U.S. patent application number 15/985699 was filed with the patent office on 2019-03-28 for drug delivery system and methods of treating open angle glaucoma and ocular hypertension.
This patent application is currently assigned to Mati Therapeutics Inc.. The applicant listed for this patent is Mati Therapeutics Inc.. Invention is credited to Suzanne Cadden, Yong Hao, Deepank Utkhede.
Application Number | 20190091066 15/985699 |
Document ID | / |
Family ID | 49955680 |
Filed Date | 2019-03-28 |
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United States Patent
Application |
20190091066 |
Kind Code |
A1 |
Cadden; Suzanne ; et
al. |
March 28, 2019 |
Drug Delivery System and Methods of Treating Open Angle Glaucoma
and Ocular Hypertension
Abstract
A method of decreasing intraocular pressure (IOP) in an eye of a
patient in need thereof includes implanting a first lacrimal
implant through an upper punctum and into an upper lacrimal
canaliculus of the eye of the patient. The method may further
comprise implanting a second lacrimal implant through a lower
punctum and into a lower lacrimal canaliculus of the eye of the
patient, and releasing, on a sustained basis a therapeutically
effective amount of an intraocular pressure-reducing therapeutic
agent.
Inventors: |
Cadden; Suzanne; (North
Vancouver, CA) ; Hao; Yong; (Vancouver, CA) ;
Utkhede; Deepank; (Surrey, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Mati Therapeutics Inc. |
Austin |
TX |
US |
|
|
Assignee: |
Mati Therapeutics Inc.
Austin
TX
|
Family ID: |
49955680 |
Appl. No.: |
15/985699 |
Filed: |
May 22, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13779628 |
Feb 27, 2013 |
9974685 |
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15985699 |
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13598573 |
Aug 29, 2012 |
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13779628 |
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61644397 |
May 8, 2012 |
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61528736 |
Aug 29, 2011 |
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61717615 |
Oct 23, 2012 |
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61680641 |
Aug 7, 2012 |
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61659921 |
Jun 14, 2012 |
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61644401 |
May 8, 2012 |
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61642287 |
May 3, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0051 20130101;
A61K 9/0092 20130101; A61F 9/00781 20130101; A61F 9/0017 20130101;
A61F 9/00772 20130101; A61K 31/5575 20130101 |
International
Class: |
A61F 9/00 20060101
A61F009/00; A61F 9/007 20060101 A61F009/007; A61K 31/5575 20060101
A61K031/5575; A61K 9/00 20060101 A61K009/00 |
Claims
1. A kit for treating a patient with Open Angle Glaucoma (OAG) or
Ocular Hypertension (OH) in an eye, comprising: a unit dosage
format per eye of a prostaglandin analog comprising a first
lacrimal implant and a second lacrimal implant, wherein the first
lacrimal implant comprises a sustained release formulation of a
prostaglandin analog configured for release in a therapeutically
effective dose from the first lacrimal implant over a treatment
period; and, wherein the second lacrimal implant is a blank
lacrimal implant that does not comprise a prostaglandin analog.
2. The kit of claim 1, wherein the first or second lacrimal implant
is a punctual plug.
3. The kit of claim 1, wherein the first or second lacrimal implant
comprises a first member defining a first axis and having a first
end along the first axis; a second member defining a second axis
and having a second end along the second axis; and a third member
connecting the first end of the first member and the second end of
the second member at a first angle to form an angled
intersection.
4. The kit of claim 3, wherein in the second member of the first or
second lacrimal implant further comprises a cavity for insertion of
a drug core comprising the prostaglandin analog.
5. The kit of claim 3, wherein the third member of the first or
second lacrimal implant further comprises a bore that is
characterized by a third axis and a second angle, wherein the first
angle is defined by the first axis with respect to the second axis,
the second angle is defined by the first axis with respective to
the third axis, and the bore is configured to be accessible to an
insertion tool for facilitating insertion of the implant.
6. The kit of claim 3, wherein the lacrimal implant further
comprises the prostaglandin analog dispersed throughout the
implant.
7. The kit of claim 1, wherein the first or second lacrimal implant
is configured with a retention rate of about 90% or greater at week
12 in a lower punctum.
8. The kit of claim 1, wherein the first or second lacrimal implant
is configured with a retention rate of about 85% or greater at week
8 in the upper punctum.
