlets that are
rotationally offset from each other about the longitudinal axis 525
to facilitate drainage through the implant 500. For example, the
implant 500 can include four inlets offset by 90 degrees from each
other, such that if one or more of the inlets is obstructed (e.g.,
by the cornea 12 and/or iris 13) one or more additional inlets
would be properly oriented to be in fluid communication with the
anterior chamber 20. Similarly, the implant 500 can include four
outlets offset by 90 degrees from each other, to facilitate
drainage into Schlemm's canal 23. Various numbers of inlets can be
included (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more inlets). Various
numbers of outlets can be included (e.g., 1, 2, 3, 4, 5, 6, 7, 8,
or more outlets).
[0364] The shell 506 can be made of various biocompatible
materials, as described herein, including metal (e.g., titanium)
and ceramic materials. In some embodiments, molding the shell 506
from a ceramic material can be advantageous for reliably forming
the small and detailed structure of the implant 500 (e.g., the
inflow pathway 512, the outflow pathway 514, the flange 520, and/or
the standoffs 518). In some embodiments, the interior chamber 508
of the shell 506, which is a drug reservoir, can be open to the
drainage fluid pathway (e.g., open to the inflow pathway 512). For
example, when molding the shell 506, a core pin can be used to form
the pathway 516, and the core pin can be extracted through the
interior chamber 508. Accordingly, in some implementations, to
facilitate the manufacturing of the shell 506, the interior chamber
508 of the shell 506 can be open to the inflow pathway 512, pathway
516, and/or outflow pathway 514.
[0365] The implant 500 can include a seal 528 configured to seal
the interior chamber 508 from the inflow pathway 512, to prevent or
impede the drug in the interior chamber 508 from escaping via the
inflow pathway 512 and/or outflow pathway 514. The implant 500 can
also include a drug release element 530, which can be held in place
by a retainer 532, as discussed herein. FIG. 36 is a
cross-sectional view of the implant 500 showing the seal 528 and
the drug release element 530 installed. FIG. 37 is a distal
exploded perspective view of the implant 500. FIG. 38 is a proximal
exploded perspective view of the implant 500. FIG. 39 is a distal
exploded perspective view of the seal 528. FIG. 40 is a proximal
exploded perspective view of the seal 528.
[0366] The seal 528 can include an O-ring 534. The O-ring 534 can
fit into a groove 538 on the seal base 536. The base 536 can be
made of various biocompatible materials (e.g., a ceramic material
or a metal, such as titanium). The seal base 536 can be rigid. The
seal base 536 can have a diameter that is less than the diameter of
the internal chamber 508 such that the base 536 can be inserted
through the proximal end 504 and pushed longitudinally to the
distal end of the interior chamber 508. The O-ring 534 can have an
outer diameter that is greater than the diameter of the interior
chamber 508, such that the O-ring is compressed and seals against
the wall of the interior chamber 508. The O-ring can be made of a
compressible material that is impermeable or substantially
impermeable to the drug, such as silicone. The groove 538 on the
base 536 can be configured to maintain the O-ring 534 on the base
536 as the base 536 slides distally across the interior chamber
508. In some embodiments, a lubricant can be applied to the seal
528 (e.g., to the O-ring) and/or to the interior chamber 508 before
insertion of the seal 528.
[0367] In some embodiments, the seal 528 can include a distal
barrier 540. The distal barrier 540 can be made of a compressible
material that is impermeable or substantially impermeable to the
drug, such as silicone. The distal barrier 540 can have the shape
of a disc. As can be seen in FIG. 35, the shell 506 can include a
distal end wall 542 of the interior chamber 508. The distal barrier
540 can be positioned distal of the seal base 536, and can be
compressed between the seal base 536 and the distal end wall 542 at
the distal end of the interior chamber 508. In some embodiments,
the distal end of the base 536 can be substantially flat. The
barrier 540 and the O-ring 534 can cooperate to seal the interior
chamber 508 from the drainage fluid pathways (e.g., the inflow
pathway 512). In some embodiments, the barrier 540 or the O-ring
534 can be omitted.
[0368] In some embodiments, the seal base 536 can include a recess
544 on the proximal side thereof. FIG. 43 shows a cross-sectional
view of the implant 500 with the seal 528 installed. As can be seen
in FIG. 43, the recess 544 can be in fluid communication with the
interior chamber 508, such that the drug can fill the recess 544 to
provide additional volume for holding a larger capacity of the
drug. In some embodiments, as shown in FIG. 35, the positioning
protrusion 526 can be hollow forming a recess 546. The recess 546
can be in fluid communication with the interior chamber 508, such
that the drug can enter the recess to provide additional volume for
holding a larger capacity of the drug. In some embodiments, the
recess 546 can be omitted, and the internal wall of the interior
chamber 508 can be flush across the area corresponding to the
external positioning protrusion 526.
[0369] FIG. 41 shows a distal exploded perspective view of the drug
release element 530. FIG. 42 shows a proximal exploded perspective
view of the drug release element 530. The drug release element 530
can be configured to slowly elute the drug, as described herein. In
some instances, the drug release element 530 is referred to as a
cap. The drug release element 530 can be positioned at or near the
proximal end 504 of the implant 500. As can be seen in FIGS. 35 and
38, the shell 506 can include a shelf 548. The proximal portion of
the shell 506 interior that is proximal of the shelf 548 can have a
larger diameter than the portion that is distal of the shelf 548.
In some embodiments, the shelf 548 can include a consistent annulus
size around its circumference. In some embodiments, the shelf 548
does not have a consistent annulus around its circumference, and in
some cases the shelf 548 can be one or more protrusions that create
a stop for the distal seal member, as discussed herein. The shell
506 can include one or more slots 550, which can be configured to
receive the retainer 532, as described herein. In some embodiments,
the shell 506 can include two slots 550 positioned generally
opposite each other.
[0370] The drug release element 530 can include a distal seal
member 552, a membrane 554, and a proximal seal member 556. The
distal seal member 552 can be seated against the shelf 548 on the
shell 506. The distal seal member 552 can have an outer diameter
that is greater than the distal portion of the shell interior
(distal of the shelf 548) and that is less than the proximal
portion of the shell interior (proximal of the shelf 548). The
distal seal member 552 can have a generally annular shape and/or
can have an opening 558 extending therethrough. The proximal seal
member 556 can have an outer diameter that is greater than the
distal portion of the shell interior (distal of the shelf 548) and
that is less than the proximal portion of the shell interior
(proximal of the shelf 548). The proximal seal member 556 can be
inserted into the proximal end 504 of the shell 506. The proximal
seal member 556 can be generally disc shaped. The proximal seal
member 556 can include at least one opening 560 extending
therethrough. In the illustrated embodiment, the proximal seal
member 556 includes two openings 560. The membrane 554 can be
positioned between the distal seal member 552 and the proximal seal
member 556, and in some embodiments, the membrane 554 can be
compressed between the distal seal member 552 and the proximal seal
member 556. The retainer 532 can retain the drug release element
530 in the compressed state (e.g., with the membrane 554
compressed), as discussed herein. The distal seal member 552 can
include a step 562. FIG. 43 shows the membrane 554 in an undeformed
state. When compressed, the membrane 554 can deform to fill the
space of the step 562.
[0371] The distal seal member 552 and/or the proximal seal member
556 can be made of various biocompatible materials, as discussed
herein, such as ceramic or metal (e.g., titanium). In some
embodiments, forming the members 552 and/or 556 out of a ceramic
material can be advantageous for creating small details on the
parts. In some embodiments, one or both of the seal members 552 and
556 can be made from a resilient biocompatible material that is
impermeable, or substantially impermeable, to the drug (e.g.,
silicone). The membrane 554 can be made from various suitable
materials that allow the drug to elute from the implant 500. In
some embodiments, the membrane can be made from ethylene vinyl
acetate (EVA). The rate of elution of the drug can depend, at least
in part, on the percentage concentration of vinyl acetate in the
EVA material. The vinyl acetate concentration can be less than or
equal to about 40%, less than or equal to about 30%, less than or
equal to about 25%, at least about 10%, at least about 20%, at
least about 25%, and/or at least about 30%, although values outside
these ranges may be used in some embodiments. The vinyl acetate
concentration can be between about 10% and about 30%, between about
20% and about 30%, or between about 25% and about 30% of the EVA
material. In some embodiments, the vinyl acetate concentration can
be about 25% or about 28% of the EVA material.
[0372] As discussed herein, the membrane 554 can be compressed
between the distal seal member 552 and the proximal seal member
556. The proximal seal member 556 can be pressed distally to
compress the membrane 554, and the retainer 532 can be inserted
through the slot 550 such that the retainer is positioned
proximally of the proximal seal member 556. The retainer 532 can
have a length that is greater than the inner diameter of the
proximal portion of the shell interior and a length that is less
than or equal to the outer diameter of the shell 506 at the slots
550. When inserted, the retainer 532 can extend into two opposing
slots 550. The force from the compressed membrane 554 can press the
retainer 532 in the proximal direction, and the slots 550 can hold
the retainer in place to maintain the membrane 554 in the
compressed configuration. The retainer 532 can have a generally
hourglass shape, although other shapes can also be used, in some
embodiments. The retainer can include one or more tabs 564, which
can be folded down to secure the retainer 532. FIG. 43 is a
cross-sectional view that shows the retainer 532 inserted with the
tabs 564 up. FIG. 44 is a partial cross-sectional view that shows
the retainer 532 inserted with the tabs 564 folded down to engage
the proximal seal member 556. When folded down, the tabs 564 can
enter the one or more openings 560 and can engage the proximal seal
member 556, which can prevent or impede the retainer 532 from
moving (e.g., from sliding out of the slot 550). In some
embodiments, when the membrane 554 is compressed, a portion of the
membrane 554 can be pushed proximally into the one or more openings
560, and the folded tabs 564 can engage the membrane 554, which can
facilitate the securement of the membrane 554.
[0373] The drug can elute from the proximal end of the implant 500.
The drug can pass from the internal chamber 508, through the at
least one opening 558 in the distal seal member 552, to the
membrane 554. The membrane 554 can be configured to permit the drug
to pass through the membrane 554 at a desired elution rate. The
drug can pass through the at least one hole 560 in the proximal
seal member 556, past the retainer 532, and out of the proximal end
504 of the implant 500. In FIG. 44, the elution of the drug is
shown by two arrows. In some embodiments, the thickness and/or
compression of the membrane 554 can affect, at least in part, the
elution rate of the drug. In some embodiments, the membrane 554 can
have a compressed thickness of at least about 50 microns, at least
about 75 microns, at least about 80 microns, at least about 90
microns, at least about 95 microns, at least about 100 microns,
less than or equal to about 200 microns, less than or equal to
about 150 microns, less than or equal to about 125 microns, less
than or equal to about 110 microns, less than or equal to about 105
microns, less than or equal to about 100 microns, less than or
equal to about 95 microns, and/or less than or equal to about 90
microns, although values outside these ranges may be used in some
embodiments. The compressed thickness 566 of the membrane 554 can
be between about 75 microns and about 125 microns, between about 85
microns and about 105 microns, or between about 90 microns and
about 100 microns. In some embodiments the compressed thickness 566
of the membrane 554 can be about 95 microns. The membrane can be
compressed by at least about 10 microns, at least about 20 microns,
at least about 30 microns, at least about 40 microns, less than
about 50 microns, less than about 40 microns, less than about 30
microns, and/or less than about 20 microns, although values outside
these ranges may be used, in some embodiments. The membrane 554 can
be compressed by an amount between about 20 microns and about 40
microns, or about 25 microns and about 35 microns. The membrane 554
can be compressed by about 30 microns, in some embodiments.
Compression of the membrane 554 can improve the long term operation
of the membrane 554 over the course of several years.
[0374] The amount of compression applied to the membrane 554 can be
applied reliably without dependence on human determinations because
the amount of compression applied to the membrane 554 is
established by the dimensions of the implant 500 parts, not by a
determination made by a human during assembly. By way of example,
the longitudinal distance 568 between the shelf 548 and the
proximal end of the slot 550 can be about 235 microns. The distal
seal member 558 can have a longitudinal thickness 570 of about 65
microns. The proximal seal member 556 can have a longitudinal
thickness 572 of about 50 microns. The retainer 532 can have a
longitudinal thickness of about 25 microns. A membrane 554 with a
longitudinal thickness of about 125 microns can be compressed to a
longitudinal thickness 566 of about 95 microns (or less), and a
retainer 532 having a longitudinal thickness 574 of about 25
microns can be inserted to maintain the membrane 554 in the
compressed form. Accordingly, the dimensions of the respective
parts dictate that the membrane 554 will be compressed by 30
microns, from a thickness of 125 microns to a thickness of 95
microns.
