U.S. patent application number 16/372167 was filed with the patent office on 2019-07-25 for anterior chamber drug-eluting ocular implant.
The applicant listed for this patent is GLAUKOS CORPORATION. Invention is credited to Harold Heitzmann, Vanessa Tasso.
Application Number | 20190224046 16/372167 |
Document ID | / |
Family ID | 65898451 |
Filed Date | 2019-07-25 |
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United States Patent
Application |
20190224046 |
Kind Code |
A1 |
Heitzmann; Harold ; et
al. |
July 25, 2019 |
ANTERIOR CHAMBER DRUG-ELUTING OCULAR IMPLANT
Abstract
Disclosed herein are drug delivery ocular implants comprising an
elongate outer shell having a proximal end, and distal end and
being shaped to define an interior lumen, at least one therapeutic
agent positioned within the lumen, wherein the outer shell has at
least a first thickness, the outer shell comprises one or more
regions of drug release, and the implant is dimensioned for
implantation within the anterior chamber of the eye.
Inventors: |
Heitzmann; Harold; (Laguna
Hills, CA) ; Tasso; Vanessa; (Laguna Hills,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GLAUKOS CORPORATION |
San Clemente |
CA |
US |
|
|
Family ID: |
65898451 |
Appl. No.: |
16/372167 |
Filed: |
April 1, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13490346 |
Jun 6, 2012 |
10245178 |
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16372167 |
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61494085 |
Jun 7, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 2205/0266 20130101;
A61F 2210/0004 20130101; A61K 9/0051 20130101; A61M 2210/0612
20130101; A61K 9/2072 20130101; A61F 2220/00 20130101; A61M 31/002
20130101; A61F 2250/0068 20130101; A61M 2205/04 20130101; A61F
9/0017 20130101 |
International
Class: |
A61F 9/00 20060101
A61F009/00; A61M 31/00 20060101 A61M031/00; A61K 9/00 20060101
A61K009/00 |
Claims
1.-21. (canceled)
22. A drug delivery ocular implant comprising: an outer shell
having an open proximal end and a distal end, the outer shell being
shaped to define an interior cavity; at least one therapeutic agent
positioned within the interior cavity; a material covering the open
proximal end, the material of increased permeability to the at
least one therapeutic agent relative to a permeability of the outer
shell; and a retention protrusion is configured to retain the
implant within an irido-corneal angle of an eye.
23. The implant of claim 22, wherein the retention protrusion
comprises at least one ridge.
24. The implant of claim 22, wherein the at least one orifice is
positioned on the proximal end of the outer shell.
25. The implant of claim 22, wherein the retention protrusion is
positioned on the distal end of the outer shell.
26. The implant of claim 22, wherein the permeability of the
material is configured to module a release rate of the at least one
therapeutic agent.
27. The implant of claim 22, wherein the at least one therapeutic
agent comprises one or more of prostaglandins, prostaglandin
analogs, alpha-blockers, beta-blockers and combinations
thereof.
28. The implant of claim 27, wherein said at least one therapeutic
agent is selected from the group consisting of: latanoprost,
travoprost, timolol, and brimonidine.
29. The implant of claim 22, wherein the therapeutic agent is an
anti-vascular endothelial growth factor (anti-VEGF) drug.
30. The implant of claim 29, wherein the anti-VEGF drug is selected
from the group consisting of: ranibizumab (LUCENTIS.TM.),
bevacizumab (AVASTIN.TM.), pegaptanib (MACUGEN.TM.), sunitinib, and
sorafenib.
31. The implant of claim 22, wherein the retention protrusion is
configured to anchor to an ocular tissue.
32. The drug delivery ocular implant of claim 31, wherein the
ocular tissue comprises the sclera.
33. The implant of claim 22, wherein the implant is configured to
elute the at least one therapeutic agent through the material for
targeted delivery to the anterior chamber of the eye.
34. The implant of claim 22, wherein the implant is shaped and
sized so as to be suitable for implantation within the anterior
chamber of the eye.
35. The implant of claim 22, wherein the outer shell is
biodegradable.
36. The implant of claim 22, wherein the material is biodegradable.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/494,085, filed Jun. 7, 2011, the entirety of
which is incorporated by reference herein.
BACKGROUND
Field of the Invention
[0002] 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 of the anterior chamber of the eye including, but not
limited to, indications of glaucoma, ophthalmic anterior segment
disorders such inflammatory conditions (iritis, anterior uveitis or
iridocyclitis, conjunctivitis), ocular infection (anti-infective
therapies) and dry eye, and ocular surface disease. In certain
embodiments, diseases or conditions associated with the posterior
chamber of the eye are concurrently or alternatively treated. In
certain embodiments, several embodiments relate to treatment of
ocular disorders wherein a drug delivery device is implanted within
the anterior chamber of the eye.
Description of the Related Art
[0003] 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.
[0004] 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. Other ocular
diseases or conditions include anterior segment disorders including
inflammatory conditions (iritis, anterior uveitis or iridocyclitis,
conjunctivitis), ocular infection and dry eye, and ocular surface
disease.
[0005] 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.
[0006] 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
[0007] In accordance with several embodiments, there is provided a
drug delivery ocular implant dimensioned so as to be suitable for
implantation within the anterior chamber of the eye 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
one therapeutic agent positioned within said interior lumen. In
certain embodiments, the outer shell comprises at least a first
thickness, wherein said outer shell comprises one or more regions
of drug release.