9. The kit of claim 1, wherein the first or second lacrimal implant
is made of a material that comprises a plastic, a rubber, a
polymer, a composite or a material that comprises a liquid silicone
rubber, or a mixture including a liquid silicone rubber.
10. The kit of claim 9, wherein the first or second lacrimal
implant further comprises a green colorant.
11. The kit of claim 1, wherein the first or second lacrimal
implant comprises a first member, a second member and a heel that
is at least partially fabricated with silicone
12. (canceled)
13. (canceled)
14. The kit of claim 1, wherein the first lacrimal implant is
configured for insertion into an upper punctum of the eye.
15. The kit of claim 1, wherein the second lacrimal implant is
configured for insertion into a lower punctum of the eye.
16-24. (canceled)
25. The kit of claim 1, wherein the sustained release formulation
is configured to provide a dosage of the prostaglandin analog
sufficient to reduce the intraocular pressure of the eye by at
least 5 mm Hg from baseline for a continuous period of time
selected from at least 12 weeks after implantation of the first
lacrimal implant and second lacrimal implant.
26. The kit of claim 1, wherein the treatment period is at least 4
weeks.
27. The kit of claim 1, wherein the treatment period is at least 8
weeks.
28. The kit of claim 1, wherein the treatment period is at least 12
weeks.
29. The kit of claim 1, further comprising an insertion tool.
30. The kit of claim 1, wherein the patient has a baseline TOP
between about 22 mm Hg and about 33 mm Hg.
31. The kit of claim 1, wherein the first or second lacrimal
implant comprises a first member defining a first axis and having a
first end along the first axis; a second member defining a second
axis and having a second end along the second axis; and a third
member connecting the first end of the first member and the second
end of the second member at a first angle to form an angled
intersection and wherein the third member of the lacrimal implant
further comprises a bore defining a third axis and a second angle
having an upper surface, wherein the first angle is defined by the
first axis with respect to the second axis, the second angle is
defined by the first axis with respect to the third axis, and the
bore is configured to be accessible to an insertion tool for
facilitating insertion of the implant and extended from the upper
surface into the third member.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. Ser. No.
13/598,573, filed Aug. 29, 2012, which claims priority to U.S.
Provisional Patent Application No. 61/528,736, filed on Aug. 29,
2011, and U.S. Provisional Patent Application No. 61/644,397, filed
on May 8, 2012, the disclosures of each of which are incorporated
herein by reference in their entirety for all purposes. This
application claims the benefit under 35 U.S.C. 1.19(e) of U.S.
Provisional Patent Application No. 61/642,287, filed May 3, 2012;
U.S. Provisional Patent Application No. 61/644,401 filed May 8,
2012; U.S. Provisional Patent Application No. 61/644,397 filed May
8, 2012; U.S. Provisional Patent Application No. 61/659,921 filed
Jun. 14, 2012; 61/680,641 filed Aug. 7, 2012 and U.S. Provisional
Patent Application No. 61/717,615 filed Oct. 23, 2012, the
disclosures of each of which are incorporated herein by reference
in their entirety for all purposes.
FIELD OF THE INVENTION
[0002] This application pertains generally to methods of treating
ocular diseases, particularly those with elevated intraocular
hypertension.
BACKGROUND OF THE INVENTION
[0003] Glaucoma is a collection of disorders characterized by
progressive visual field loss due to optic nerve damage. It is the
leading cause of blindness in the United States, affecting 1-2% of
individuals aged 60 and over. Although there are many risk factors
associated with the development of glaucoma (age, race, myopia,
family history, and injury), elevated intraocular pressure (IOP),
also known as ocular hypertension (OH), is the only risk factor
successfully manipulated and correlated with the reduction of
glaucomatous optic neuropathy. Public health figures estimate that
2.5 million Americans manifest ocular hypertension.
[0004] In glaucoma associated with an elevation in eye pressure the
source of resistance to outflow is in the trabecular meshwork. The
tissue of the trabecular meshwork allows the "aqueous" to enter
Schlemm's canal, which then empties into aqueous collector channels
in the posterior wall of Schlemm's canal and then into aqueous
veins. The aqueous or aqueous humor is a transparent liquid that
fills the region between the cornea at the front of the eye and the
lens. The aqueous humor is constantly secreted by the ciliary body
around the lens, so there is a continuous flow of the aqueous humor
from the ciliary body to the eye's front chamber. The eye's
pressure is determined by a balance between the production of
aqueous and its exit through the trabecular meshwork (major route)
or via uveal scleral outflow (minor route). The trabecular meshwork
is located between the outer rim of the iris and the internal
periphery of the cornea. The portion of the trabecular meshwork
adjacent to Schlemm's canal causes most of the resistance to
aqueous outflow (juxtacanalicular meshwork).