[0375] Many variations are possible. For example, FIG. 45 shows a
perspective view of an example embodiment of an alternative seal
576, which can be used in place of the seal 528, in some
embodiments. The seal 576 can be a single integral piece, and can
be formed of a resilient material (e.g., silicone) that is
impermeable or substantially impermeable to the drug. The seal 576
can include a distal bulge 578 and a proximal bulge 580, both of
which can be configured to seal against the inside wall of the
internal chamber 508. FIG. 46 is a perspective view of an example
embodiments of an alternative upper seal member 582, which can be
used in place of the upper seal member 556 discussed herein. The
upper seal member 582 is generally annular or ring-shaped. The
upper seal member 582 includes a single, relatively large hole 584
instead of the two relatively smaller holes 560 of the upper seal
member 556 discussed herein. The larger hole 584 can produce a
faster elution rate than the two smaller holes 560. Similarly, the
size and number of holes in the distal seal member 552 can affect,
at least in part, the elution rate of the drug. The implant 500 can
be configured to have an elution rate of less than or equal to
about 100 nanograms per day, less than or equal to about 75
nanograms per day, less than or equal to about 50 nanograms per
day, less than or equal to about 40 nanograms per day, less than or
equal to about 30 nanograms per day, less than or equal to about 25
nanograms per day, less than or equal to about 20 nanograms per
day, at least about 10 nanograms per day, at least about 15
nanograms per day, at least about 20 nanograms per day, at least
about 25 nanograms per day, at least about 30 nanograms per day,
and/or at least about 40 nanograms per day, although values outside
these ranges may be used, in some embodiments. The elution rate can
be between about 15 nanograms per day and about 35 nanograms per
day, or between about 20 nanograms per day and about 30 nanograms
per day. The elusion rate, in some cases, can be about 25 nanograms
per day. The elution rate and volume of the drug can provide drug
delivery for a time period of at least about 1 year, at least about
2 year, at least about 3 year, at least about 4 years, at least
about 5 years, at least about 6 year, at least about 7 years, at
least about 8 years, at least about 9 years, at least about 10
years, less than or equal to about 15 years, less than or equal to
about 12 years, less than or equal to about 10 years, less than or
equal to about 8 years, less than or equal to about 6 years, and/or
less than or equal to about 4 years, although values outside there
ranges can be used in some embodiments.
[0376] Drug delivery ocular implants such as the implant 500 can be
configured to hold various volumes of drugs, as discussed herein.
FIGS. 47 and 48 are perspective views of an example embodiment of a
drug delivery ocular implant 600, which can include the same
features as described in connection with the ocular implant 500, or
in connection with other embodiments disclosed herein. In some
embodiments, the implant 600 does not include the flange 520 that
was included on the implant 500. Accordingly, the implant 600 can
have a drug reservoir with a larger diameter than the implant 500,
can hold a larger volume of the drug. By way of example, the
implant 500 can have an internal diameter of about 0.28 mm and can
hold about 58 nanoliters, while the implant 600 can have an
internal diameter of about 0.36 mm and can hold about 97
nanoliters. FIGS. 49 and 50 are perspective views of another
example embodiment of a drug delivery ocular implant 700, which can
include some of the same features as described in connection with
the implant 500, the implant 600, or any other embodiment disclosed
herein. In some embodiments, the implant 700 does not include the
inflow pathway 512 and outflow pathway 514, and the implant 700
also does not include the positioning protrusion 526. Accordingly,
the implant 700 can have a drug reservoir that has a larger
diameter than the implant 500 and the implant 600, and can hold a
larger volume of the drug. By way of example, the implant 700 can
have an internal diameter of about 0.41 mm and a volume of about
115 nanoliters. Drug delivery ocular implants can be made to hold a
variety of different drug volumes. The implants can hold at least
about 30 nanoliters, at least about 40 nanoliters, at least about
50 nanoliters, at least about 60 nanoliters, at least about 70
nanoliters, at least about 80 nanoliters, at least about 90
nanoliters, at least about 100 nanoliters, at least about 110
nanoliters, at least about 120 nanoliters, at least about 130
nanoliters, at least about 140 nanoliters, at least about 150
nanoliters, less than or equal to about 200 nanoliters, less than
or equal to about 175 nanoliters, less than or equal to about 150
nanoliters, less than or equal to about 130 nanoliters, less than
or equal to about 120 nanoliters, less than or equal to about 110
nanoliters, less than or equal to about 100 nanoliters, less than
or equal to about 90 nanoliters, less than or equal to about 80
nanoliters, less than or equal to about 70 nanoliters, less than or
equal to about 60 nanoliters, and/or less than about 50 nanoliters,
although values outside these ranges may be used, in some
embodiments. The implants can hold a volume of drug between about
40 nanoliters and about 150 nanoliters, or between about 50
nanoliters and about 120 nanoliters.
[0377] FIG. 51 is a cross-sectional view of the implant 700. With
reference to FIGS. 49-51, the implant 700 can include an outer
shell 706, which can be made from a variety of suitable
biocompatible materials, such as ceramic or metal (e.g., titanium).
In some embodiments, the implant 700 does not include inflow and
outflow passageways, and the shell 706 can be of sufficiently
simple shape that it can be constructed of metal (e.g., titanium).
In some embodiments, the seal 528 discussed in connection with the
implant 500 can be omitted from the implant 700, because the
implant 700 does not include the inflow and outflow passages. The
implant 700 can include a drug release element 730, retainer 732,
retention protrusion 710, and slot 750, which can be similar to the
drug release element 530, retainer 532, retention protrusion 710,
and slot 550 of the implant 500 discussed herein. As shown in FIG.
51, the tabs 764 of the retainer 732 can engage the membrane 754
when the tabs 764 are bent downward. The upper seal member 756 and
the lower seal member 752 can both include a single large opening
760 and 758, respectively, which can have the same or substantially
the same size. As discussed above, the internal reservoir 708 can
hold more volume of the drug than the internal reservoir 508 of the
implant 500. Also, the larger openings 758 and 760 can cause the
implant 700 to have a faster elution rate than the implant 500. It
should be understood that although the drawings are not necessarily
all drawn to scale, the dimensions, proportions, orientations, and
other structural aspect shown in the Figures are intended to form
part of the disclosure.
[0378] Various other embodiments disclosed herein can include a
drug release element, which can be similar to or the same as the
drug release elements 530 and/or 730 or the other drug release
elements illustrated and discussed herein. For example, in some
embodiments an ocular implant can be configured to be positioned at
least partially in the supraciliary space and/or suprachoroidal
space and can include a drug release element that has features
similar to or the same as the drug release elements disclosed
herein (e.g., the drug release elements 530 and/or 730). FIG. 55
shows a perspective view of an example embodiment of an ocular
implant 900. FIG. 56 shows a side view of the example embodiment of
an ocular implant 900. FIG. 57 shows a cross-sectional view of the
example embodiment of an ocular implant 900. Various features of
the ocular implant 900 can be similar to or the same as features
illustrated by, or described in connection with, FIGS. 12B-12C.
[0379] The ocular implant 900 can include an outer shell 906. The
outer shell 906 can define an interior chamber 908, which can be a
drug reservoir for holding one or more drugs as discussed herein.
The outer shell 906 can be configured to be implanted into the
supraciliary space and/or suprachoroidal space of a patient's eye.
The outer shell 906 can have a generally straight configuration, or
the implant can be pre-curved to a curvature that is configured to
conform generally to the supraciliary space and/or suprachoroidal
space. The outer shell 906 can be flexible, in some embodiments,
such as to enable the ocular implant to have a generally straight
configuration when positioned in a delivery apparatus and to have a
curved configuration when implanted into the eye (e.g., in the
supraciliary space and/or the suprachoroidal space). The outer
shell 906 can include a distal end 902, which can be tapered to
facilitate insertion into the supraciliary space and/or the
suprachoroidal space.
[0380] The outer shell 906 can include a proximal end portion 904,
which can include a drug release element 930. In some embodiments,
the proximal end portion 904 can have an increased outer diameter
such that a step or ridge 905 is formed between the proximal end
portion 904 and the central portion of the outer shell 906. In some
embodiments, the ocular implant 900 can be inserted into the eye
(e.g., into the supraciliary space and/or the suprachoroidal space)
until the step or ridge 905 abuts against eye tissue adjacent to
the insertion site (e.g., ciliary tissue). The step or ridge 905
can help impede over-insertion of the ocular implant 900. The
ocular implant 900 can be configured to release (e.g., elute) a
drug, as discussed herein, such as from the proximal end of the
ocular implant 900, for example, into the anterior chamber 20. The
drug release location (e.g., the proximal end) can be spaced apart
from the step or ridge 905 by a distance 907 to prevent the eye
tissue that is adjacent the insertion site from covering or
otherwise blocking the drug release location of the ocular implant
900. By way of example, the distance can be about 25 microns, about
50 microns, about 75 microns, about 100 microns, about 150 microns,
about 200 microns, about 300 microns, about 400 microns, about 500
microns, about 750 microns, about 1000 microns, about 1250 microns,
about 1500 microns, or any values therebetween including ranges
that are bound by any of these distances. In some embodiments, the
step or ridge 905 can extend laterally outward further than shown
in FIGS. 55-57. The step or ridge 905 can extend laterally outward
by a distance that can be about 25 microns, about 50 microns, about
75 microns, about 100 microns, about 150 microns, about 200
microns, about 300 microns, about 400 microns, about 500 microns,
about 750 microns, about 1000 microns, or any values therebetween
including ranges that are bound by any of these distances.
[0381] The ocular implant 900 can include one or more retention
features 910 configured to anchor the implant in place when
implanted in the eye. The one or more retention features 910 can
include one or more annular ribs on an outer surface of the outer
shell 906. The ribs can have angled distal sides and/or can be
barbed to facilitate insertion of the ocular implant 900 into the
eye while impeding the ocular implant 900 from unintentionally
releasing from the eye tissue. In some embodiments, the ribs can
have an outer diameter that is substantially the same as the outer
diameter of the proximal end portion 904, to facilitate placement
in a delivery apparatus. In some embodiments, the one or more
retention features 910 can be configured to engage the eye tissue
that is adjacent to the insertion site. For example, the one or
more retention features 910 can be on or near the proximal end
portion 904 or at or near the step or ridge 905. In some
embodiments, the retention features 910 can be omitted, and the
outer shell 906 can be held in place by friction against the
surrounding eye tissue.
[0382] The ocular implant 900 can include a drug release element
930. The drug release element can include a distal seal member 952,
a membrane 954, and a proximal seal member 956, which can be the
same as, or similar to, the other distal seal members, membranes,
and proximal seal members discussed and illustrated herein (e.g.,
in connection with FIGS. 31-54). The disclosure provided herein for
other embodiments that include a drug release element can be
applied to the ocular implant 900, and is not repeated here. The
membrane 954 can be compressed between the distal seal member 952
and the proximal seal member 956, as discussed herein. A retainer
932 can hold the drug release element 930 in place, as discussed
herein. The outer shell 906 can include one or more slots 950, and
the retainer 932 can engage the one or more slots 950 proximally of
the proximal seal member 956. Two slots 950 can be positioned on
opposite sides of the outer shell 906 and the retainer 930 can be
inserted through one of the slots 950, across the interior chamber
908, and into the other of the slots 950. The distal seal member
952 can be seated against a shelf in the interior chamber 908. The
compressed membrane 954 can apply a force that presses the distal
seal member 952 against the shelf and that presses the proximal
seal member 956 against the retainer 932.
[0383] It will be appreciated that the elements discussed above are
not to be read as limiting the implants to the specific
combinations or embodiments described. Rather, the features
discussed are freely interchangeable to allow flexibility in the
construction of a drug delivery implant in accordance with this
disclosure.
Delivery Instruments
[0384] Another aspect of the systems and methods described herein
relates to delivery instruments for implanting an implant for
delivering a drug to the eye and optionally for draining fluid from
the anterior chamber into a physiologic outflow space. In some
embodiments, the implant is inserted into the eye from a site
transocularly situated from the implantation site. The delivery
instrument is 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 may
be flexible. The instrument may comprise a plurality of members
longitudinally moveable relative to each other. In some
embodiments, the plurality of members comprises one or more
slideable guide tubes. In some embodiments, at least a portion of
the delivery instrument is curved. In some embodiments, a portion
of the delivery instrument is rigid and another portion of the
instrument is flexible.
[0385] In some embodiments, the delivery instrument has a distal
curvature. The distal curvature of the delivery instrument may be
characterized in some embodiments as a radius of approximately 10
to 30 mm. In some embodiments the distal curvature has a radius of
about 20 mm.
[0386] In some embodiments, the delivery instrument has a distal
angle 88 (with a measure denoted by .chi. in FIG. 21). The angle
measure .chi. may be characterized as approximately 90 to 180
degrees relative to the proximal segment 94 of the delivery
instrument. In some embodiments, the angle measure .chi. may be
characterized as between about 145 and about 170 degrees. In some
embodiments the angle measure is between about 150 and about 170
degrees, or between about 155 and about 165 degrees. The angle can
incorporate a small radius of curvature at the "elbow" so as to
make a smooth transition from the proximal segment of the delivery
instrument to the distal segment. The length of the distal segment
may be approximately 0.5 to 7 mm in some embodiments, while in some
other embodiments, the length of the distal segment is about 2 to 3
mm.