[0008] In some embodiments, the implant is dimensioned to be
positioned within the irido-corneal angle of the anterior chamber
of the eye. In several embodiments, the implant's dimensions are
suitable for retaining said implant within the irido-corneal angle
of the anterior chamber of the eye. Some embodiments further
comprise a retention protrusion for retaining said implant within
the irido-corneal angle of the anterior chamber of the eye. In
certain embodiments the retention protrusion comprises one or more
of ridges, flexible ribs, expanding material (such as a hydrogel),
biocompatible adhesives, claws, threads, rivet-like shapes,
flexible barbs, barbed tips, and the like.
[0009] According to some embodiments, the implant is biodegradable.
Certain embodiments employ non-biodegradable implants. In some
embodiments, the outer shell comprises a non-rigid polymer, which
may be either biodegradable or essentially non-biodegradable. In
some such embodiments, the non-rigid polymer is selected from the
group consisting of silicone elastomer, polyurethane, and
silicone-polyurethane co-polymer. In additional embodiments, other
non-rigid polymers may be used to make the outer shell, or to make
other features of the implants disclosed herein.
[0010] According to some embodiments, the interior lumen has
positioned within it at least one therapeutic agent that acts on
therapeutic targets in the eye, including the anterior segment of
the eye. In addition to being placed in the interior or lumen of an
implant, the therapeutic agents may also be coated onto an implant,
or otherwise be included within the structure of the implant (e.g.,
co-extruded into the shell material), or some combination of these
methods of including a therapeutic agent with the implant. In some
embodiments, the therapeutic target is at least the ciliary body.
Other anterior chamber tissues are targeted in other embodiments.
In still other embodiments, anterior chamber tissues are targeted
in conjunction with one or more posterior chamber targets. In
several embodiments, said at least one therapeutic agent is one or
more of prostaglandins, prostaglandin analogs, alpha-blockers, or
beta-blockers. In some embodiments, said at least one therapeutic
agent is selected from the group consisting of latanoprost,
travoprost, timolol, and brimonidine. In several embodiments, said
at least one therapeutic agent is capable of acting on a
therapeutic target in the posterior segment of the eye to treat
retinal disease (or other posterior chamber malady). In certain
embodiments, said at least one therapeutic agent is capable of
acting as a neuroprotectant to provide a therapeutic effect to at
least one of the optic nerve or retinal ganglion cells.
[0011] According to several embodiments, certain implants
comprising one or more regions of drug release are configured to
modulate the release rate of the at least one therapeutic agent
from the lumen of said implant. In certain embodiments, said outer
shell is semi-permeable to the at least one therapeutic agent. In
some embodiments, said outer shell is substantially impermeable to
the at least one therapeutic agent and comprises one or more
orifices for elution of said at least one therapeutic agent. In
several embodiments, said one or more orifices further comprise a
material that is semi-permeable to said at least one therapeutic
agent. According to some embodiments, said outer shell has at least
a second thickness that is less than said first thickness, thereby
forming a region of reduced thickness in said outer shell for
elution of said at least one therapeutic agent. In several
embodiments, combinations of one or more orifices, semi-permeable
or substantially impermeable materials, and regions of varied
thickness are used to tailor the release of the therapeutic agent
from the implant.
[0012] According to several embodiments, said at least one
therapeutic agent is configured to have a modulated release rate
from the implant. In some embodiments, said at least one
therapeutic agent is compounded with an excipient that modulates
the elution of the drug into ocular fluid. In several embodiments,
said at least one therapeutic agent is blended or coated with a
polymer that modulates the elution of the drug into ocular fluid.
In certain embodiments, said at least one therapeutic agent is
formulated as one or more micro-tablets.
[0013] In accordance with several embodiments, there is disclosed a
method for delivering an ocular implant as herein disclosed,
comprising advancing a needle comprising an actuator and containing
one or more ocular implants through the corneal tissue of the eye
of a subject thereby creating an incision in said corneal tissue,
wherein said incision is proximate to the limbus, advancing the
needle to a position adjacent to the irido-corneal angle;
activating said actuator and expelling said one or more ocular
implants from the needle, wherein said expulsion results in said
one or more ocular implants becoming substantially immobilized in
the irido-corneal angle; and withdrawing said needle.
[0014] In accordance with several embodiments, there is disclosed a
drug delivery ocular implant design for implantation within the
irido-corneal angle of the anterior chamber of the eye comprising
an elongate outer shell shaped to define an interior lumen
containing at least a first active drug, wherein said outer shell
has a length between about 5 mm and about 11 mm and a diameter
between about 0.3 mm and about 0.7 mm. In certain embodiments, said
at least a first active drug is embodied in one or more
micro-tablets. In some embodiments, said outer shell has a first
thickness. In several embodiments, said outer shell comprises one
or more regions of drug release. And some embodiments, said outer
shell further comprises a retention protrusion.
[0015] According to several embodiments, said outer shell has a
length between about 6 mm and about 10 mm. In certain embodiments,
said outer shell has a length between about 7 mm and about 9 mm. In
further embodiments, said outer shell has a diameter between about
0.4 mm and about 0.6 mm. Moreover, in some embodiments, said outer
shell has a length of about 8 mm and a diameter of about 0.5
mm.
[0016] According to several embodiments, said elongate shell is
formed by extrusion. In some embodiments, said retention protrusion
comprises 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 certain
embodiments, said elongate shell comprises a biodegradable
polymer.