[0005] Glaucoma is grossly classified into two categories:
closed-angle glaucoma and open-angle glaucoma. Closed-angle
glaucoma is caused by closure of the anterior angle by contact
between the iris and the inner surface of the trabecular meshwork.
Closure of this anatomical angle prevents normal drainage of
aqueous humor from the anterior chamber of the eye. Open-angle
glaucoma (OAG) is any glaucoma in which the angle of the anterior
chamber remains open, but the exit of aqueous through the
trabecular meshwork is diminished. The exact cause for diminished
filtration is unknown for most cases of open-angle glaucoma.
However, there are secondary open-angle glaucomas that may include
edema or swelling of the trabecular spaces (from steroid use),
abnormal pigment dispersion, or diseases such as hyperthyroidism
that produce vascular congestion.
[0006] Although there is no known cure, the principal objective in
treating patients with OAG or OH is to preserve visual function by
the reduction and maintenance of IOP. As such all current therapies
for glaucoma are directed at decreasing intraocular pressure.
Self-administered topical agents or pills are usually the
first-line choice of therapy for reducing IOP. This therapy reduces
the production of aqueous humor or increases the outflow of
aqueous. Other means to treat glaucoma and ocular hypertension,
involve surgical therapy for open-angle glaucoma such as laser
(trabeculoplasty), trabeculectomy and aqueous shunting implants
after failure of trabeculectomy or if trabeculectomy is unlikely to
succeed. Trabeculectomy is a major surgery that is most widely used
and is augmented with topically applied anticancer drugs such as
5-flurouracil or mitomycin-c to decrease scarring and increase
surgical success.
[0007] Topical eye drops, though effective, can be inefficient. For
instance, when an eye drop is instilled in an eye, it often
overfills the conjunctival sac (i.e., the pocket between the eye
and the lids) causing a substantial portion of the drop to be lost
due to overflow of the lid margin and spillage onto the cheek. In
addition, a large portion of the drop remaining on the ocular
surface can be washed away into and through a lacrimal canaliculus,
thereby diluting the concentration of the drug before it can treat
the eye. Further, in many cases, topically applied medications have
a peak ocular effect within about two hours, after which additional
applications of the medications should be performed to maintain the
therapeutic benefit. PCT Publication WO 06/014434 (Lazar), which is
incorporated herein by reference in its entirety, may be relevant
to these or other issues associated with eye drops.
[0008] Compounding ocular management difficulty, patients often do
not use their eye drops as prescribed. Noncompliance rates of at
least 25% are reported. This poor compliance can be due to
discomfort and the normal reflex to protect the eye. Therefore, one
or more drops may miss the eye. Older patients may have additional
problems instilling drops due to arthritis, unsteadiness, and
decreased vision. Pediatric and psychiatric populations pose
difficulties as well.
[0009] Prostaglandins are one group of drugs administered as eye
drops to patients diagnosed with glaucoma. Latanoprost is an ester
analogue of prostaglandin F.sub.2.alpha. that reduces IOP by
increasing uveoscleral outflow. Latanoprost is marketed as
Xalatan.RTM. (latanoprost ophthalmic solution) 0.005% (50 .mu.g/mL)
(Xalatan PI 2011). The IOP-lowering efficacy of Xalatan lasts for
up to 24 hours after a single topical dose, which allows for a once
daily dosage regimen.
[0010] Lacrimal implants are devices that are inserted into a
punctum and an associated lacrimal canaliculus of an eye, either to
block drainage of tears (to prevent conditions such as dry eye), or
to contain a quantity of drug for release into the eye.
[0011] FIGS. 1-2 illustrate example views of anatomical tissue
structures associated with an eye 100. Certain of the anatomical
tissue structures shown may be suitable for treatment using the
various lacrimal implants and methods discussed herein. The eye 100
is a spherical structure including a wall having three layers: an
outer sclera 102, a middle choroid layer 104 and an inner retina
106. The sclera 102 includes a tough fibrous coating that protects
the inner layers. It is mostly white except for the transparent
area at the front, commonly known as the cornea 108, which allows
light to enter the eye 100.