[0387] In other embodiments, a curved distal end is preferred. In
such embodiments, the height of the delivery instrument/shunt
assembly (dimension 90 in FIG. 22) is less than about 3 mm in some
embodiments, and less than 2 mm in other embodiments.
[0388] In some embodiments, the instruments have a sharpened
feature at the forward end and are self-trephinating, i.e.,
self-penetrating, so as to pass through tissue without pre-forming
an incision, hole or aperture. In some embodiments, instruments
that are self-trephinating are configured to penetrate the tissues
of the cornea and/or limbus only. In other embodiments, instruments
that are self-trephinating are configured to penetrate internal eye
tissues, such as those in the anterior chamber angle, in order to
deliver an implant. Alternatively, a separate trocar, scalpel,
spatula, or similar instrument can be used to pre-form an incision
in the eye tissue (either the cornea/sclera or more internal
tissues) before passing the implant into such tissue. In some
embodiments, the implant is blunt at the distal end, to aid in
blunt dissection (and hence reduce risk of tissue trauma) of the
ocular tissue. In other embodiments, however, the implant is also
sharpened, tapered or otherwise configured to penetrate ocular
tissues to aid in implantation.
[0389] For delivery of some embodiments of the drug eluting ocular
implant, the instrument has a sufficiently small cross section such
that the insertion site self seals without suturing upon withdrawal
of the instrument from the eye. An outer dimension of the delivery
instrument is preferably no greater than about 18 gauge and is not
smaller than about 27 or 30 gauge.
[0390] For delivery of some embodiments of the drug eluting ocular
implant, an incision in the corneal tissue is made with a hollow
needle through which the implant is passed. The needle has 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 may also 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 may be used to place the ocular implant or may
cooperate with a delivery instrument to allow implantation through
the same incision without withdrawing the incision-forming
instrument. Of course, in other modes, various surgical instruments
may be passed through one or more corneal incisions multiple
times.
[0391] Some embodiments include a spring-loaded pusher system. In
some embodiments, the spring-loaded pusher 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.
[0392] In some embodiments, an over-the wire system is used to
deliver the implant. The implant may be delivered over a wire. In
some embodiments, the wire is self-trephinating. The wire may also
function as a trocar. The wire may be superelastic, flexible, or
relatively inflexible with respect to the implant. The wire may be
pre-formed to have a certain shape. The wire may be curved. The
wire may have shape memory, or be elastic. In some embodiments, the
wire is a pull wire. The wire may also be a steerable catheter.
[0393] In some embodiments, the wire is positioned within a lumen
in the implant. The wire may be axially movable within the lumen.
The lumen may or may not include valves or other flow regulatory
devices.
[0394] In some embodiments, the delivery instrument is a trocar.
The trocar may be angled or curved. In some embodiments, the trocar
is flexible. In other embodiments the trocar is relatively rigid.
In other embodiments, the trocar is stiff. In embodiments where the
trocar is stiff, the implant is relatively flexible. The diameter
of the trocar is about 0.001 inches to about 0.01 inches. In some
embodiments, the diameter of the trocar is 0.001, 0.002, 0.003,
0.004, 0.005, 0.006, 0.007, 0.008, 0.009, or 0.01 inches.
[0395] In some embodiments, delivery of the implant is achieved by
applying a driving force at or near the proximal end of the
implant. The driving force may be a pulling or a pushing applied to
the end of the implant.
[0396] The instrument may include a seal or coating 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 aids in preventing backflow. 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 may
additionally comprise a seal between various members comprising the
instrument. The seal may comprise a hydrophobic or hydrophilic
coating between slip-fit surfaces of the members of the instrument.
The seal may be disposed proximate of the implant when carried by
the delivery instrument. In some embodiments, the seal is present
on at least a section of each of two devices that are machined to
closely fit with one another.
[0397] The delivery instrument may include a distal end having a
beveled shape. The delivery instrument may include a distal end
having a spatula shape. The beveled or spatula shape may or may not
include a recess to contain the implant. The recess can include a
pusher or other suitable means to push out or eject the
implant.
[0398] The delivery instrument may be configured to deliver
multiple implants. In some such embodiments, the implants may be
arranged in tandem (or serially for implant numbers greater than
two) within the device.
[0399] FIG. 52 shows an example embodiment of an insertion tube 800
for implanting a drug delivery ocular implant (e.g., implant 600),
as discussed herein. The insertion tube 800 can have a flared
distal end 802. The insertion tube 800 can include a slit 804 that
is configured to receive the positioning protrusion 626 of the
implant 600. The slit 804 can have rounded ends 806 to facilitate
guiding the positioning protrusion 626 into the slit 804. The slit
804 can include a locking portion 808 that is offset from the main
linear path of the slit 804. The locking portion 808 can engage the
positioning protrusion 626, for example as shown in FIG. 52 to lock
the implant 600 onto the insertion tube 800. In the locked
position, movement of the insertion tube 800 in the distal
direction can cause the proximal wall 810 to press against the
positioning protrusion 626 to drive the implant 600 forward in the
distal direction (e.g., for implantation). In the locked position,
movement of the insertion tube 800 in the proximal direction can
cause the distal wall 812 to press against the positioning
protrusion 626 to drive the implant 600 rearward in the proximal
direction (e.g., for explantation). The user can rotate the
insertion tube 800 in order to rotate the implant 600 via the
positioning protrusion 626, as discussed herein.
[0400] To remove the implant 600 from the insertion tube 800, the
user can rotate the insertion tube 800 until the positioning
protrusion 626 is out of the locking portion 808 and is position in
the main linear path of the slit 804. Then, the user can withdraw
the insertion tube 800 in the proximal direction, and the
positioning protrusion 626 can slide along the slit 804 until it
exits the insertion tube 800. To engage an implant 600 with the
insertion tube 800, a user can align the slit 804 with the
positioning protrusion 626 and can move the insertion tube 800
forward, distally so that the positioning protrusion 626 enters the
slit 804 and slides back to the location of the turn to the locking
portion 808. Then the user can rotate the insertion tube 800 so
that the positioning protrusion 626 enters the locking portion
808.
[0401] FIG. 53 shows another example embodiment of an insertion
tube 800 for use with an implant 500, or with various other
implants, as discussed herein. The insertion tube 800 can include a
notch 814 and a biasing member 816 (e.g., a cantilever spring),
which can facilitate the locking of the positioning protrusion 526
into the locking portion 808. To engage the locking portion 808,
the positioning protrusion 526 can displace the biasing member 816
so that the positioning protrusion 526 can move past the notch 814
into the locking portion. To disengage from the locking portion
808, the user can press the insertion tube forward to displace the
biasing member 816 while rotating the insertion tube 800 so that
the positioning protrusion 526 can move past the notch 814 and exit
the locking portion 808. Accordingly, the notch 814 and biasing
member 816 can prevent or impede accidental disengagement of the
locking portion 808.
Procedures
[0402] For delivery of some embodiments of the ocular implant, the
implantation occurs in a closed chamber with or without
viscoelastic.
[0403] The 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, now U.S. Pat. No.
7,331,984, issued Feb. 19, 2008, 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 an applicator to create an elevated fluid pressure
at the forward end of the implant to ease implantation.
[0404] In one embodiment of the invention, a delivery apparatus (or
"applicator") similar to that used for placing a trabecular stent
through a trabecular meshwork of an eye is used. Certain
embodiments of such a delivery apparatus are disclosed in U.S.
Patent Publication 2004/0050392, filed Aug. 28, 2002, now U.S. Pat.
No. 7,331,984, issued Feb. 19, 2008; U.S. Publication No.:
2002/0133168, entitled APPLICATOR AND METHODS FOR PLACING A
TRABECULAR SHUNT FOR GLAUCOMA TREATMENT, now abandoned; and U.S.
Provisional Application No. 60/276,609, filed Mar. 16, 2001,
entitled APPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNT FOR
GLAUCOMA TREATMENT, now expired, each of which is incorporated by
reference and made a part of this specification and disclosure.
[0405] In one embodiment, the delivery apparatus 2000 includes a
handpiece, an elongate tip, a holder and an actuator, which are
schematically depicted in FIG. 20F. The handpiece 1000 has a distal
end 1002 and a proximal end 1004. The elongate tip 1010 is
connected to the distal end of the handpiece. The elongate tip has
a distal portion and is configured to be placed through a corneal
incision and into an anterior chamber of the eye. The holder 1020
(e.g., an insertion tube) is attached to the distal portion of the
elongate tip. The holder is configured to hold and release the drug
delivery implant. The actuator 1040 is on the handpiece and
actuates the holder to release the drug delivery implant from the
holder. In one embodiment, a deployment mechanism within the
delivery apparatus includes a push-pull type plunger.
[0406] In some embodiments, the holder comprises a clamp. In some
embodiments, the apparatus further comprises a spring within the
handpiece that is configured to be loaded when the drug delivery
implant is being held by the holder, the spring being at least
partially unloaded upon actuating the actuator, allowing for
release of the drug delivery implant from the holder.
[0407] In various embodiments, the clamp comprises a plurality of
claws configured to exert a clamping force onto at least the
proximal portion of the drug delivery implant. The holder may also
comprise a plurality of flanges.
[0408] In some embodiments, the distal portion of the elongate tip
is made of a flexible material. This can be a flexible wire. The
distal portion can have a deflection range, preferably of about 45
degrees from the long axis of the handpiece. The delivery apparatus
can further comprise an irrigation port in the elongate tip.
[0409] In some embodiments, the method includes using a delivery
apparatus that comprises a handpiece having a distal end and a
proximal end and an elongate tip connected to the distal end of the
handpiece. The elongate tip has a distal portion and being
configured to be placed through a corneal incision and into an
anterior chamber of the eye. The apparatus further has a holder
attached to the distal portion of the elongate tip, the holder
being configured to hold and release the drug delivery implant, and
an actuator on the handpiece that actuates the holder to release
the drug delivery implant from the holder.
[0410] The delivery instrument may be advanced through an insertion
site in the cornea and advanced either transocularly or posteriorly
into the anterior chamber. angle and positioned at base of the
anterior chamber angle. Using the anterior chamber angle as a
reference point, the delivery instrument can be advanced further in
a generally posterior direction to drive the implant into the iris,
inward of the anterior chamber angle.
[0411] Optionally, based on the implant structure, the implant may
be laid within the anterior chamber angle, taking on a curved shape
to match the annular shape of the anterior chamber angle.
[0412] In some embodiments, the implant may be brought into
position adjacent the tissue in the anterior chamber angle or the
iris tissue, and the pusher tube advanced axially toward the distal
end of the delivery instrument. As the pusher tube is advanced, the
implant is also advanced. When the implant is advanced through the
tissue and such that it is no longer in the lumen of the delivery
instrument, the delivery instrument is retracted, leaving the
implant in the eye tissue.
[0413] The placement and implantation of the implant may be
performed using a gonioscope or other conventional imaging
equipment. In some embodiments, the delivery instrument 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.
[0414] In one embodiment, the drug delivery implant is affixed to
an additional portion of the iris or other intraocular tissue, to
aid in fixating the implant. In one embodiment, this additional
affixation may be performed with a biocompatible adhesive. In other
embodiments, one or more sutures may be used. In another
embodiment, the drug delivery implant is held substantially in
place via the interaction of the implant body's outer surface and
the surrounding tissue of the anterior chamber angle.
[0415] FIG. 23 illustrates 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.
In some embodiments, the first incision is posterior to the limbus
21, including about 3 mm posterior to the limbus. In some
embodiments, the incision is made such that a surgical tool may be
inserted into the anterior chamber at a shallow angle (relative to
the anteroposterior axis), as shown in FIG. 23. In other
embodiments, the first incision may be made to allow a larger angle
of instrument insertion (see, e.g. FIGS. 24-26). 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.
[0416] A portion of the upper and lower surfaces of the drug
delivery implant can be grasped securely by the surgical tool, for
example, a forceps, so that the forward end of the implant is
oriented properly. The implant may also be secured by viscoelastic
or mechanical interlock with the pusher tube or wall of the implant
delivery device. 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 is disposed through the first incision.
[0417] The delivery instrument may 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 eye
tissue at a location just inward of the scleral spur toward the
iris.
[0418] Optionally, based on the implant structure, the shearing
edge of the insertion head of the implant can pass between the
scleral spur and the ciliary body 16 posterior to the trabecular
meshwork.