[0017] According to some embodiments, 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. Moreover, in certain
embodiments said first active drug is present in an amount of at
least 70% by weight of a total weight of the micro-tablet. In some
embodiments, said micro-tablets have a surface area to volume ratio
of about 13 to 17, and in some embodiments said 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 said micro-tablets are configured to balance
osmotic pressure between said interior lumen and the ocular
environment external to an implant after implantation. In certain
embodiments, said micro-tablets are coated with a coating that
regulates the release of said first active drug from said
micro-tablet, in some embodiments the coating is a polymeric
coating. According to several embodiments, said first active drug
is chosen from the following group: latanoprost, travoprost,
timololis, and brimonidine.
[0018] According to several embodiments, said outer shell comprises
polyurethane, and in some embodiments said polyurethane comprises a
polysiloxane-containing polyurethane elastomer.
[0019] According to several embodiments, said regions of drug
release are configured to allow a different rate of drug elution as
compared to said elution through the outer shell. In certain
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 some embodiments, said orifices are positioned along the long
axis of the implant shell. Certain embodiments additionally
comprise one or more coatings that alter the rate of drug elution
from the implant. Moreover, in some embodiments, the elution of
said drug from said implant continues for at least a period of at
least one year.
[0020] According to several embodiments, there is disclosed herein
a method of 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
implant through the opening, inserting the drug delivery implant
into the anterior chamber of the eye, wherein upon insertion into
the anterior chamber, the implant is substantially immobilized
within the irido-corneal angle of the eye, 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 of the method, the drug elutes from the implant so
as to achieve a therapeutic effect for a period of at least one
year.
[0021] In accordance with one embodiment there is provided a drug
delivery ocular implant designed for implantation within the
irido-corneal angle of the anterior chamber of the eye comprising
an elongate outer shell shaped to define a lumen, one or more
micro-tablets comprising at least a first active drug, wherein the
tablet(s) are positioned within the interior lumen. The outer shell
of such an ocular implant has a length between about 5 mm and about
11 mm and a diameter between about 0.3 mm and about 0.7 mm. The
outer shell, which has a given thickness, also comprises one or
more regions of drug release and retention protrusions.
[0022] According to some embodiments, the ocular implants may
further comprise one or more coatings that alter the rate of drug
elution from the implant. Moreover, the rate of drug elution of any
of the embodiments may continue for at least a period of at least
one year or, alternatively, for a much shorter period.
[0023] Also disclosed herein is a method of 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 implant through the opening, inserting the
drug delivery implant as disclosed herein into the anterior chamber
of the eye, withdrawing the delivery device from the eye, wherein
drug elutes from the implant in sufficient quantity to treat an
ocular condition or disorder. Moreover, the drug may elute from the
implant so as to achieve a therapeutic effect for a period of at
least one year.
[0024] Disclosed herein is a drug delivery ocular implant. In
certain embodiments, the implant comprises an elongate outer shell
having a proximal end, and a distal end and being shaped to define
an interior lumen and at least one therapeutic agent positioned
within said interior lumen, wherein said outer shell has at least a
first thickness, said outer shell comprises one or more regions of
drug release, and said implant is dimensioned so as to be suitable
for implantation within the anterior chamber of the eye.
[0025] Also disclosed herein is a method for delivering an ocular
implant. In certain embodiments, the method comprises advancing a
needle comprising an actuator and containing one or more ocular
implants through the eye in the area of the limbus, advancing the
needle to a position adjacent to the irido-corneal angle,
activating said actuator and expelling said one or more ocular
implants from the needle wherein said expulsion results in said one
or more ocular implants becoming substantially immobilized in the
irido-corneal angle, and withdrawing said needle.
[0026] Also disclosed herein is a drug delivery ocular implant
design for implantation within the irido-corneal angle of the
anterior chamber of the eye. In certain embodiments, the implant
comprises an elongate outer shell shaped to define an interior
lumen and one or more micro-tablets comprising at least a first
active drug, wherein said one or more micro-tablets are positioned
within said interior lumen, said outer shell has a length between
about 5 mm and about 11 mm and a diameter between about 0.3 mm and
about 0.7 mm, said outer shell has a first thickness, said outer
shell comprises one or more regions of drug release, and said outer
shell further comprises a retention protrusion.
[0027] Also disclosed herein is a method of treating an ocular
condition or disorder in an intraocular target tissue. The method
comprises 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 implant through the opening,
inserting the drug delivery implant into the anterior chamber of
the eye wherein upon insertion into the anterior chamber, the
implant is substantially immobilized within the irido-corneal angle
of the eye, and withdrawing the delivery device from the eye,
wherein drug elutes from the implant in sufficient quantity to
treat an ocular condition or disorder.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] 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.
[0029] FIG. 1 illustrates a schematic cross sectional view of an
eye.
[0030] FIGS. 2A-2E illustrate a drug delivery device in accordance
with embodiments disclosed herein.
[0031] FIG. 3 illustrates a drug delivery device in accordance with
embodiments disclosed herein.
[0032] FIGS. 4A-4C illustrate drug delivery implants in accordance
with embodiments disclosed herein.
[0033] FIGS. 5A-5Q illustrate various retention protrusion elements
used in some embodiments disclosed herein.
[0034] FIGS. 6A-6I illustrate various aspects of a drug delivery
device in accordance with embodiments disclosed herein.
[0035] FIGS. 7A-7B illustrate various embodiments of implants as
disclosed therein that house one or more drug-containing pellets
within the implant.