[0012] The choroid layer 104, situated inside the sclera 102,
contains many blood vessels and is modified at the front of the eye
100 as a pigmented iris 110. A biconvex lens 112 is situated just
behind the pupil. A chamber 114 behind the lens 112 is filled with
vitreous humor, a gelatinous substance. Anterior and posterior
chambers 116 are situated between the cornea 108 and iris 110,
respectively and filled with aqueous humor. At the back of the eye
100 is the light-detecting retina 106.
[0013] The cornea 108 is an optically transparent tissue that
conveys images to the back of the eye 100. It includes a vascular
tissue to which nutrients and oxygen are supplied via bathing with
lacrimal fluid and aqueous humor as well as from blood vessels that
line the junction between the cornea 108 and sclera 102. The cornea
108 includes a pathway for the permeation of drugs into the eye
100.
[0014] Turning to FIG. 2, other anatomical tissue structures
associated with the eye 100 including the lacrimal drainage system,
which includes a secretory system 230, a distributive system and an
excretory system, are shown. The secretory system 230 comprises
secretors that are stimulated by blinking and temperature change
due to tear evaporation and reflex secretors that have an efferent
parasympathetic nerve supply and secrete tears in response to
physical or emotional stimulation. The distributive system includes
the eyelids 202 and the tear meniscus around the lid edges of an
open eye, which spread tears over the ocular surface by blinking,
thus reducing dry areas from developing.
[0015] The excretory system of the lacrimal drainage system
includes, in order of flow, drainage, the lacrimal puncta, the
lacrimal canaliculi, the lacrimal sac 204 and the lacrimal duct
206. From the lacrimal duct 206, tears and other flowable materials
drain into a passage of the nasolacrimal system. The lacrimal
canaliculi include an upper (superior) lacrimal canaliculus 208 and
a lower (inferior) lacrimal canaliculus 210, which respectively
terminate in an upper 212 and lower 214 lacrimal punctum. The upper
212 and lower 214 punctum are slightly elevated at the medial end
of a lid margin at the junction 216 of the ciliary and lacrimal
portions near a conjunctival sac 218. The upper 212 and lower 214
punctum are generally round or slightly ovoid openings surrounded
by a connective ring of tissue. Each of puncta 212, 214 leads into
a vertical portion 220, 222 of their respective canaliculus before
turning more horizontal at a canaliculus curvature 250 to join one
another at the entrance of the lacrimal sac 204. The canaliculi
208, 210 are generally tubular in shape and lined by stratified
squamous epithelium surrounded by elastic tissue, which permits
them to be dilated. As shown, a lacrimal canaliculus ampulla 252
exists near an outer edge of each canaliculus curvature 250.
[0016] For numerous reasons (e.g., the size, shape, positioning,
and materials of some conventional lacrimal implants, and
variability in punctum size and shape), retention of the implants
in the punctum and associated lacrimal canaliculus has been
inconsistent. Users of lacrimal implants may inadvertently dislodge
the lacrimal implant by wiping their eye. Further, some
configurations of lacrimal implants may dislodge themselves, such
as when a user sneezes, or tears excessively.
[0017] Accordingly, it is desirable to have a lacrimal implant that
solves these problems and provides improved retention across
different sizes of puncta, while providing efficient administration
of a therapeutic agent for treatment of open angle glaucoma (OAG)
and/or ocular hypertension (OH).
SUMMARY OF THE INVENTION
[0018] In an exemplary embodiment, the present invention provides
methods of reducing intraocular pressure (IOP) in an eye. In an
exemplary embodiment, the method of the invention utilizes a
latanoprost-eluting lacrimal implant inserted into at least the
upper punctum of an eye. Previous methods of delivering latanoprost
to the eye using a latanoprost-eluting lacrimal implant have met
with varied and minimal success. For example, as show in FIG. 16,
in an eye implanted with a single latanoprost-eluting plug in the
lower punctum, the reduction in IOP is minimal, and is
substantially identical across a range of latanoprost loadings:
from 3.5 .mu.g to 95 .mu.g, the IOP does not decrease even though
more latanoprost is being delivered by the plugs with higher
latanoprost loading. See, FIG. 17. Thus, it is surprising that the
methods of the present invention, in which an eye has a
latanoprost-eluting punctal implant in at least the upper punctum
yields a statistically significant reduction in IOP after about two
weeks.