[0419] The drug delivery implant may be continually advanced
posteriorly 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. The distal
end of the elongate body of the drug delivery implant can be
disposed into the suprachoroidal space of the eye so that the
second end of the conduit is placed into fluid communication with
the suprachoroidal space. Alternatively, the implant may be brought
into position adjacent the tissue in the anterior chamber angle,
and the pusher tube advanced axially toward the distal end of the
delivery instrument. As the pusher tube is advanced, the implant is
also advanced. When the implant is advanced through the tissue and
such that it is no longer in the lumen of the delivery instrument,
the delivery instrument is retracted, leaving the implant in the
eye tissue.
[0420] The placement and implantation of the implant may be
performed using a gonioscope or other conventional imaging
equipment. In some embodiments, the delivery instrument 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.
[0421] In one embodiment, the drug delivery implant is sutured to a
portion of the sclera 11 to aid in fixating the implant. In one
embodiment, the first incision is subsequently sutured closed. As
one will appreciate, the suture used to fixate the drug delivery
implant may also be used to close the first incision. In another
embodiment, the drug delivery implant is 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 and/or choroid 12
without suturing the implant to the sclera 11. Additionally, in one
embodiment, the first incision is 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.
[0422] As discussed herein, in some embodiments the drug delivery
implant additionally includes a shunt comprising a lumen configured
provide a drainage device between the anterior chamber 20 and the
suprachoroidal space. Upon implantation, the drainage device may
form a cyclodialysis with the implant providing a permanent, patent
communication of aqueous humor through the shunt along its length.
Aqueous humor is thus delivered to the suprachoroidal space where
it can be absorbed, and additional reduction in pressure within the
eye can be achieved.
[0423] 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. 24). 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 may be flexible to facilitate
delivery along the curvature or may be more loosely held to move
easily along an accurate path. In the latter case, the implant may
be relatively rigid. The delivery instrument may incorporate an
implant advancement element (e.g. pusher) that is flexible enough
to pass through the distal angle.
[0424] In some embodiments, the implant and delivery instrument are
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 (e.g. exposed
to the suprachoroidal space defined between the sclera 11 and the
choroid 12). FIG. 24 illustrates a transocular implantation
approach that may be used with the delivery instrument inserted
well above the limbus 21. In other embodiments (see, e.g., FIG.
25), the incision may be made more posterior and closer to the
limbus 21. In one embodiment, the incision will be placed on the
nasal side of the eye with the implanted location of the drug
delivery implant 40 on the temporal side of the eye. In another
embodiment, the incision may be made temporally such that the
implanted location of the drug delivery implant is on the nasal
side of the eye. In some embodiments, the operator simultaneously
pushes on a pusher device while pulling back on the delivery
instrument, such that the drug delivery implant outlet portion
maintains its location in the posterior region of the
suprachoroidal space near the macula 34, as illustrated in FIG. 26.
The implant is released from the delivery instrument, and the
delivery instrument retracted proximally. The delivery instrument
is withdrawn from the anterior chamber through the incision.
[0425] In some embodiments, it is desirable to implant a drug
delivery implant with continuous aqueous outflow through the
fibrous attachment zone, thus connecting the anterior chamber 20 to
the uveoscleral outflow pathway, 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.
[0426] In several embodiments, microinvasive methods of implanting
a drug delivery implant are provided. In several such embodiments,
an ab externo technique is utilized. In some embodiments, the
technique is non-penetrating, thereby limiting the invasiveness of
the implantation method. As discussed herein, in some embodiments,
the drug delivery device that is implanted comprises a shunt. In
some embodiments, such implants facilitate removal of fluid from a
first location, while simultaneously providing drug delivery. In
some embodiments, the implants communicate fluid from the anterior
chamber to the suprachoroidal space, which assists in removing
fluid (e.g., aqueous humor) from and reducing pressure increases in
the anterior chamber.
[0427] In some embodiments (see e.g., FIG. 27), a window (e.g. a
slit or other small incision) is surgically made through the
conjunctiva and the sclera 11 to the surface of the choroid 28
(without penetration). In some embodiments, the slit is made
perpendicular to the optical axis of the eye. In some embodiments,
a depth stop is used in conjunction with an incising device. In
certain embodiments, the incising device is one of a diamond or
metal blade, a laser, or the like. In some embodiments, an initial
incision is made with a sharp device, while the final portion of
the incision to the choroid surface is made with a less sharp
instrument, thereby reducing risk of injury to the highly vascular
choroid. In some embodiments, the slit is created at or nearly at a
tangent to the sclera, in order to facilitate entry and
manipulation of an implant.
[0428] In some embodiments, a small core of sclera is removed at or
near the pars plana, again, without penetration of the choroid. In
order to avoid penetration of the choroid, scleral thickness can
optionally be measured using optical coherence tomography (OCT),
ultrasound, or visual fixtures on the eye during the surgical
process. In such embodiments, the scleral core is removed by a
trephining instrument (e.g., a rotary or static trephintor) that
optionally includes a depth stop gauge to ensure an incision to the
proper depth. In other embodiments, a laser, diamond blade, metal
blade, or other similar incising device is used.
[0429] After a window or slit is made in the sclera and the
suprachoroidal space is exposed, an implant 40 can be introduced
into the window or slit and advanced in multiple directions through
the use of an instrument 38a (see e.g., FIG. 27B-27C). Through the
use of the instrument 38a, the implant 40 can be maneuvered in a
posterior, anterior, superior, or inferior direction. The
instrument 38a is specifically designed to advance the implant to
the appropriate location without harming the choroid or other
structures. The instrument 38a can then be removed and the implant
40 left behind. In some embodiments, the window in the conjunctiva
and sclera is small enough to be a self sealing incision. In some
embodiments, it can be a larger window or slit which can be sealed
by means of a suture, staple, tissue common wound adhesive, or the
like. A slit or window according to these embodiments can be 1 mm
or less in length or diameter, for example. In some embodiments,
the length of the incision ranges from about 0.2 to about 0.4 mm,
about 0.4 to about 0.6 mm, about 0.6 mm to about 0.8 mm, about 0.8
mm to about 1.0 mm, about 1.0 to about 1.5 mm, and overlapping
ranges thereof. In some embodiments larger incision (slit or
window) dimensions are used.
[0430] In several embodiments, the implant 40 is tubular or oval
tubular in shape. In some embodiments, such a shape facilitates
passage of the implant through the small opening. In some
embodiments, the implant 40 has a rounded closed distal end, while
in other embodiments, the distal end is open. In several
embodiments wherein open ended implants are used, the open end is
filled (e.g., blocked temporarily) by a portion of the insertion
instrument in order to prevent tissue plugging during advancement
of the implant (e.g., into the suprachoroidal space). In several
embodiments, the implant is an implant as described herein and
comprises a lumen that contains a drug which elutes through holes,
pores, or regions of drug release in the implant. As discussed
herein, drug elution, in some embodiments, is targeted towards the
posterior of the eye (e.g., the macula or optic nerve), and
delivers therapeutic agents (e.g., steroids or anti VEGFs) to treat
retinal or optic nerve disease.
[0431] In several embodiments, the implant 40 and implantation
instrument 38a is designed with an appropriate tip to allow the
implant to be advanced in an anterior direction and penetrate into
the anterior chamber without a scleral cutdown. In some
embodiments, the tip that penetrates into the anterior chamber is a
part of the implant while in some embodiments, it is part of the
insertion instrument. In such embodiments, the implant functions as
a conduit for aqueous humor to pass from the anterior chamber to
the suprachoroidal space to treat glaucoma or ocular hypertension
(e.g., a shunt). In several embodiments, the implant is configured
to deliver a drug to the anterior chamber to treat glaucoma. In
some embodiments, the drug is configured (e.g., produced) to elute
over a relatively long period of time (e.g., weeks to months or
even years). Non-liming examples of such agents are beta blockers
or prostaglandins. In some embodiments, a single implant is
inserted, while in other embodiments, two or more implants are
implanted in this way, at the same or different locations and in
any combination of aqueous humor conduit or drug delivery
mechanisms.
[0432] FIG. 28 shows an illustrative transocular method for placing
any of the various implant embodiments taught or suggested herein
at the implant site within the eye 10. A delivery apparatus 100b
generally comprises a syringe portion 116 and a cannula portion
118. The distal section of the cannula 118 optionally has at least
one irrigating hole 120 and a distal space 122 for holding the drug
delivery implant 30. The proximal end 124 of the lumen of the
distal space 122 is sealed from the remaining lumen of the cannula
portion 118. The delivery apparatus of FIG. 28 may be employed with
the any of the various drug delivery implant embodiments taught or
suggested herein. In some embodiments, the target implant site is
the inferior portion of the iris. It should be understood that the
angle of the delivery apparatus shown in FIG. 28 is illustrative,
and angles more or less shallow than that shown may be preferable
in some embodiments.
[0433] FIG. 29 shows an illustrative method for placing any of the
various implant embodiments taught or suggested herein at implant
site on the same side of the eye. In one embodiment, the drug
delivery implant is inserted into the anterior chamber 20 of the
eye 10 to the iris with the aid of an applicator or delivery
apparatus 100c that creates a small puncture in the eye from the
outside. In some embodiments, the target implant site is the
inferior portion of the iris.
[0434] FIG. 30 illustrates a drug delivery implant consistent with
several embodiments disclosed herein affixed to the iris 13 of the
eye 10 consistent with several implantation methods disclosed
herein. It shall be appreciated that the iris is but one of many
tissues that an implant as described here may be anchored to.
[0435] FIG. 31 illustrates another possible embodiment of placement
of a drug delivery implant consistent with several embodiments
disclosed herein. In one embodiment, the outer shell 54 of an
implant consistent with several embodiments disclosed herein is
shown (in cross section) positioned in the anterior chamber angle.
In one embodiment, the transocular delivery method and apparatus
may be used to position the drug delivery implant wholly within the
anterior chamber angle, wherein the drug delivery implant
substantially tracks the curvature of the anterior angle. In some
embodiments, the implant is positioned substantially within the
anterior chamber angle along the inferior portion of the iris.
[0436] In some embodiments, the placement of the implant may result
in the drug target being upstream of the natural flow of aqueous
humor in the eye. For example, aqueous humor flows from the ciliary
processes to the anterior chamber angle, which, based on the site
of implantation in certain embodiments, may create a flow of fluid
against which a drug released from an implant may have to travel in
order to make contact with a target tissue. Thus, in certain
embodiments, for example when the target tissue is the ciliary
processes, eluted drug must diffuse through iris tissue to get from
the anterior chamber to target receptors in the ciliary processes
in the posterior chamber. The requirement for diffusion of drug
through the iris, and the flow of the aqueous humor, in certain
instances, may limit the amount of eluted drug reaching the ciliary
body.
[0437] To overcome these issues, certain embodiments involve
placement of a peripheral iridotomy (PI), or device-stented PI, at
a location adjacent to a drug eluting implant to facilitate
delivery of a drug directly to the intended site of action (i.e.,
the target tissue). The creation of a PI opens a relatively large
communication passage between the posterior and anterior chambers.
While a net flow of aqueous humor from the posterior chamber to the
anterior chamber still exists, the relatively large diameter of the
PI substantially reduces the linear flow velocity. Thus, eluted
drug is able to diffuse through the PI without significant
opposition from flow of aqueous humor. In certain such embodiments,
a portion of the implant is structured to penetrate the iris and
elute the drug directly into the posterior chamber at the ciliary
body. In other embodiments, the implant is implanted and/or
anchored in the iris and elutes drug directly to the posterior
chamber and adjacent ciliary body.
[0438] FIG. 22 shows a meridional section of the anterior segment
of the human eye and schematically illustrates another embodiment
of a delivery instrument 38 that may be used with embodiments of
drug delivery implants described herein. In FIG. 22, arrows 82 show
the fibrous attachment zone of the ciliary muscle 84 to the sclera
11. The ciliary muscle 84 is coextensive with the choroid 28. The
suprachoroidal space 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.
[0439] 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 90 in FIG. 22) is less than about 3 mm in some
embodiments, and less than 2 mm in other embodiments.
[0440] The suprachoroidal space between the choroid 28 and the
sclera 11 generally forms an angle 96 of about 55.degree. with the
optical axis 98 of the eye. This angle, 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.
[0441] The overall geometry of the drug delivery implant system
makes it advantageous that the delivery instrument 38 incorporates
a distal curvature 86, as shown in FIG. 22, a distal angle 88, as
shown in FIG. 21, or a combination thereof. The distal curvature
(FIG. 23) is expected to pass more smoothly through the corneal or
scleral incision at the limbus. In this embodiment, the drug
delivery implant may be curved or flexible. Alternatively, in the
design of FIG. 21, the drug delivery implant may be mounted on the
straight segment of the delivery instrument, distal of the "elbow"
or angle 88. In this case, the drug delivery implant may be
straight and relatively inflexible, and the delivery instrument may
incorporate a delivery mechanism that is flexible enough to advance
through the angle. In some embodiments, the drug delivery implant
may be a rigid tube, provided that the implant is no longer than
the length of the distal segment 92.