[0036] FIGS. 8A-8C illustrate a rechargeable drug delivery device
in accordance with embodiments disclosed herein.
[0037] FIGS. 9A-9C illustrate various views of an eye with an
implant implanted in the anterior chamber of the eye including
schematic cross-section views of an eye and a frontal view of an
eye.
DETAILED DESCRIPTION
Introduction
[0038] 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. On the periphery of the
anterior chamber 20 is the angle of the anterior chamber or
irido-corneal angle 24. 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.
[0039] Achieving local ocular administration of a drug may require
direct injection or application, but in order to achieve
long-lasting drug delivery, specialized devices may be required.
For example, a drug-eluting implant sized and shaped to rest in the
irido-corneal angle of the eye without abrading or inflaming
adjacent tissue is utilized, in several embodiments, for localized
and/or long-term treatment of the eye. Use of a drug-eluting
implant allows 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 an anterior chamber drug-eluting implant
particularly allows for the targeted delivery of a drug to the iris
and cornea and other tissues located in the anterior chamber. Use
of a drug-eluting implant also provides 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").
[0040] Should a drug be required only acutely, an implant may also
be made completely biodegradable. Such biodegradability can be
achieved with biodegradable polymers whose lifespan within the eye
would be relatively short. Thus, a short-term drug-eluting implant
would deliver a drug for only a short time until the implant itself
disintegrated. However, the implant need not be biodegradable to
achieve a short duration of drug delivery. For example, the amount
of drug contained in the implant may be minimal, or the drug may by
formulated to elute more quickly thereby exhausting the drug
contained in the implant within a relatively short time period.
[0041] Several embodiments of drug-eluting ocular implants are
designed to minimize trauma to the healthy tissues of the eye which
thereby reduces ocular morbidity. In several such embodiments, the
implants comprise biocompatible materials and are suitably sized so
as to minimize interference with the biological operations of the
eye. For example, the implants are designed to not impede the flow
of aqueous humor around or out of the anterior chamber.
[0042] Several of the implants disclosed herein preferably do not
require an osmotic or ionic gradient to release the drug(s).
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.
[0043] According to some embodiments, the design of a drug delivery
device disclosed herein affords a safe and minimally invasive
procedure for introduction into the eye. The procedure does not
necessarily require special equipment or surgical techniques on the
part of the surgeon. The small size of the device and the
simplicity of the procedure are compatible with an out-patient
procedure.
[0044] 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 (or otherwise incorporated into
or with) 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. Some embodiments are combined with one or more
drugs in a targeted and controlled release fashion to treat
multiple ocular pathologies or a single pathology and its
symptoms.
[0045] 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 of the listed values.
Device Design
[0046] In some embodiments, the drug delivery device is generally
tubular in shape. In addition, other shapes may be used, such as
oval-shaped, round, or cylindrical implants. Smooth, rounded ends
and surfaces are generally preferred, although some embodiments may
not include such features. Moreover, irrespective of the shape,
some embodiments are flexible or deformable. Such embodiments are
constructed using any suitable materials that can be deformed and
subsequently return to its original shape (e.g., shape memory or
elastic materials). For example, several embodiments, are
constructed in an arcuate initial shape to match the curvature of
the irido-corneal angle, and are straightened for placement in a
delivery device, but return to the original shape when removed from
the delivery device (e.g., placed in the anterior chamber). The eye
is a sensitive organ, and the tissues contained in the anterior
chamber are particularly sensitive, which requires implants whose
design and composition are compatible with the normal operations of
the eye. Thus, some embodiments are sized and shaped to rest in
particular anatomical locations such as the irido-corneal angle,
without abrading or inflaming adjacent tissue. In several
embodiments, the implants are formed from a non-rigid biocompatible
polymer such as silicone elastomer, polyurethane, or
silicone-polyurethane co-polymer
1. Structure
[0047] 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, wherein the outer shell
comprises a permeable material or material comprising orifices that
allow for fluid and/or solute transfer. The outer shell is
polymeric in some embodiments, and in some 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 is created by virtue of the reduced thickness. In
some embodiments the outer 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 some 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
some embodiments, 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 a distal end of an oblong or cylindrical device or in
the distal portion of such a 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 herein, 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, 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.
[0048] In some embodiments, the device comprises at least one lumen
for holding an active pharmaceutical ingredient, for example
latanoprost, travoprost, timolol, or brimonidine. These drugs act
upon receptors in the anterior segment of the eye, for example in
the ciliary body. Drugs contained in some embodiments of the
implants disclosed herein can also be used in therapies for the
following conditions (among others): indications of glaucoma,
ophthalmic anterior segment disorders (e.g., inflammatory
conditions such as iritis, anterior uveitis or iridocyclitis,
conjunctivitis, ocular infection, dry eye, ocular surface disease,
and the like. Some embodiments are also suitable for delivery of
these or other pharmaceuticals that can diffuse to the posterior
segment of the eye to treat retinal disease, or may act as
neuroprotectants upon the optic nerve, retinal ganglion cells, or
other neural tissue.
[0049] 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. Orifices can
comprise any suitable shape or size and can be located anywhere on
the device depending on the purpose of the device, the drug or
drugs to be eluted from the device, etc. In some embodiments, 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.
[0050] According to some embodiments, a drug delivery device may
form the shape of a tube and may further contain plugs of
semi-permeable material to regulate the elution, or may be
substantially impermeable, or may contain holes or microporous
material to regulate the elution rate.