[0019] In an exemplary embodiment, the methods of the invention
provide a reduction in IOP of at least about 4 mm Hg, at least
about 5 mm Hg, at least about 6 mm Hg or at least about 7 mm Hg
from baseline during the treatment period during which the lacrimal
implant is inserted into at least the upper punctum,
[0020] In various embodiments, the method of the invention includes
implanting a first lacrimal implant through a first lacrimal
punctum and into a first lacrimal canaliculus of the eye of the
patient. The first lacrimal implant is configured to release an
intraocular pressure-reducing therapeutic agent to the eye of the
patient on a sustained basis. In an exemplary embodiment, the first
implant contains approximately 0 .mu.g (blank), 46 .mu.g or 95
.mu.g of latanoprost and a second implant contains about 95 .mu.g
of latanoprost or is a "blank" implant and does not comprise
latanoprost. In an exemplary embodiment, the first implant is
installed in the upper punctum and the second implant is installed
in the lower punctum. In various embodiments, the location of the
implants is reversed. In other embodiments, only the first lacrimal
implant is installed in the upper punctum and no implant is placed
in the lower punctum.
[0021] In certain embodiments, the method of the invention can
include implanting more than one implant in more than one punctum
of one or more eye. Thus, in various embodiments, the method also
includes implanting a second lacrimal implant through a second
punctum and into a second lacrimal canaliculus of the eye of the
patient, the second lacrimal implant being configured to release
the intraocular pressure-reducing therapeutic agent to the eye of
the patent on a sustained basis. In an alternative embodiment, the
second lacrimal implant is a blank.
[0022] In various embodiments, the implant is configured to
release, on a sustained basis over a selected time course to the
eye, a total amount of the intraocular pressure-reducing
therapeutic agent from a combination of the first lacrimal implant
and the second lacrimal implant greater than or equal to a
recommended daily total dose of the intraocular pressure-reducing
therapeutic agent in eye drop form to reduce intraocular pressure
of the eye by at least 4 mm Hg from baseline for a continuous
period of time of at least 4 weeks after implantation of the first
lacrimal implant and the second lacrimal implant.
[0023] In an exemplary embodiment, the invention provides a method
for reducing intraocular pressure in an eye of a subject in need
thereof. An exemplary method includes implanting a first lacrimal
implant through a first punctum and into a first lacrimal
canaliculus of an eye of the subject. The first lacrimal implant is
configured to release a therapeutically effective amount of an
intraocular pressure-reducing therapeutic agent to the eye of the
patient on a sustained basis. In various embodiments a second
implant is installed in a second punctum or in a second eye. Thus,
there is provided a method as set forth above, further comprising
implanting a second lacrimal implant through a second punctum and
into a second lacrimal canaliculus of the eye of the subject. The
second lacrimal implant is configured to release the intraocular
pressure-reducing therapeutic agent to the eye of the patent on a
sustained basis. The method also includes, once the one or more
implant is installed in an eye, releasing, on a sustained basis
over a selected time course to the eye, a total amount of the
intraocular pressure-reducing therapeutic agent from a combination
of the first lacrimal implant and the second lacrimal implant. The
total amount of therapeutic agent released is sufficient to reduce
the intraocular pressure.
[0024] The implant can be of any useful form, structure or
composition. In an exemplary embodiment, the implant includes, a
first member defining a first axis and having a first end along the
first axis. The implant also includes a second member defining a
second axis and having a second end along the second axis; and a
third member connecting the first end of the first member and the
second end of the second member at a first angle to form an angled
intersection, and the third member comprising a bore that is
characterized by a third axis and a second angle. In general, the
first angle is defined by the first axis with respect to the second
axis, the second angle is defined by the first axis with respective
to the third axis, and the bore is configured to be accessible to
an insertion tool for facilitating insertion of the implant.
[0025] Also provided are kits that include at least one implant. An
exemplary kit includes one or more implant operatively engaged to
an implanting tool of use in implanting the device in the punctum
of a subject's eye.