[0442] The distal curvature 86 of delivery instrument 38 may be
characterized as a radius of between about 10 to 30 mm in some
embodiments, and about 20 mm in certain embodiments. The distal
angle of the delivery instrument in an embodiment as depicted in
FIG. 21 may be characterized as between about 90 to 170 degrees
relative to an axis of the proximal segment 94 of the delivery
instrument. In other embodiments, the angle may be between about
145 and about 170 degrees. The angle incorporates a small radius of
curvature at the "elbow" so as to make a smooth transition from the
proximal segment 94 of the delivery instrument to the distal
segment 92. The length of the distal segment 92 may be
approximately 0.5 to 7 mm in some embodiments, and about 2 to 3 mm
in certain embodiments.
[0443] In some embodiments, a viscoelastic, or other fluid is
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 exposes more of the choroidal
and scleral tissue area, provides lubrication and protection for
tissues during implantation, and increases uveoscleral outflow in
embodiments where the drug delivery implant includes a shunt,
causing a lower intraocular pressure (IOP). In some embodiments,
the viscoelastic material is injected with a 25 or 27 G cannula,
for example, through an incision in the ciliary muscle attachment
or through the sclera (e.g. from outside the eye). The viscoelastic
material may also be injected through the implant itself either
before, during or after implantation is completed.
[0444] In some embodiments, a hyperosmotic agent is injected into
the suprachoroidal space. Such an injection can delay IOP
reduction. Thus, hypotony may be avoided in the acute postoperative
period by temporarily reducing choroidal absorption. The
hyperosmotic agent may 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 IOP, and avoiding transient
hypotony.
[0445] FIG. 54 is a flowchart showing an example embodiment of a
method 5400 for preparing a drug delivery ocular implant, such as
the implants 500, 600, or 700 or any other suitable ocular implant
disclosed herein. The description of method 5400 will be discussed
in connection with the implant 500, although similar methods can be
used in connection with implants 600 and 700 as well as with other
embodiments disclosed herein. At block 5402 the outer shell 506 is
provided. Providing the outer shell 506 can include opening a
package and removing an outer shell from its packaging, picking an
outer shell 506 out of a container, selecting one of several outer
shells for using the method 5400, or otherwise accessing an outer
shell 506. Providing the outer shell 506 does not require that the
performer of the method 5400 manufacture the outer shell 506. At
block 5404, the seal 528 is inserted to seal off the drug reservoir
508 from the drainage pathway (e.g., the inflow pathway 512). In
some embodiments, a lubricant can be applied to the seal 528 (e.g.,
to the O-ring 534) and/or to the interior of the shell 506, to
facilitate insertion of the seal 528. In some embodiments, the
barrier 540 and the O-ring 534 can be coupled to the seal base 536
and the seal assembly 528 can be inserted into the shell 506, or
the barrier 540 can be inserted separately from the base 536 and
O-ring 534. In some embodiments, a tool can be used to press the
seal 528 distally until it abuts the distal end of the interior
chamber 508.
[0446] At block 5406 the drug reservoir (e.g., the interior chamber
508) is filled with the drug. In some embodiments, the interior
chamber 508 is filled with a precise volume of the drug that is
configured to enable the implant to be sealed with no air or
substantially no air in the drug reservoir. In some instances,
implants with substantially no air in the drug reservoir can refer
to implants that include small amounts of air (e.g., air bubbles
with a diameter of not more than 10% or 25% of the diameter of the
internal chamber 508). It can be undesirable to have air in the
drug reservoir. For example, in some instances, air adjacent to the
membrane can interfere with elution of the drug (e.g., by
interfering with the osmotic pressure across the membrane). In some
embodiments, the drug reservoir is not overfilled, such that the
drug is not wasted. In some embodiments, the drug reservoir can be
overfilled with the drug, which can result in some wasted amount of
the drug, but can facilitate preparation of the implants with no
air or substantially no air in the drug reservoir.
[0447] At block 5408, the distal seal member 552 is inserted. The
distal seal member 552 can be seated against the shelf 548, as
discussed herein. The membrane 554 can be inserted over the distal
seal member 552, at block 5410. At block 5412, the proximal seal
member 556 can be inserted over the membrane 554. In some cases,
the distal seal member 552, the membrane 554, and/or the proximal
seal member 556 can be inserted together (e.g., as an assembly
after being coupled together). At block 5414, the membrane 554 can
be compressed. For example, a force in the distal direction can be
applied to the proximal seal member 556 (e.g., using a tool), which
can compress the membrane 554 between the distal seal member 552
and the proximal seal member 556. In some embodiments, the same
tool that inserts the proximal seal member 556 into the shell 506
(e.g., along with the membrane 554 and/or distal seal 552 can be
used to apply distal force to compress the membrane 554. For
example, the tool can advance to insert the proximal seal member
556 into the shell 506 and the tool can continue to advance
distally to compress the membrane 554. In some embodiments, in
which the drug reservoir was overfilled, blocks 5408, 5410, 5412,
and/or 5414 can cause drug to overflow from the drug reservoir
(e.g., out of the proximal end of the shell 506).
[0448] At block 5416, the retainer 532 is inserted over the
proximal seal member 556 (e.g., via one of the slots 550). The
slots 550 can engage the retainer 532 to prevent the compressed
membrane 554 from pushing the retainer 532 proximally out of the
shell 506. The tabs 564 can be bent down to engage the proximal
seal member 556 to secure the retainer 532, as discussed
herein.
[0449] In some cases, the method 5400 can include additional steps,
not shown in FIG. 54. For example, if the implant was overfilled
and some of the drug overflowed from the drug reservoir, the
implant can be cleaned (e.g., wiped, swapped, rinsed). In some
embodiments, a heparin coating can be applied to some or all of the
implant (e.g., to the retention protrusion 510). In some
embodiments, the implant can be sterilized. In some embodiments,
steps of the method 5400 can be omitted, combined, divided into
multiple steps, and additional steps can be added. In some
embodiments that do not include drainage pathways, block 5404 can
be omitted.
[0450] Many alternatives and variations are possible. For example,
in some cases, assembly of the embodiment shown in FIGS. 18R and
18S can include providing an outer shell 54, filling the drug
reservoir (e.g., similar to block 5406 of method 5400). A cap 54a
with a membrane 60 can be applied over the proximal end of the
shell 54. In some embodiments, the cap 54a can be advanced distally
until a desired amount of membrane 60 compression (e.g., 30 microns
or any other suitable amount as discussed herein) is achieved, and
the cap 54a can then be crimped onto the shell 54. In some
embodiments, a micrometer can be used to determine the amount of
membrane compression. In some embodiments, shell 54 includes a
groove, and the cap 54a can be crimped into the groove. In some
embodiments, the cap 54a and/or shell 54 can spin during the
crimping of the cap 54a onto the shell 54, for example, such that
all sides of the cap 54a are crimped.
Controlled Drug Release
[0451] The drug delivery implants as described herein, function to
house a drug and provide drug elution from the implant in a
controlled fashion, based on the design of the various components
of the implant, for an extended period of time. Various elements of
the implant composition, implant physical characteristics, implant
location in the eye, and the composition of the drug work in
combination to produce the desired drug release profile.
[0452] As described above the drug delivery implant may be made
from any biological inert and biocompatible materials having
desired characteristics. Desirable characteristics, in some
embodiments, include permeability to liquid water or water vapor,
allowing for an implant to be manufactured, loaded with drug, and
sterilized in a dry state, with subsequent rehydration of the drug
upon implantation. Also desirable is an implant constructed of a
material comprising microscopic porosities between polymer chains.
These porosities may interconnect, which forms channels of water
through the implant material. In several embodiments, the resultant
channels are convoluted and thereby form a tortuous path which
solubilized drug travels during the elution process. Implant
materials advantageously also possess sufficient permeability to a
drug such that the implant may be a practical size for
implantation. Thus, in several embodiments, the implant material is
sufficiently permeable to the drug to be delivered that the implant
is dimensioned to reside wholly contained within the eye of a
subject. Implant material also ideally possesses sufficient
elasticity, flexibility and potential elongation to not only
conform to the target anatomy during and after implantation, but
also remain unkinked, untorn, unpunctured, and with a patent lumen
during and after implantation. In several embodiments, implant
material would advantageously processable in a practical manner,
such as, for example, by molding, extrusion, thermoforming, and the
like.
[0453] Illustrative, examples of suitable materials for the outer
shell include polypropylene, polyimide, glass, nitinol, polyvinyl
alcohol, polyvinyl pyrolidone, collagen, chemically-treated
collagen, polyethersulfone (PES), poly(styrene-isobutyl-styrene),
polyurethane, ethyl vinyl acetate (EVA), polyetherether ketone
(PEEK), Kynar (Polyvinylidene Fluoride; PVDF),
Polytetrafluoroethylene (PTFE), Polymethylmethacrylate (PMMA),
Pebax, acrylic, polyolefin, polydimethylsiloxane and other silicone
elastomers, polypropylene, hydroxyapetite, titanium, gold, silver,
platinum, other metals and alloys, ceramics, plastics and mixtures
or combinations thereof. Additional suitable materials used to
construct certain embodiments of the implant include, but are not
limited to, poly(lactic acid), poly(tyrosine carbonate),
polyethylene-vinyl acetate, poly(L-lactic acid),
poly(D,L-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, copolymers, or block co-polymers, polyester urethanes,
polyester amides, polyester ureas, polythioesters, thermoplastic
polyurethanes, silicone-modified polyether urethanes,
poly(carbonate urethane), or polyimide. Thermoplastic polyurethanes
are polymers or copolymers which may comprise aliphatic
polyurethanes, aromatic polyurethanes, polyurethane
hydrogel-forming materials, hydrophilic polyurethanes (such as
those described in U.S. Pat. No. 5,428,123, which is incorporated
in its entirety by reference herein), or combinations thereof.
Non-limiting examples include elasthane (poly(ether urethane)) such
as Elasthane.TM. 80A, Lubrizol, Tecophilic.TM., Pellethane.TM.,
Carbothane.TM., Tecothane.TM., Tecoplast.TM., and Estane.TM.. In
some embodiments, polysiloxane-containing polyurethane elastomers
are used, which include Carbosil.TM. 20 or Pursil.TM. 20 80A,
Elast-Eon.TM., and the like. Hydrophilic and/or hydrophobic
materials may be used. Non-limiting examples of such elastomers are
provided in U.S. Pat. No. 6,627,724, which is incorporated in its
entirety by reference herein. Poly(carbonate urethane) may include
Bionate.TM. 80A or similar polymers. In several embodiments, such
silicone modified polyether urethanes are particularly advantageous
based on improved biostability of the polymer imparted by the
inclusion of silicone. In addition, in some embodiments, oxidative
stability and thrombo-resistance is also improved as compared to
non-modified polyurethanes. In some embodiments, there is a
reduction in angiogenesis, cellular adhesion, inflammation, and/or
protein adsorption with silicone-modified polyether urethanes. In
other embodiments, should angiogenesis, cellular adhesion or
protein adsorption (e.g., for assistance in anchoring an implant)
is preferable, the degree of silicone (or other modifier) may be
adjusted accordingly. Moreover, in some embodiments, silicone
modification reduces the coefficient of friction of the polymer,
which reduces trauma during implantation of devices described
herein. In some embodiments, silicone modification, in addition to
the other mechanisms described herein, is another variable that can
be used to tailor the permeability of the polymer. Further, in some
embodiments, silicone modification of a polymer is accomplished
through the addition of silicone-containing surface modifying
endgroups to the base polymer. In other embodiments, flurorocarbon
or polyethylene oxide surface modifying endgroups are added to a
based polymer. In several embodiments, one or more biodegradable
materials are used to construct all or a portion of the implant, or
any other device disclosed herein. Such materials include any
suitable material that degrades or erodes over time when placed in
the human or animal body, whether due to a particular chemical
reaction or enzymatic process or in the absence of such a reaction
or process. Accordingly, as the term is used herein, biodegradable
material includes bioerodible materials. In such biodegradable
embodiments, the degradation rate of the biodegradable outer shell
is another variable (of many) that may be used to tailor the drug
elution rate from an implant.
[0454] In some embodiments, such as where the drug is sensitive to
moisture (e.g. liquid water, water vapor, humidity) or where the
drug's long term stability may be adversely affected by exposure to
moisture, it may be desirable to utilize a material for the implant
or at least a portion of the implant, which is water resistant,
water impermeable or waterproof such that it presents a significant
barrier to the intrusion of liquid water and/or water vapor,
especially at or around human body temperature (e.g. about
35-40.degree. C. or 37.degree. C.). This may be accomplished by
using a material that is, itself, water resistant, water
impermeable or waterproof.
[0455] In some circumstances, however, even materials that are
generally considered water impermeable may still allow in enough
water to adversely affect the drug within an implant. For example,
it may be desirable to have 5% by weight of the drug or less water
intrusion over the course of a year. In one embodiment of implant,
this would equate to a water vapor transmission rate for a material
of about 1.times.10.sup.-3 g/m.sup.2/day or less. This may be as
much as one-tenth of the water transmission rate of some polymers
generally considered to be water resistant or water impermeable.