[0051] While some embodiments of a drug delivery device may be
dimensioned to hold one micro-tablet of a therapeutic agent
(micro-tablets are discussed in greater detail below), it shall be
appreciated that, in some embodiments, an interior lumen of the
device may be dimensioned to hold a plurality of micro-tablets (or
other form of the agent) comprising the same or differing
therapeutic agents. Advantageously, several such embodiments employ
an extruded shell that houses one or more micro-pellets and allows
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.
[0052] According to some embodiments, drug delivery devices are
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 the extruded tubing. By implanting 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 for a given time period. For
example, release times can be designed such that a drug "holiday"
occurs, in which little or no drug is eluted from the implant.
[0053] FIGS. 2A-2E depict a cross sectional schematic of various
embodiments 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 embodiments, other shell shapes
are used that 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.
[0054] In some embodiments, the shape of distal portion 50 is less
round and has a bullet-like shape (e.g., non-pointed, but having a
having a tapered end with a lower profile than outer shell 54),
examples of which are illustrated by FIGS. 2B-2E. Each successive
figure illustrates distal portion 50 as progressively longer or
having a progressively lower profile. However, in some embodiments,
despite having an elongated tip, the tip lacks a sharpened point so
as to not damage any intraocular tissue with which it comes into
contact. In some embodiments, distal portion 50 has a lower profile
than outer shell 54 so as wedge in the irido-corneal angle without
touching or abrading the corneal endothelium. In some embodiments,
the distal portion has a different profile as compared to the
proximal portion. Despite the elongated profiles, in some
embodiments the distal and/or proximal ends are still suitable for
releasing drug from the implant.
[0055] In several embodiments, a plurality of lumens--e.g., one
long lumen or separate lumens--are present in the proximal and/or
distal portions of the implant (see FIG. 3; 58a and 58,
respectively). In such embodiments both the proximal portion 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 (or more) different drugs 62a
(proximal) and 62 (distal) in the lumens. See FIG. 3. In some
embodiments, the proximal and distal portion of the implant 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, in several embodiments the regions of drug release are
placed to specifically release drug to 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.
[0056] Moreover, in some embodiments of the implant, some of which
comprise the shape of a tube, a micro-pellet is housed within a
compartment defined by endpieces or partitions (e.g., a defined
lumen or sub-lumen). In some embodiments, the endpieces defining
each lumen or compartment are thermoformed from the same material
as that which forms the device itself. In other embodiments, the
endpieces are 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 can
comprise the same polymer as the extruded polymeric tube, or a
different polymer.
[0057] 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 can 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 can
be used to form two sub-lumens within the implant shell. See e.g.,
FIG. 4A. 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. 4B.
Alternatively, the dividers may be positioned such that the
sub-lumens are not of equivalent dimension.
[0058] In some embodiments, one or more of the sub-lumens formed by
the dividers traverse the entire length of the implant. In some
embodiments, one or more of the sub-lumens are defined or blocked
off by a transversely, or diagonally placed divider or partition.
The blocked off sub-lumens are, in several embodiments, formed with
any dimensions as required to accommodate a particular dose or
concentration of drug.
[0059] 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. 4C. 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.
2. Materials
[0060] In several embodiments, combinations of materials are 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).
[0061] Some embodiments comprise flexible materials such as tubing
or layering that forms at a least a portion of a surface of the
eluting devices. One example of a flexible material is flexible
tubing, of which a tube of Nu-Sil 4765 silicone is a non-limiting
example. Of course, other flexible materials may also be used. Some
embodiments can also comprise shape memory materials (e.g., shape
memory alloys or shape memory polymers) or elastic/elastomeric
materials.
[0062] Some embodiments are biostable while others are
biodegradable. Moreover, they may be comprised of material that is
semi-permeable to a drug, such that the elution rate of a drug is
regulated by the rate of diffusion from a drug lumen through the
walls of the device. In some embodiments, the materials comprising
the outer shell or attached to the outer shell can have any one of
or a combination of the following characteristics to regulate the
elution rate of a drug occurring by diffusion: slight permeability,
substantial impermeability, one or more holes or orifices, or one
or more microporous regions.
[0063] Illustrative, examples of suitable materials for the drug
delivery device or ocular implant 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)
be 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, fluorocarbon
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 rate
of drug elution from an implant.
3. Sizing
[0064] Several embodiments of the ocular implants disclosed herein
are appropriately sized for placement in the anterior chamber of
the eye. Moreover, some embodiments are particularly sized for
placement in the irido-corneal angle. A small dimension helps avoid
irritation, corneal edema, or elevated intraocular pressure. Some
embodiments are shaped or preformed or preset for placement in a
particular part of the anterior chamber or to accommodate the
particular needs of a patient (e.g., custom fitting the patient's
eye or more generally constructed in a variety of sizes-such as
small, medium, or large). Such shapes include curves of various
sizes, lengths, and radii and in various combinations. Some
embodiments with a length of about 8 mm and an outer diameter of
approximately 0.5 mm may rest in approximately one-quarter of the
circumference of the irido-corneal angle without generating
irritation, corneal edema, or elevated intraocular pressure. It
shall be appreciated that certain embodiments disclosed herein are
useful for implantation and drug delivery to other anatomical
targets within or surrounding the eye.
[0065] In some embodiments having a preset shape, the shape is a
curve approximating the curvature of the anterior chamber. Because
the anterior chamber is circular, with a radius of about 6 mm, some
embodiments are designed to fit within an anterior chamber having a
radius of about 6 mm. This may entail a curvature actually
approximating the curvature of the anterior chamber, or it may
entail a curvature slightly less than that of the anterior chamber.