[0026] The devices and methods described herein include a
removable, and optionally drug releasing, lacrimal implant, which
can be implanted in the lacrimal canaliculus through a lacrimal
punctum. In various embodiments, the lacrimal implants described
herein utilize the features of the nasolacrimal drainage system
(e.g., by mimicking the shape of the lacrimal canaliculus) to
provide improved patient comfort and implant retention in the
ocular anatomy. In this way, exemplary lacrimal implants described
herein overcome drawbacks associated with current implants. The
lacrimal implants described herein are easily implanted and removed
without much biasing of the lacrimal punctum or associated
canaliculus, and are securely retained in the lacrimal canaliculus
upon implantation, optionally without being pre-sized to a
particular lacrimal punctum or canaliculus diameter. In various
embodiments, the implants are drug delivery system, providing
sustained, localized release of one or more drugs or other
therapeutic agents at a desired therapeutic level for an extended
period of time.
[0027] In an exemplary embodiment, the invention provides an
implant for insertion into a lacrimal canaliculus. An exemplary
implant includes, a first member defining a first axis and having a
first end along the first axis. The implant also includes a second
member defining a second axis and having a second end along the
second axis. The implant further includes a third member connecting
the first end of the first member and the second end of the second
member at a first angle to form an angled intersection. The third
member includes a bore that is characterized by a third axis and a
second angle. The bore is configured to be accessible to an
insertion tool for facilitating insertion of the implant. In
various embodiments, the first angle is defined by the first axis
with respect to the second axis and the second angle is defined by
the first axis with respective to the third axis.
[0028] In various embodiments, the invention includes a kit having
an implant of the invention and an insertion tool for inserting the
implant into the punctum.
[0029] Also provided is a method of treating an ocular disease
using one or more punctal implant.
[0030] These and other embodiments, advantages, and aspects of the
methods disclosed herein are set forth in part in following
detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] In the drawings, like numerals describe similar components
throughout the several views. Like numerals having different letter
suffixes represent different instances of similar components. The
drawings illustrate generally, by way of example, but not by way of
limitation, various embodiments disclosed herein.
[0032] FIG. 1 illustrates an example of anatomical tissue
structures associated with an eye, certain of these tissue
structures providing a suitable environment in which a lacrimal
implant can be used.
[0033] FIG. 2 illustrates another example of anatomical tissue
structures associated with an eye, certain of these tissue
structures providing a suitable environment in which a lacrimal
implant can be used.
[0034] FIG. 3A provides a perspective view of an implant in
accordance with an embodiment of the present invention.
[0035] FIG. 3B is a side view of an implant in accordance with an
embodiment of the present invention.
[0036] FIG. 3C is a side view illustrating the second member and
the third member of an implant in accordance with an embodiment of
the present invention.
[0037] FIG. 3D is a back view of an implant in accordance with an
embodiment of the present invention.
[0038] FIG. 3E is a cross-sectional view taken about line
III(E)-III(E) of FIG. 3D depicting an implant with a bore, in
accordance with an embodiment of the present invention.
[0039] FIG. 3F is a partially enlarged view of FIG. 3E taken about
circle III(F) depicting the second member, the third member and a
bore formed in the third member of an implant, in accordance with
an embodiment of the present invention.
[0040] FIG. 4A provides a perspective view of an implant in
accordance with an embodiment of the present invention.
[0041] FIG. 4B is a cross-sectional view depicting an implant
having a cavity formed in the second member, in accordance with an
embodiment of the present invention.
[0042] FIG. 4C is a partially enlarged view taken about circle
IV(C) of FIG. 4B depicting a cavity in the second member and a bore
in the third member of an implant, in accordance with an embodiment
of the present invention.
[0043] FIG. 5 provides a partial cross-sectional view of an implant
in accordance with one embodiment of the present invention.
[0044] FIG. 6 provides a partial cross-section view of an implant
in accordance with another embodiment of the present invention.
[0045] FIG. 7 depicts engagement of an insertion tool with an
implant in accordance with an embodiment of the present
invention.
[0046] FIG. 8A provides initial retention data for various
exemplary implants in accordance with various embodiments of the
present invention.
[0047] FIG. 8B lists retention data for various exemplary implants
over one day, in accordance with various embodiments of the present
invention.
[0048] FIG. 8C lists retention data for various exemplary implants
over one week, in accordance with various embodiments of the
present invention.
[0049] FIG. 8D lists retention data for various exemplary implants
over two weeks, in accordance with various embodiments of the
present invention.
[0050] FIG. 8E lists retention data for various exemplary implants
over four weeks, in accordance with various embodiments of the
present invention.
[0051] FIG. 8F lists retention data for various exemplary implants
over eight weeks, in accordance with various embodiments of the
present invention.