Therefore, it may be desirable to increase the water resistance or
water impermeability of a material.
[0456] The water resistance or water impermeability of a material
may be increased by any suitable method. Such methods of treatment
include providing a coating for a material (including by
lamination) or by compounding a material with a component that adds
water resistance or increases impermeability. For example, such
treatment may be performed on the implant (or portion of the
implant) itself, it may be done on the material prior to
fabrication (e.g. coating a polymeric tube), or it may be done in
the formation of the material itself (e.g. by compounding a resin
with a material prior to forming the resin into a tube or sheet).
Such treatment may include, without limitation, one or more of the
following: coating or laminating the material with a hydrophobic
polymer or other material to increase water resistance or
impermeability; compounding the material with hydrophobic or other
material to increase water resistance or impermeability;
compounding or treating the material with a substance that fills
microscopic gaps or pores within the material that allow for
ingress of water or water vapor; coating and/or compounding the
material with a water scavenger or hygroscopic material that can
absorb, adsorb or react with water so as to increase the water
resistance or impermeability of the material.
[0457] One type of material that may be employed as a coating to
increase water resistance and/or water impermeability is an
inorganic material. Inorganic materials include, but are not
limited to, metals, metal oxides and other metal compounds (e.g.
metal sulfides, metal hydrides), ceramics, and main group materials
and their compounds (e.g. carbon (e.g. carbon nanotubes), silicon,
silicon oxides). Examples of suitable materials include aluminum
oxides (e.g. Al.sub.2O.sub.3) and silicon oxides (e.g. SiO.sub.2).
Inorganic materials may be advantageously coated onto a material
(at any stage of manufacture of the material or implant) using
techniques such as are known in the art to create extremely thin
coatings on a substrate, including by vapor deposition, atomic
layer deposition, plasma deposition, and the like. Such techniques
can provide for the deposition of very thin coatings (e.g. about 20
nm-40 nm thick, including about 25 nm thick, about 30 nm thick, and
about 35 nm thick) on substrates, including polymeric substrates,
and can provide a coating on the exterior and/or interior luminal
surfaces of small tubing, including that of the size suitable for
use in implants disclosed herein. Such coatings can provide
excellent resistance to the permeation of water or water vapor
while still being at least moderately flexible so as not to
undesirably compromise the performance of an implant in which
flexibility is desired.
[0458] In order to control the dose or duration of treatment, in
embodiments wherein the therapeutic agents are delivered via
flexible tethered implants (see, e.g., FIGS. 16-17), one or more
flexible sheets or discs may be simultaneously used. Similarly the
material used to construct the sheets or discs and/or the coatings
covering them may be prepared to control the rate of release of the
drug, similar to as discussed below.
[0459] The drugs carried by the drug delivery implant may be in any
form that can be reasonably retained within the device and results
in controlled elution of the resident drug or drugs over a period
of time lasting at least several days and in some embodiments up to
several weeks, and in certain preferred embodiments, up to several
years. Certain embodiments utilize drugs that are readily soluble
in ocular fluid, while other embodiments utilize drugs that are
partially soluble in ocular fluid.
[0460] For example, the therapeutic agent may be in any form,
including but not limited to a compressed pellet, a solid, a
capsule, multiple particles, a liquid, a gel, a suspension, slurry,
emulsion, and the like. In certain embodiments, drug particles are
in the form of micro-pellets (e.g., micro-tablets), fine powders,
or slurries, each of which has fluid-like properties, allowing for
recharging by injection into the inner lumen(s). As discussed
above, in some embodiments, the loading and/or recharging of a
device is accomplished with a syringe/needle, through which the
therapeutic agent is delivered. In some embodiments, micro-tablets
are delivered through a needle of about 23 gauge to about 32 gauge,
including 23-25 gauge, 25 to 27 gauge, 27-29 gauge, 29-30 gauge,
30-32 gauge, and overlapping ranges thereof. In some embodiments,
the needle is 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 gauge.
[0461] When more than one drug is desired for treatment of a
particular pathology or when a second drug is administered such as
to counteract a side effect of the first drug, some embodiments may
utilize two agents of the same form. In other embodiments, agents
in different form may be used. Likewise, should one or more drugs
utilize an adjuvant, excipient, or auxiliary compound, for example
to enhance stability or tailor the elution profile, that compound
or compounds may also be in any form that is compatible with the
drug and can be reasonably retained with the implant.
[0462] In some embodiments, treatment of particular pathology with
a drug released from the implant may not only treat the pathology,
but also induce certain undesirable side effects. In some cases,
delivery of certain drugs may treat a pathological condition, but
indirectly increase intraocular pressure. Steroids, for example,
may have such an effect. In certain embodiments, a drug delivery
shunt delivers a steroid to an ocular target tissue, such as the
retina or other target tissue as described herein, thereby treating
a retinal pathology but also possibly inducing increased
intraocular pressure which may be due to local inflammation or
fluid accumulation. In such embodiments, the shunt feature reduces
undesirable increased intraocular pressure by transporting away the
accumulated fluid. Thus, in some embodiments, implants functioning
both as drug delivery devices and shunts can not only serve to
deliver a therapeutic agent, but simultaneously drain away
accumulated fluid, thereby alleviating the side effect of the drug.
Such embodiments can be deployed in an ocular setting, or in any
other physiological setting where delivery of a drug coordinately
causes fluid accumulation which needs to be reduced by the shunt
feature of the implant. In some such embodiments, drainage of the
accumulated fluid is necessary to avoid tissue damage or loss of
function, in particular when the target tissue is pressure
sensitive or has a limited space or capacity to expand in response
to the accumulated fluid. The eye and the brain are two
non-limiting examples of such tissues.
[0463] It will be understood that embodiments as described herein
may include a drug mixed or compounded with a biodegradable
material, excipient, or other agent modifying the release
characteristics of the drug. 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 will also be understood that in
certain embodiments as described herein, the drug positioned within
the lumen of the implant is not compounded or mixed with any other
compound or material, thereby maximizing the volume of drug that is
positioned within the lumen.
[0464] It may be desirable, in some embodiments, to provide for a
particular rate of release of drug from a PLGA copolymer or other
polymeric material. As the release rate of a drug from a polymer
correlates with the degradation rate of that polymer, control of
the degradation rate provides a means for control of the delivery
rate of the drug contained within the therapeutic agent. Variation
of the average molecular weight of the polymer or copolymer chains
which make up the PLGA copolymer or other polymer may 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.
[0465] 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.
[0466] 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.
[0467] As described above, the outer shell of the implant comprises
a polymer in some embodiments. Additionally, the shell may further
comprise one or more polymeric coatings in various locations on or
within the implant. The outer shell and any polymeric coatings are
optionally biodegradable. The biodegradable outer shell and
biodegradable polymer coating may 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.
[0468] As described above, some embodiments of the implants
comprise a polymeric outer shell that is permeable to ocular fluids
in a controlled fashion depending on the constituents used in
forming the shell. For example, the concentration of the polymeric
subunits dictates the permeability of the resulting shell.
Therefore, the composition of the polymers making up the polymeric
shell determines the rate of ocular fluid passage through the
polymer and if biodegradable, the rate of biodegradation in ocular
fluid. The permeability of the shell will also impact the release
of the drug from the shell. Also as described above, the regions of
drug release created on the shell will alter the release profile of
a drug from the implant. Control of the release of the drug can
further be controlled by coatings in or on the shell that either
form the regions of drug release, or alter the characteristics of
the regions of drug release (e.g., a coating over the region of
drug release makes the region thicker, and therefore slows the rate
of release of a drug).
[0469] For example, a given combination of drug and polymer will
yield a characteristic diffusion coefficient D, such that:
Elution rate = [ D .times. A .times. ( C i - C o ) ] d ##EQU00001##
[0470] where [0471] D=diffusion coefficient (cm.sup.2/sec) [0472]
A=area of the region of drug release [0473] (Ci-Co)=difference in
drug concentration between the inside and outside of the device.
[0474] d=thickness of the region of drug release
[0475] Thus, the area and thickness of the region of drug release
are variables that determine, in part, the rate of elution of the
drug from the implant, and are also variable that can be controlled
during the process of manufacturing the implant. In some
embodiments using a highly insoluble drug, the region of drug
release could be manufactured to be thin (d is small) or with a
large overall area (A is large) or a combination of the two (as
dictated by the structural sufficiency of the outer shell). In
either case, the end result is that the elution rate of the drug
can be increased to compensate for the low solubility of the drug
based on the structure and design of the implant.
[0476] In contrast, in some embodiments using a highly soluble
drug, the regions of drug release are made of substantially the
same thickness as the remainder of the outer shell, made of small
area, or combinations thereof.
[0477] Additionally, certain embodiments use additional polymer
coatings to either (i) increase the effective thickness (d) of the
region of drug release or (ii) decrease the overall permeability of
the of that portion of the implant (region of drug release plus the
coating), resulting in a reduction in drug elution. In still other
embodiments, multiple additional polymer coatings are used. By
covering either distinct or overlapping portions of the implant and
the associated regions of drug release on the outer shell, drug
release from various regions of the implant are controlled and
result in a controlled pattern of drug release from the implant
overall. For example, an implant with at least two regions of drug
release may be coated with two additional polymers, wherein the
additional polymers both cover over region of release and only a
single polymer covers the other region. Thus the elution rate of
drug from the two regions of drug release differ, and are
controllable such that, for example, drug is released sequentially
from the two regions. In other embodiments, the two regions may
release at different rates. In those embodiments with multiple
interior lumens, different concentrations or different drugs may
also be released. It will be appreciated that these variables are
controllable to alter to rate or duration of drug release from the
implant such that a desired elution profile or treatment regimen
can be created.
[0478] In several embodiments as described herein, there are no
direct through holes or penetrating apertures needed or utilized to
specifically facilitate or control drug elution. As such, in those
embodiments, there is no direct contact between the drug core
(which may be of very high concentration) and the ocular tissue
where adjacent to the site where the implant is positioned. In some
cases, direct contact of ocular tissue with high concentrations of
drug residing within the implant could lead to local cell toxicity
and possible local cell death.
[0479] It shall however, be appreciated that, in several other
embodiments, disclosed herein, that the number, size, and placement
of one or more orifices through the outer shell of the implant may
be altered in order to produce a desired drug elution profile. As
the number, size, or both, of the orifices increases relative to
surface area of the implant, increasing amounts of ocular fluid
pass across the outer shell and contact the therapeutic agent on
the interior of the implant. Likewise, decreasing the ratio of
orifice:outer shell area, less ocular fluid will enter the implant,
thereby providing a decreased rate of release of drug from the
implant. Additionally, multiple orifices provides a redundant
communication means between the ocular environment that the implant
is implanted in and the interior of the implant, should one or more
orifices become blocked during implantation or after residing in
the eye. In other embodiments, the outer shell may contain one (or
more) orifice(s) in the distal tip of the implant. As described
above, the shape and size of this orifice is selected based on the
desired elution profile. In some embodiments, a biodegradable
polymer plug is positioned within the distal orifice, thereby
acting as a synthetic cork. Tissue trauma or coring of the ocular
tissue during the process of implantation is also reduced, which
may prevent plugging or partial occlusion of the distal orifice.
Additionally, because the polymer plug may be tailored to
biodegrade in a known time period, the plug ensures that the
implant can be fully positioned before any elution of the drug
takes place. Still other embodiments comprise a combination of a
distal orifice and multiple orifices placed more proximally on the
outer shell, as described above.
[0480] Moreover, the addition of one or more permeable or
semi-permeable coatings on an implant (either with orifices or
regions of drug release) may also be used to tailor the elution
profile. Additionally, combinations of these various elements may
be used in some embodiments to provide multiple methods of
controlling the drug release profile.
[0481] Further benefitting the embodiments described herein is the
expanded possible range of uses for some ocular therapy drugs. For
example, a drug that is highly soluble in ocular fluid may have
narrow applicability in treatment regimes, as its efficacy is
limited to those pathologies treatable with acute drug
administration. However, when coupled with the implants as
disclosed herein, such a drug could be utilized in a long term
therapeutic regime. A highly soluble drug positioned within the
distal portion of the implant containing one or more regions of
drug release may be made to yield a particular, long-term
controlled release profile.
[0482] Alternatively, or in addition to one or more regions of drug
release, one or more polymeric coatings may be located outside the
implant shell, or within the interior lumen, enveloping or
partially enveloping the drug. In some embodiments comprising one
or more orifices, the polymeric coating is the first portion of the
implant in contact with ocular fluid, and thus, is a primary
controller of the rate of entry of ocular fluid into the drug
containing interior lumen of the implant. By altering the
composition of the polymer coating, the biodegradation rate (if
biodegradable), and porosity of the polymer coating the rate at
which the drug is exposed to and solubilized in the ocular fluid
may be controlled. Thus, there is a high degree of control over the
rate at which the drug is released from such an embodiment of an
implant to the target tissue of the eye. Similarly, a drug with a
low ocular fluid solubility may be positioned within an implant
coated with a rapidly biodegradable or highly porous polymer
coating, allowing increased flow of ocular fluid over the drug
within the implant.