For example, see FIG. 9B, which illustrates an embodiment implanted
into the anterior chamber in which the curvature of the implant is
slightly less than that of the eye so that the implant is slightly
visible within the eye. The curvature of some embodiments has a
larger or smaller radius, for example, about 2-3 mm, about 3-4 mm,
about 4-5 mm, and overlapping ranges thereof. A larger radius can
be desirable to form an arc between two points on the circumference
of the anterior chamber. In certain embodiments, the radius of the
curvature is slightly larger than 6 mm to assure contact at the end
points of the implant with ocular tissue. Suitable radii will
depend on the desired fit and orientation of the implant or on the
patient's needs. For example, the radius of the curvature of some
embodiments can be anywhere from 5 mm to 7 mm or from 4 mm to 8
mm.
[0066] Of course, implants with other dimensions can also be used
for placement in the irido-corneal angle. Some embodiments comprise
a generally cylindrical shape wherein the outer diameter of the
cylinder is from about 0.3 mm to about 0.7 mm and the length of the
cylinder is from about 5 mm to about 11 mm. Some embodiments will
exhibit outer diameters between about 0.4 mm and about 0.6 mm. Some
embodiments will exhibit lengths between about 6 mm and about 10
mm, or about 7 mm and about 9 mm. The exact combination of outer
diameters and lengths will vary with different embodiments and
possibly from patient to patient. In some embodiments, implants are
customized to a particular patient's ocular dimensions.
4. Retention Protrusions
[0067] Various embodiments may include retention protrusions to
position the device in place and minimize possible damage to the
surfaces of the anterior chamber that might be caused by a
free-floating device. Such damage to be avoided includes abrasion
of tissues, corneal edema, or otherwise adversely affecting the
tissue within the anterior chamber of the eye or causing discomfort
to the patient.
[0068] In some embodiments, the tips or ends of the device are
wedged into or against the curvature of the irido-corneal angle of
the eye such that the ends themselves act as retention protrusions.
In some embodiments, the ends further comprise ribbing, texturing,
or expanding material to aid in the wedging of the ends into the
curvature of the irido-corneal angle. In some embodiments, the ends
are designed to self-wedge in the irido-corneal angle. In some
embodiments, the ends are designed to be wedged into place by a
physician.
[0069] FIGS. 5A-5Q illustrate 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. 5G-5M). Suitable target intraocular tissue include, but are
not limited to, the iris, iris root, iris rolls, sclera, cornea,
pectinate ligament, Descemet's membrane, endothelium, and
trabecular meshwork. 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 is wedged within an ocular space (e.g.,
irido-corneal angle) based on the outer dimensions of the implant
providing a sufficient amount of friction against the ocular tissue
to hold the implant in place.
[0070] The retention protrusions are optionally 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.
[0071] In several embodiments, an expandable material 100 is used
for retention. Upon contact with an appropriate solvent, which
includes ocular fluid, the expandable material expands, thus
exerting pressure on the surrounding tissue. In some embodiments,
an external stimulus is used to induce the expansion of the
expandable material 100. Suitable external stimuli include, but are
not limited to, light energy, electromagnetic energy, heat,
ultrasound, radio frequency, or laser energy. In some 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. 5A-5F. 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.
5A-5F). As a result, the expanded material exerts pressure on the
surrounding ocular tissue, which secures the implant in
position.
[0072] In other embodiments, such as those schematically depicted
in FIGS. 5E and 5F, 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.
[0073] The expandable material can be positioned on the implant by
dipping, molding, coating, spraying, or other suitable process
known in the art.
[0074] 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 cause 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 solvent that
would not affect the structure or permeability characteristics of
the outer shell.
[0075] 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 the implant such that
the expanded material exerts pressure on the surrounding ocular
tissue, thereby securing the implant in position. Such a
configuration may be used to secure the implant within the
irido-corneal angle of the anterior chamber, though other regions
of the anterior chamber would also be suitable. 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.
[0076] Although FIGS. 5A and 5B 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.
[0077] FIGS. 5E and 5F 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.
[0078] In some embodiments, see for example FIG. 5G, 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. 5H). 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. 5I; ribs 140, as shown in FIG. 5J; a rivet shaped
base portion 146, as shown in FIG. 5K; biocompatible adhesive 150
encircling the retention element 359 where it passes through an
ocular tissue, as shown in FIG. 5L; or barbs 170, as shown in FIG.
5M. In some embodiments, the retention protrusion is positioned
within an ocular tissue, which may result in part of the retention
protrusion residing within a pre-existing intraocular cavity or
space, shown generally as 20. For example, as depicted in FIG. 5N,
an elongated blade 34 resides within Schlemm's canal 22 and is
attached to a base portion 130 that traverses the trabecular
meshwork 23. Of course, other intraocular tissues can also be used
to anchor implants within the anterior chamber such as those
tissues found in and around the irido-corneal angle including the
iris, iris root, iris rolls, sclera, cornea, pectinate ligament,
descemet's membrane, and endothelium. In other embodiments, as
depicted in FIG. 5O, 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, the key being to sufficiently anchor the implant to the
intraocular tissue around base portion 130 or shorter base
130a.
[0079] In certain embodiments, an expandable material 100 is used
in conjunction with or in place of a physical retention protrusion.