[0052] FIG. 8G lists retention data for various exemplary implants
over twelve weeks, in accordance with various embodiments of the
present invention.
[0053] FIG. 9 is a plot comparing retention rates of an implant of
the invention (lower punctum) with a commercial implant (upper
punctum). The two implants are implanted in the same eye of the
patient.
[0054] FIG. 10A illustrates a side view of a commercial implant
used for the comparison studies herein.
[0055] FIG. 10B illustrates a top view of the commercial implant
used for the comparison studies herein.
[0056] FIG. 10C is a cross-sectional view taken about line A-A of
FIG. 10A illustrating a modified cavity formed in the commercial
implant for the comparison studies herein.
[0057] FIG. 10D is a partially enlarged view taken about circle B
of FIG. 10C illustrating a lip at an opening of the modified cavity
in the commercial implant for the comparison studies herein.
[0058] FIG. 11 provides the baseline demographics for the
comparison studies herein.
[0059] FIG. 12 lists retention data for various exemplary implants
over four weeks, in accordance with various embodiments of the
present invention.
[0060] FIG. 13 illustrates mean intraocular pressure (IOP) change
from baseline during treatment with a sustained release ophthalmic
drug delivery system according to an embodiment of the present
invention over a four-week period.
[0061] FIG. 14 illustrates percentage of subjects achieving
categorical absolute intraocular pressure (IOP) reduction from
baseline during treatment with the sustained release ophthalmic
drug delivery system according to an embodiment of the present
invention over the four-week period.
[0062] FIG. 15 illustrates percent change in IOP from baseline
during treatment with a sustained release ophthalmic drug delivery
system according to an embodiment of the present invention over a
four-week period.
[0063] FIG. 16 illustrates the lack of dose dependency of
intraocular pressure reduction when latanoprost is administered
from a single punctal implant.
[0064] FIG. 17 illustrates the dosages of latanoprost delivered by
the punctal implants of FIG. 16.
[0065] FIG. 18 is a graphical illustration comparing change in IOP
from baseline during treatment in the GLAU 11 and GLAU 12 Studies
with a sustained release opthalmic drug delivery system according
to an embodiment of the present invention. The data marked
(.box-solid.) are for a punctal plug with an unoptimized drug core.
141 .mu.g, the maximum dosage, is administered by upper (46 .mu.g)
and lower (95 .mu.g) plugs. The data marked (.diamond-solid.) are
for a punctal plug modified to enhance insertion and retention. The
maximum dosage, 141 .mu.g, is administered by upper (46 .mu.g) and
lower (95 .mu.g) plugs. The results show a comparable, in two
studies, sustained reduction in IOP at week 4 of more than 5 mmHg.
N=number of eyes.
[0066] FIG. 19 is a graphical illustration comparing change in IOP
from baseline during treatment with a sustained release ophthalmic
drug delivery system according to an embodiment of the present
invention. The data marked (.diamond-solid.) are for a punctal plug
modified to enhance insertion and retention. The maximum dosage, 95
.mu.g, is administered by an upper (95 .mu.g) plug. The lower plug
is a blank. The data marked (.box-solid.) are for a punctal plug
modified to enhance insertion and retention. The maximum dosage, 95
.mu.g, is administered by an upper (95 .mu.g) plug. The lower plug
is open. The data marked (.tangle-solidup.) are for a punctal plug
modified to enhance insertion and retention. The maximum dosage, 95
.mu.g, is administered by lower (95 .mu.g) plug. The upper plug is
a blank
[0067] FIG. 20 is a graphical illustration comparing change in IOP
from baseline during treatment with a sustained release ophthalmic
drug delivery system according to an embodiment of the present
invention. The data marked (.diamond-solid.) are for a punctal plug
modified to enhance insertion and retention. The maximum dosage
administered is 95 .mu.g. The data marked (.box-solid.) are for a
punctal plug modified to enhance insertion and retention. The
maximum dosage adminstered is 141 .mu.g. The data marked
(.tangle-solidup.) are for a punctal plug modified to enhance
insertion and retention. The maximum dosage administered is 190
.mu.g.