[0483] In certain embodiments described herein, the polymer coating
envelopes the therapeutic agent within the lumen of the implant. In
some such embodiments, the ocular fluid passes through the outer
shell of the implant and contacts the polymer layer. Such
embodiments may be particularly useful when the implant comprises
one or more orifices and/or the drug to be delivered is a liquid,
slurry, emulsion, or particles, as the polymer layer would not only
provide control of the elution of the drug, but would assist in
providing a structural barrier to prevent uncontrolled leakage or
loss of the drug outwardly through the orifices. The interior
positioning of the polymer layer could, however, also be used in
implants where the drug is in any form.
[0484] In some ocular disorders, therapy may require a defined
kinetic profile of administration of drug to the eye. It will be
appreciated from the above discussion of various embodiments that
the ability to tailor the release rate of a drug from the implant
can similarly be used to accomplish achieve a desired kinetic
profile. For example the composition of the outer shell and any
polymer coatings can be manipulated to provide a particular kinetic
profile of release of the drug. Additionally, the design of the
implant itself, including the thickness of the shell material, the
thickness of the shell in the regions of drug release, the area of
the regions of drug release, and the area and/or number of any
orifices in the shell provide a means to create a particular drug
release profile. Likewise, the use of PLGA copolymers and/or other
controlled release materials and excipients, may provide particular
kinetic profiles of release of the compounded drug. By tailoring
the ratio of lactic to glycolic acid in a copolymer and/or average
molecular weight of polymers or copolymers having the drug therein
(optionally with one or more other excipients), sustained release
of a drug, or other desirable release profile, may be achieved.
[0485] In certain embodiments, zero-order release of a drug may be
achieved by manipulating any of the features and/or variables
discussed above alone or in combination so that the characteristics
of the implant are the principal factor controlling drug release
from the implant. Similarly, in those embodiments employing PLGA
compounded with the drug, tailoring the ratio of lactic to glycolic
acid and/or average molecular weights in the copolymer-drug
composition can adjust the release kinetics based on the
combination of the implant structure and the biodegradation of the
PLGA copolymer.
[0486] In other embodiments, pseudo zero-order release (or other
desired release profile) may be achieved through the adjustment of
the composition of the implant shell, the structure and dimension
of the regions of drug release, the composition any polymer
coatings, and use of certain excipients or compounded formulations
(PLGA copolymers), the additive effect over time replicating true
zero-order kinetics.
[0487] For example, in one embodiment, an implant with a polymer
coating allowing entry of ocular fluid into the implant at a known
rate may contain a series of pellets that compound PLGA with one or
more drugs, wherein the pellets incorporate at least two different
PLGA copolymer formulations. Based on the formulation of the first
therapeutic agent, each subsequent agent may be compounded with
PLGA in a manner as to allow a known quantity of drug to be
released in a given unit of time. As each copolymer biodegrades or
erodes at its individual and desired rate, the sum total of drug
released to the eye over time is in effect released with zero-order
kinetics. It will be appreciated that embodiments additionally
employing the drug partitions as described herein, operating in
conjunction with pellets having multiple PLGA formulations would
add an additional level of control over the resulting rate of
release and kinetic profile of the drug.
[0488] Non-continuous or pulsatile release may also be desirable.
This may be achieved, for example, by manufacturing an implant with
multiple sub-lumens, each associated with one or more regions of
drug release. In some embodiments, additional polymer coatings are
used to prevent drug release from certain regions of drug release
at a given time, while drug is eluted from other regions of drug
release at that time. Other embodiments additionally employ one or
more biodegradable partitions as described above to provide
permanent or temporary physical barriers within an implant to
further tune the amplitude or duration of period of lowered or
non-release of drug from the implant. Additionally, by controlling
the biodegradation rate of the partition, the length of a drug
holiday may be controlled. In some embodiments the biodegradation
of the partition may be initiated or enhanced by an external
stimulus. In some embodiments, the intraocular injection of a fluid
stimulates or enhances biodegradation of the barrier. In some
embodiments, the externally originating stimulus is one or more of
application of heat, ultrasound, and radio frequency, or laser
energy.
[0489] Certain embodiments are particularly advantageous as the
regions of drug release minimize tissue trauma or coring of the
ocular tissue during the process of implantation, as they are not
open orifices. Additionally, because the regions are of a known
thickness and area (and therefore of a known drug release profile)
they can optionally be manufactured to ensure that the implant can
be fully positioned before any elution of the drug takes place.
[0490] Placement of the drug within the interior of the outer shell
may also be used as a mechanism to control drug release. In some
embodiments, the lumen may be in a distal position, while in others
it may be in a more proximal position, depending on the pathology
to be treated. In those embodiments employing a nested or
concentric tube device, the agent or agents may be placed within
any of the lumens formed between the nested or concentric polymeric
shells
[0491] Further control over drug release is obtained by the
placement location of drug in particular embodiments with multiple
lumens. For example, when release of the drug is desired soon after
implantation, the drug is placed within the implant in a first
releasing lumen having a short time period between implantation and
exposure of the therapeutic agent to ocular fluid. This is
accomplished, for example by juxtaposing the first releasing lumen
with a region of drug release having a thin outer shell thickness
(or a large area, or both). A second agent, placed in a second
releasing lumen with a longer time to ocular fluid exposure elutes
drug into the eye after initiation of release of the first drug.
This can be accomplished by juxtaposing the second releasing lumen
with a region of drug release having a thicker shell or a smaller
area (or both). Optionally, this second drug treats side effects
caused by the release and activity of the first drug.
[0492] It will also be appreciated that the multiple lumens as
described above are also useful in achieving a particular
concentration profile of released drug. For example, in some
embodiments, a first releasing lumen may contain a drug with a
first concentration of drug and a second releasing lumen containing
the same drug with a different concentration. The desired
concentration profile may be tailored by the utilizing drugs having
different drug concentration and placing them within the implant in
such a way that the time to inception of drug elution, and thus
concentration in ocular tissues, is controlled.
[0493] Further, placement location of the drug may be used to
achieve periods of drug release followed by periods of no drug
release. By way of example, a drug may be placed in a first
releasing lumen such that the drug is released into the eye soon
after implantation. A second releasing lumen may remain free of
drug, or contain an inert bioerodible substance, yielding a period
of time wherein no drug is released. A third releasing lumen
containing drug could then be exposed to ocular fluids, thus
starting a second period of drug release.
[0494] It will be appreciated that the ability to alter any one of
or combination of the shell characteristics, the characteristics of
any polymer coatings, any polymer-drug admixtures, the dimension
and number of regions of drug release, the dimension and number of
orifices, and the position of drugs within the implant provides a
vast degree of flexibility in controlling the rate of drug delivery
by the implant.
[0495] The drug elution profile may also be controlled by the
utilization of multiple drugs contained within the same interior
lumen of the implant that are separated by one or more plugs. By
way of example, in an implant comprising a single region of drug
release in the distal tip of the implant, ocular fluid entering the
implant primarily contacts the distal-most drug until a point in
time when the distal-most drug is substantially eroded and eluted.
During that time, ocular fluid passes through a first
semi-permeable partition and begins to erode a second drug, located
proximal to the plug. As discussed below, the composition of these
first two drugs, and the first plug, as well as the characteristics
of the region of drug release may each be controlled to yield an
overall desired elution profile, such as an increasing
concentration over time or time-dependent delivery of two different
doses of drug. Different drugs may also be deployed sequentially
with a similar implant embodiment.
[0496] Partitions may be used if separation of two drugs is
desirable. A partition is optionally biodegradable at a rate equal
to or slower than that of the drugs to be delivered by the implant.
The partitions are designed for the interior dimensions of a given
implant embodiment such that the partition, when in place within
the interior lumen of the implant, will seal off the more proximal
portion of the lumen from the distal portion of the lumen. The
partitions thus create individual compartments within the interior
lumen. A first drug may be placed in the more proximal compartment,
while a second drug, or a second concentration of the first drug,
or an adjuvant agent may be placed in the more distal compartment.
As described above, the entry of ocular fluid and rate of drug
release is thus controllable and drugs can be released in tandem,
in sequence or in a staggered fashion over time.
[0497] Partitions may also be used to create separate compartments
for therapeutic agents or compounds that may react with one
another, but whose reaction is desired at or near ocular tissue,
not simply within the implant lumen. As a practical example, if
each of two compounds was inactive until in the presence of the
other (e.g. a prodrug and a modifier), these two compounds may
still be delivered in a single implant having at least one region
of drug release associated only with one drug-containing lumen.
After the elution of the compounds from the implant to the ocular
space the compounds would comingle, becoming active in close
proximity to the target tissue. As can be determined from the above
description, if more than two drugs are to be delivered in this
manner, utilizing an appropriately increased number of partitions
to segregate the drugs would be desirable.
[0498] In certain embodiments, a proximal barrier serves to seal
the therapeutic agent within a distally located interior lumen of
the implant. The purpose of such a barrier is to ensure that the
ocular fluid from any more distally located points of ocular fluid
entry is the primary source of ocular fluid contacting the
therapeutic agent. Likewise, a drug impermeable seal is formed that
prevents the elution of drug in an anterior direction. Prevention
of anterior elution not only prevents dilution of the drug by
ocular fluid originating from an anterior portion of the eye, but
also reduces potential side of effects of drugs delivered by the
device. Limiting the elution of the drug to sites originating in
the distal region of the implant will enhance the delivery of the
drug to the target sites in more posterior regions of the eye. In
embodiments that are fully biodegradable, the proximal cap or
barrier may comprise a biocompatible biodegradable polymer,
characterized by a biodegradation rate slower than all the drugs to
be delivered by that implant. It will be appreciated that the
proximal cap is useful in those embodiments having a single central
lumen running the length of the implant to allow recharging the
implant after the first dose of drug has fully eluted. In those
embodiments, the single central lumen is present to allow a new
drug to be placed within the distal portion of the device, but is
preferably sealed off at or near the proximal end to avoid
anteriorly directed drug dilution or elution.
[0499] Similar to the multiple longitudinally located compartments
that may be formed in an implant, drugs may also be positioned
within one or more lumens nested within one another. By ordering
particularly desirable drugs or concentrations of drugs in nested
lumens, one may achieve similarly controlled release or kinetic
profiles as described above.
[0500] Wicks, as described above, may also be employed to control
the release characteristics of different drugs within the implant.
One or more wicks leading into separate interior lumens of an
implant assist in moving ocular fluid rapidly into the lumen where
it may interact with the drug. Drugs requiring more ocular fluid
for their release may optionally be positioned in a lumen where a
wick brings in more ocular fluid than an orifice alone would allow.
One or more wicks may be used in some embodiments.
[0501] In some embodiments, drugs are variably dimensioned to
further tailor the release profile by increasing or limiting ocular
fluid flow into the space in between the drug and walls of the
interior lumen. For example, if it was optimal to have a first
solid or semi solid drug elute more quickly than another solid or
semi-solid drug, formation of the first drug to a dimension
allowing substantial clearance between the drug and the walls of
the interior lumen may be desirable, as ocular fluid entering the
implant contacts the drug over a greater surface area. Such drug
dimensions are easily variable based on the elution and solubility
characteristics of a given drug. Conversely, initial drug elution
may be slowed in embodiments with drugs dimensioned so that a
minimal amount of residual space remains between the therapeutic
agent and the walls of the interior lumen. In still other
embodiments, the entirety of the implant lumen is filled with a
drug, to maximize either the duration of drug release or limit the
need to recharge an implant.
[0502] Certain embodiments may comprise a shunt in addition to the
drug delivery portion of the implant. For example, once the implant
is positioned in the desired intraocular space (in an
anterior-posterior direction), a shunt portion of the implant
comprising at least one outflow channel can be inserted into a
physiological outflow space (for example anchored to the trabecular
meshwork and releasing fluid to Schlemm's canal). In some
embodiments, a plurality of apertures thus assists in maintaining
patency and operability of the drainage shunt portion of the
implant. Moreover, as described above, a plurality of apertures can
assist in ameliorating any unwanted side effects involving excess
fluid production or accumulation that may result from the actions
of the therapeutic agent delivered by the implant.
[0503] As described above, duration of drug release is desired over
an extended period of time. In some embodiments, an implant in
accordance with embodiments described herein is capable of
delivering a drug at a controlled rate to a target tissue for a
period of several (i.e. at least three) months. In certain
embodiments, implants can deliver drugs at a controlled rate to
target tissues for about 6 months or longer, including 3, 4, 5, 6,
7, 8, 9, 12, 15, 18, and 24 months, without requiring recharging.