For example, in FIG. 5P, 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 intraocular tissue 23 and
Schlemm's canal 22 in FIG. 5P. Expansion can also exert pressure on
other intraocular tissues such as those found in and around the
irido-corneal angle including the iris, iris root, iris rolls,
sclera, cornea, pectinate ligament, Descemet's membrane, and
endothelium.
[0080] In some embodiments, an external stimulus is used to induce
the expansion of the expandable material 100. As depicted in FIG.
5Q, 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 intraocular tissue
23 and Schlemm's canal 22 in FIG. 5Q. Suitable external stimuli
include, but are not limited to, light energy, electromagnetic
energy, heat, ultrasound, radio frequency, or laser energy.
[0081] 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.
Drug Delivery
[0082] In some embodiments, a drug delivery ocular implant contains
at least one lumen for holding an active pharmaceutical ingredient,
which can include many classes and types of drugs, pharmaceutical
compositions, or other compounds whose administration to the
anterior chamber of the eye is desired.
1. Drug Listing
[0083] Examples of drugs 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 (additional non-limiting examples of such
anti-VEGF compounds are described in Appendix A, which is attached
herewith and made a part of this application); 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.
[0084] Other examples of drugs 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, fluorometholone, loteprednol,
medrysone, fluocinolone acetonide, triamcinolone acetonide,
triamcinolone, triamcinolone acetonide, beclomethasone, budesonide,
flunisolide, fluorometholone, fluticasone, hydrocortisone,
hydrocortisone acetate, loteprednol, rimexolone and non-steroidal
anti-inflammatory agents including, for example, diclofenac,
flurbiprofen, ibuprofen, bromfenac, nepafenac, and ketorolac,
salicylate, indomethacin, ibuprofen, naxopren, piroxicam and
nabumetone; anti-infective or antimicrobial agents such as
antibiotics including, for example, tetracycline,
chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,
cephalexin, oxytetracycline, chloramphenicol, rifampicin,
ciprofloxacin, tobramycin, gentamycin, erythromycin, penicillin,
sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole,
sulfisoxazole, nitrofurazone, sodium propionate, aminoglycosides
such as gentamicin and tobramycin; fluoroquinolones such as
ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin,
norfloxacin, ofloxacin; bacitracin, erythromycin, fusidic acid,
neomycin, polymyxin B, gramicidin, trimethoprim and sulfacetamide;
antifungals such as amphotericin B and miconazole; antivirals such
as idoxuridine trifluorothymidine, acyclovir, gancyclovir,
interferon; antimicotics; immune-modulating agents such as
antiallergenics, including, for example, sodium chromoglycate,
antazoline, methapyriline, chlorpheniramine, cetrizine, pyrilamine,
prophenpyridamine; anti-histamine agents such as azelastine,
emedastine and levocabastine; immunological drugs (such as vaccines
and immune stimulants); MAST cell stabilizer agents such as
cromolyn sodium, ketotifen, lodoxamide, nedocrimil, olopatadine and
pemirolastciliary body ablative agents, such as gentimicin and
cidofovir; and other ophthalmic agents such as verteporfin,
proparacaine, tetracaine, cyclosporine and pilocarpine; inhibitors
of cell-surface glycoprotein receptors; decongestants such as
phenylephrine, naphazoline, tetrahydrazoline; lipids or hypotensive
lipids; dopaminergic agonists and/or antagonists such as
quinpirole, fenoldopam, and ibopamine; vasospasm inhibitors;
vasodilators; antihypertensive agents; angiotensin converting
enzyme (ACE) inhibitors; angiotensin-1 receptor antagonists such as
olmesartan; microtubule inhibitors; molecular motor (dynein and/or
kinesin) inhibitors; actin cytoskeleton regulatory agents such as
cyctchalasin, latrunculin, swinholide A, ethacrynic acid, H-7, and
Rho-kinase (ROCK) inhibitors; remodeling inhibitors; modulators of
the extracellular matrix such as tert-butylhydro-quinolone and
AL-3037A; adenosine receptor agonists and/or antagonists such as
N-6-cylclophexyladenosine and (R)-phenylisopropyladenosine;
serotonin agonists; hormonal agents such as estrogens, estradiol,
progestational hormones, progesterone, insulin, calcitonin,
parathyroid hormone, peptide and vasopressin hypothalamus releasing
factor; growth factor antagonists or growth factors, including, for
example, epidermal growth factor, fibroblast growth factor,
platelet derived growth factor 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.
[0085] Other possible therapeutic agents 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
methoxypolyethlene 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 inhibitors such as H-1152,
HA-1077, Y27632, and
6-Chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-
phenyl}pyrimidin-2,4-diamine 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 A, delmulcents, and sodium hyaluronate.
[0086] 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 agonists such as adrenergic alpha-agonists or
peroxisome proliferator-activated receptors; 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, nitroprusside, 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.
2. Drug Form
[0087] 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.
[0088] The drug in some embodiments may be 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,
packed powder or tablet, compounded with excipients, or blended or
coated with a polymer to modulate the elution rate. Other possible
forms of the drug include capsules, gels, suspensions, and
emulsions. In some embodiments that comprise one or more
micro-tablets, the use of micro-tablets or other packed drug forms
still allows for flexibility of the ocular implant.
[0089] In some embodiments wherein a tablet form is used, each
tablet comprises a therapeutic agent (also referred to as an active
pharmaceutical ingredient) 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 period of drug release.
[0090] 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 this disclosure 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. In some embodiments, the drug positioned in the
lumen is pure drug and nothing else is placed with the drug in the
interior lumen.