In still other embodiments, the duration of controlled drug release
(without recharging of the implant) exceeds 2 years (e.g., 3, 4, 5,
or more years). It shall be appreciated that additional time frames
including ranges bordering, overlapping or inclusive of two or more
of the values listed above are also used in certain
embodiments.
[0504] In conjunction with the controlled release of a drug to a
target tissue, certain doses of a drug (or drugs) are desirable
over time, in certain embodiments. As such, in some embodiments,
the total drug load, for example the total load of a steroid,
delivered to a target tissue over the lifetime of an implant ranges
from about 10 to about 1000 .mu.g. In certain embodiments the total
drug load ranges from about 100 to about 900 .mu.g, from about 200
to about 800 .mu.g, from about 300 to about 700 .mu.g, or from
about 400 to about 600 .mu.g. In some embodiments, the total drug
load ranges from about 10 to about 300 .mu.g, from about 10 to
about 500 .mu.g, or about 10 to about 700 .mu.g. In other
embodiments, total drug load ranges from about 200 to about 500
.mu.g, from 400 to about 700 .mu.g or from about 600 to about 1000
.mu.g. In still other embodiments, total drug load ranges from
about 200 to about 1000 .mu.g, from about 400 to about 1000 .mu.g,
or from about 700 to about 1000 .mu.g. In some embodiments total
drug load ranges from about 500 to about 700 .mu.g, about 550 to
about 700 .mu.g, or about 550 to about 650 .mu.g, including 575,
590, 600, 610, and 625 .mu.g. It shall be appreciated that
additional ranges of drugs bordering, overlapping or inclusive of
the ranges listed above are also used in certain embodiments.
[0505] Similarly, in other embodiments, controlled drug delivery is
calculated based on the elution rate of the drug from the implant.
In certain such embodiments, an elution rate of a drug, for
example, a steroid, is about 0.05 .mu.g/day to about 10 .mu.g/day
is achieved. In other embodiments an elution rate of about 0.05
.mu.g/day to about 5 .mu.g/day, about 0.05 .mu.g/day to about 3
.mu.g/day, or about 0.05 .mu.g/day to about 2 .mu.g/day is
achieved. In other embodiment, an elution rate of about 2 .mu.g/day
to about 5 .mu.g/day, about 4 .mu.g/day to about 7 .mu.g/day, or
about 6 .mu.g/day to about 10 .mu.g/day is achieved. In other
embodiments, an elution rate of about 1 .mu.g/day to about 4
.mu.g/day, about 3 .mu.g/day to about 6 .mu.g/day, or about 7
.mu.g/day to about 10 .mu.g/day is achieved. In still other
embodiments, an elution rate of about 0.05 .mu.g/day to about 1
.mu.g/day, including 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4,
0.5, 0.6, 0.7, 0.8, or 0.9 .mu.g/day is achieved. It shall be
appreciated that additional ranges of drugs bordering, overlapping
or inclusive of the ranges listed above are also used in certain
embodiments.
[0506] Alternatively, or in addition to one or more of the
parameters above, the release of drug from an implant may be
controlled based on the desired concentration of the drug at target
tissues. In some embodiments, the desired concentration of a drug,
for example, a steroid, at the target tissue, ranges from about 1
nM to about 100 nM. In other embodiments the desired concentration
of a drug at the site of action ranges from about 10 nM to about 90
nM, from about 20 nM to about 80 nM, from about 30 nM to about 70
nM, or from about 40 nM to about 60 nM. In still other embodiments
the desired concentration of a drug at the site of action ranges
from about 1 nM to about 40 nM, from about 20 nM to about 60 nM,
from about 50 nM to about 70 nM, or from about 60 nM to about 90
nM. In yet other embodiments the desired concentration of a drug at
the site of action ranges from about 1 nM to about 30 nM, from
about 10 nM to about 50 nM, from about 30 nM to about 70 nM, or
from about 60 nM to about 100 nM. In some embodiments, the desired
concentration of a drug at the site of action ranges from about 45
nM to about 55 nM, including 46, 47, 48, 49, 50, 51, 52, 53, and 54
nM. It shall be appreciated that additional ranges of drugs
bordering, overlapping or inclusive of the ranges listed above are
also used in certain embodiments.
[0507] Certain embodiments described above are rechargeable. In
some such embodiments, recharging is accomplished by injecting new
drug into the lumen(s). In some embodiments, refilling the
implanted drug delivery implant entails advancing a recharging
device through the anterior chamber to the proximal end of the
implant where the clamping sleeve may slide over the proximal end
of the implant. See, e.g., FIG. 20A. An operator may then grasp the
proximal end of the implant with the flexible clamping grippers to
hold it securely. A new dose of drug in a therapeutic agent or a
new drug is then pushed to its position within the implant by a
flexible pusher tube which may be spring loaded. In some
embodiments, the pusher tube includes a small internal recess to
securely hold the therapeutic agent while in preparation for
delivery to the implant. In other embodiments a flat surface
propels the therapeutic agent into position within the implant.
[0508] The spring travel of the pusher is optionally pre-defined to
push the therapeutic agent a known distance to the distal-most
portion of the interior lumen of the implant. Alternatively, the
spring travel can be set manually, for example if a new therapeutic
agent is being placed prior to the time the resident therapeutic
agent is fully eluted from the implant, thereby reducing the
distance by which the new therapeutic agent needs to be advanced.
In cooperation with optional anchor elements, the recharging
process may be accomplished without significant displacement of the
implant from its original position.
[0509] Optionally, seals for preventing leakage during recharging
may be included in the recharging device. Such seals may desirable
if, for example, the form of the drug to be refilled is a liquid.
Suitable seals for preventing 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.
[0510] In other embodiments, recharging entails the advancement of
a recharging device through the anterior chamber by way of a
one-way valve. See FIGS. 20B and 20C. The valve comprises two or
more flaps 70, open at the proximal end and reversibly closed at
the distal end. The advancement of the recharging device opens the
flaps at the posterior end, which allows for the deposition of drug
into the posterior chamber. Upon removal of the recharging device,
the flaps return to their closed position (at the distal end),
thereby retaining the deposited drug within the lumen. In some
embodiments, the one way valve is formed such that a seal is
created to prevent backflow of liquid (including powders or
micropellets with liquid-like flow properties) drug from the lumen.
In other embodiments, a fluid-tight seal is not formed.
[0511] Other suitable retention methods may be used to hold the
newly placed drug pellet in place. For example, in some
embodiments, a deformable O-ring with an inner diameter smaller
than the newly placed pellet is used. In such embodiments, the
recharging device displaces the O-ring sufficiently to allow
passage of the drug pellet through the O-ring. Upon removal of the
device, however, the O-ring returns to its original diameter,
thereby retaining the pellet within the lumen.
[0512] In yet other embodiments a plug made of a "self-healing"
material that is penetrable by the recharging device is used. In
such embodiments, pressure from the recharging device allows the
device to penetrate the plug and deposit a new drug into the
interior lumen. Upon withdrawal of the recharging device, the plug
re-seals, and retains the drug within the lumen.
[0513] The one-way valve may be created of any material
sufficiently flexible to allow the insertion and retention of a new
drug into the lumen. Such materials include, but are not limited
to, silicone, Teflon.RTM., flexible graphite, sponge, silicone
rubber, silicone rubber with fiberglass reinforcement,
Neoprene.RTM., red rubber, wire inserted red rubber, cork &
Neoprene.RTM., vegetable fiber, cork & rubber, cork &
nitrile, fiberglass, cloth inserted rubber, vinyl, nitrile, butyl,
natural gum rubber, urethane, carbon fiber, fluoroelastomer, and
the like.
Drugs
[0514] 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 oligonucleotides, 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.
[0515] As discussed above, the therapeutic agents may be combined
with any number of excipients as is known in the art. In addition
to the biodegradable polymeric excipients discussed above, other
excipients may be used, including, but not limited to, benzyl
alcohol, ethylcellulose, methylcellulose, hydroxymethylcellulose,
cetyl alcohol, croscarmellose sodium, dextrans, dextrose, fructose,
gelatin, glycerin, monoglycerides, diglycerides, kaolin, calcium
chloride, lactose, lactose monohydrate, maltodextrins,
polysorbates, pregelatinized starch, calcium stearate, magnesium
stearate, silicon dioxide, cornstarch, talc, and the like. The one
or more excipients may be included in total amounts as low as about
1%, 5%, or 10% and in other embodiments may be included in total
amounts as high as 50%, 70% or 90%.
[0516] 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.
[0517] 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, immune stimulants, and/or immunosuppressants); 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 or antagonists thereof (such as
those disclosed in U.S. Pat. No. 7,759,472 or U.S. patent
application Ser. No. 12/465,051, 12/564,863, or 12/641,270, each of
which is incorporated in its entirety by reference herein),
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.
[0518] Other therapeutic agents may include neuroprotective agents
such as lubezole, nimodipine and related compounds, and including
blood flow enhancers such as dorzolamide or betaxolol; compounds
that promote blood oxygenation such as erythropoeitin; sodium
channels blockers; calcium channel blockers such as nilvadipine or
lomerizine; glutamate inhibitors such as memantine nitromemantine,
riluzole, dextromethorphan or agmatine; acetylcholinsterase
inhibitors such as galantamine; hydroxylamines or derivatives
thereof, such as the water soluble hydroxylamine derivative OT-440;
synaptic modulators such as hydrogen sulfide compounds containing
flavonoid glycosides and/or terpenoids, such as ginkgo biloba;
neurotrophic factors such as glial cell-line derived neutrophic
factor, brain derived neurotrophic factor; cytokines of the IL-6
family of proteins such as ciliary neurotrophic factor or leukemia
inhibitory factor; compounds or factors that affect nitric oxide
levels, such as nitric oxide, nitroglycerin, or nitric oxide
synthase inhibitors; cannabinoid receptor agonsists such as
WIN55-212-2; free radical scavengers such as methoxypolyethylene
glycol thioester (MPDTE) or methoxypolyethylene glycol thiol
coupled with EDTA methyl triester (MPSEDE); anti-oxidants such as
astaxathin, dithiolethione, vitamin E, or metallocorroles (e.g.,
iron, manganese or gallium corroles); compounds or factors involved
in oxygen homeostasis such as neuroglobin or cytoglobin; inhibitors
or factors that impact mitochondrial division or fission, such as
Mdivi-1 (a selective inhibitor of dynamin related protein 1
(Drp1)); kinase inhibitors or modulators such as the Rho-kinase
inhibitor H-1152 or the tyrosine kinase inhibitor AG1478; compounds
or factors that affect integrin function, such as the Beta
1-integrin activating antibody HUTS-21; N-acyl-ethanaolamines and
their precursors, N-acyl-ethanolamine phospholipids; stimulators of
glucagon-like peptide 1 receptors (e.g., glucagon-like peptide 1);
polyphenol containing compounds such as resveratrol; chelating
compounds; apoptosis-related protease inhibitors; compounds that
reduce new protein synthesis; radiotherapeutic agents; photodynamic
therapy agents; gene therapy agents; genetic modulators;
auto-immune modulators that prevent damage to nerves or portions of
nerves (e.g., demyelination) such as glatimir; myelin inhibitors
such as anti-NgR Blocking Protein, NgR(310)ecto-Fc; other immune
modulators such as FK506 binding proteins (e.g., FKBP51); and dry
eye medications such as cyclosporine, cyclosporine A, delmulcents,
and sodium hyaluronate.
[0519] 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, ddI, 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.
[0520] 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 implant may be combined
with embodiments of another illustrated or described shunt.
Moreover, the implants described above may be utilized for other
purposes. For example, the implants may 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.
[0521] One or more of the features illustrated in the drawings
and/or described herein may be rearranged and/or combined into a
single component or embodied in several components. Additional
components may also be added. While certain example embodiments
have been described and shown in the accompanying drawings, it is
to be understood that such embodiments are merely illustrative of
and not restrictive. Thus, the inventions are not limited to the
specific constructions and arrangements shown and described, since
various other modifications may occur to those ordinarily skilled
in the art based on the present disclosure.
[0522] Various operations of methods described above may be
performed by any suitable means capable of performing the
operations, such as various hardware and/or software component(s),
circuits, and/or module(s). Generally, any operations illustrated
in the Figures may be performed by corresponding functional means
capable of performing the operations.
[0523] The methods disclosed herein comprise one or more steps or
actions for achieving the described method. The method steps and/or
actions may be interchanged with one another without departing from
the scope of the claims. In other words, unless a specific order of
steps or actions is specified, the order and/or use of specific
steps and/or actions may be modified without departing from the
scope of the claims. Method step and/or actions disclosed herein
can be performed in conjunction with each other, and steps and/or
actions can be further divided into additional steps and/or
actions.
[0524] It is to be understood that the claims are not limited to
the precise configuration and components illustrated above. Various
modifications, changes and variations may be made in the
arrangement, operation and details of the methods and apparatus
described above.
* * * * *