[0091] 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. 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.
[0092] 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.
[0093] In some embodiments containing micro-tablets, the
micro-tablets have a surface area to volume ratio of about 13 to
17. Some embodiments can have an aspect ratio of length to diameter
of about 2.8 to 3.6. This ratio may differ based on the actual size
of the implant used as well as the density of the one or more drug
contained in the micro-tablet as discussed in the previous
paragraph.
[0094] 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.
3. Drug Elution
[0095] Non-continuous or pulsatile release may be desirable
depending on the ocular disease to be treated, the patient's needs,
the drug used, or other applicable factors. 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 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 the application of one or more of heat,
ultrasound, radio frequency, or laser energy.
[0096] In some embodiments, the device is placed in the anterior
chamber of the eye, but will elute drugs that migrate to the
posterior chamber of the eye, or the macula, the retina, the optic
nerve, the ciliary body, or the intraocular vasculature to treat,
for example, retinal disease, or may act as neuroprotectants upon
the optic nerve and retinal ganglion cells. Moreover, some
embodiments can be designed to achieve diffusion of one or more
drugs to both the posterior and anterior chambers of the eye. In
some embodiments, drug elution will primarily target indications of
glaucoma (including neuro-protective effects), all ophthalmic
anterior segment disorders including inflammatory conditions
(iritis, anterior uveitis or iridocyclitis, conjunctivitis), ocular
infection (anti-infective effects) and dry eye, and ocular surface
disease. Thus, even though placed in the anterior chamber, the drug
eluted from some embodiments can target other areas of the eye in
addition to targets located in the anterior chamber.
[0097] 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% or less than
about 1%.
[0098] 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. 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 are 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.
[0099] In several embodiments, one or more orifices traverse the
thickness of the outer shell to provide communication passages
between the environment outside the implant and an interior lumen
of the implant. 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.
[0100] 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. 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-6I
represent certain embodiments of the region of drug release. FIGS.
6A and 6B 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.
[0101] 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.
[0102] 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.
[0103] 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.
[0104] 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 can 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.
[0105] 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.
[0106] 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.
[0107] 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, 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 in 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).
[0108] 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. 7A). 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.
[0109] 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.
[0110] An additional non-limiting additional embodiment of a drug
pellet-containing implant is shown in FIG. 7B (in cross section).
In certain embodiments, the pellets are micro-pellets 62' (e.g.,
micro-tablets). 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 above. Regardless of
the material or the shape, several embodiments of the implant are
dimensioned for implantation into the anterior chamber of eye
(e.g., sized to pass through a 21 gauge, 23 gauge, 25 gauge, 27
gauge, or smaller needle).
4. Rechargeability
[0111] 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 one ore more drug. In
some embodiments, refilling the implanted drug delivery implant
entails advancing a recharging device into 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. 8A. 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 (yet
reversible) 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. 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.
[0112] In some rechargeable embodiments, 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.
[0113] In the embodiments shown in FIGS. 8A-8C (as well as other
embodiments described herein), 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. 8A, a new
dose of agent, coated in a shell and capped with proximal barrier
is inserted into the lumen of the implant. FIGS. 8B and 8C 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.
[0114] 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.
[0115] 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.
[0116] In other embodiments, recharging entails the advancement of
a recharging device through the anterior chamber by way of a
one-way valve. See FIGS. 8B and 8C. 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.
[0117] 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.
[0118] In some 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.
[0119] 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.
Device Implantation
[0120] According to some embodiments, a drug delivery device may be
implanted within the anterior chamber by delivering it through a
small, closed chamber clear corneal incision, such as would be made
with a 23-gauge or smaller needle.
[0121] FIGS. 9A-9C illustrate possible embodiments of placement of
a drug delivery implant consistent with several embodiments
disclosed herein. In one embodiment shown in FIG. 9A, the outer
shell 54 of an implant is shown arcing through the anterior chamber
wherein the ends of the implant are positioned in the irido-corneal
angle of the eye. FIG. 9B illustrates a similar embodiment as that
shown in FIG. 9A where the implant arcs through the anterior
chamber; however, FIG. 9B illustrates a frontal view of the eye
such that more of the implant can be seen. 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 as illustrated in FIG. 9C where the
implant is shown in cross section. In some embodiments, the implant
is positioned substantially within the anterior chamber angle along
the inferior portion of the iris.
[0122] In several embodiments, an implantation comprises a needle
with a beveled edge suitable for incision through the cornea, an
attached housing containing a pushrod-type advancement mechanism
and an actuator controlled by a surgeon. The drug delivery device
may be front-loaded into the lumen of the needle. The needle can be
advanced through corneal tissue at the limbus, and a surgeon can
actuate the advancement mechanism to push the device outward
through the needle into the anterior chamber of the eye. Variations
in eye pressure due to blinking, rubbing, etc, will cause the
device to move within the anterior chamber until comes to rest in
the irido-corneal angle, where it will be immobilized between the
iris and the cornea. Alternatively, the device may be placed
directly in the irido-corneal angle so as to reduce possible damage
to the tissues of the anterior chamber.
[0123] According to some embodiments, the drug delivery device is
designed to anchor itself into position between the iris and the
cornea. Non-limiting examples of suitable anchoring mechanisms are
discussed above. Alternatively, some embodiments include no
anchoring mechanism, but rather the implants are designed to wedge
or fit comfortably in the irido-corneal angle or any other suitable
location within the anterior chamber of the eye.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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.
* * * * *