[0068] FIG. 21 is a graphical illustration of the five treatment
arms of GLAU 12 and GLAU 13 (Ex. 5 and 6). N=number of subjects
[0069] FIG. 22 is a graphical illustration of the two treatment
arms for GLAU 12 Addendum exploring the effect of repeat plug
placement. N=number of subjects
[0070] FIG. 23 lists a summary of change in IOP from baseline
(mmHg) in the GLAU 12 and GLAU 13 studies for both intent to treat
(ITT) groups. N=number of eyes
[0071] FIG. 24 is a graphical illustration of the reduction in IOP
(mmHg) for the All IOP ITT group of the GLAU 12 study from day 1 to
week 12. N=number of eyes.
[0072] FIG. 25 is a graphical illustration of the reduction in IOP
(mmHg) for the second ITT group (IOP excluded after first plug
loss/removal) of the GLAU 12 study from day 1 to week 12. N=number
of eyes.
[0073] FIG. 26 is a graphical illustration of the reduction in IOP
(mmHg) for both ITT groups in the GLAU 12 addendum study during
course 2 (an additional 8 weeks after the 12 week main study).
N=number of eyes.
[0074] FIG. 27 is a graphical illustration of the reduction in IOP
(mmHg) for the All IOP ITT group of the GLAU 13 study from day 1 to
week 12. The data indicates that the effect of latanoprost and the
reduction in IOP may be influenced by the plug position. N=number
of eyes.
[0075] FIG. 28 is a graphical illustration of the reduction in IOP
(mmHg) for the second ITT group (IOP excluded after first plug
loss/removal) of the GLAU 13 study from day 1 to week 12. The data
indicates that the effect of latanoprost and the reduction in IOP
may be influenced by the plug position. N=number of eyes.
[0076] FIG. 29 is a graphical illustration of the change in IOP
(mmHg) from baseline over 12 weeks showings the percentage of eyes
with a better than 5 mmHg decrease in IOP for the All IOP ITT group
of GLAU 12. N=number of eyes.
[0077] FIG. 30 is a graphical illustration of the change in IOP
(mmHg) from baseline over 12 weeks showings the percentage of eyes
with a better than 5 mmHg decrease in IOP for the second ITT group
(IOP excluded after first plug loss/removal) of GLAU 12. N=number
of eyes.
[0078] FIG. 31 is a graphical illustration of the change in IOP
(mmHg) from baseline over 12 weeks showings the percentage of eyes
with a better than 5 mmHg decrease in IOP for the All IOP ITT group
of GLAU 13. N=number of eyes.
[0079] FIG. 32 is a graphical illustration of the change in IOP
(mmHg) from baseline over 12 weeks showings the percentage of eyes
with a better than 5 mmHg decrease in IOP for the second ITT group
(IOP excluded after first plug loss/removal) of GLAU 13. N=number
of eyes.
[0080] FIG. 33 is a list and description of the plug designs used
in the GLAU 11, 12 and 13 studies.
[0081] FIG. 34 is a graphical illustration of the upper and lower
plug retention by eye represented as a percentage at each time
point from day 1 to week 12 for the plugs used in the GLAU 12
study.
[0082] FIG. 35 is a table listing the upper and lower plug
retention by eye represented as a percentage at each time point
from day 1 to week 12 for the plugs used in the GLAU 12 study.
N=number of eyes.
[0083] FIG. 36 is a graphical illustration of the upper and lower
plug retention by eye represented as a percentage at each time
point for Course 2 (8 weeks) and Course 3 (4 weeks) for the plugs
used in the GLAU 12 addendum study.
[0084] FIG. 37 is a graphical illustration of the upper and lower
plug retention by eye represented as a percentage at each time
point from day 1 to week 12 for the plugs used in the GLAU 13
study.
[0085] FIG. 38 is a table listing the upper and lower plug
retention by eye represented as a percentage at each time point
from day 1 to week 12 for the plugs used in the GLAU 13 study.
N=number of eyes.
[0086] FIG. 39 is a table representing the upper plug retention by
eye represented as a percentage in 4 week blocks (0-4 weeks, 4-8
weeks and 8-12 weeks) for the plugs used in the GLAU 12 and GLAU 13
studies
DETAILED DESCRIPTION OF THE INVENTION
A) Introduction
[0087] In various embodiments, the present invention is directed to
the treatment of ocular diseases such as Glaucoma or ocular
hypertension. In certain embodiments, the invention includes the
use of an implant that comprises a sustained release formulation of
a therapeutic agent of use in treating the disease. The implant is
configured to deliver a therapeutically effective amount of the
therapeutic agent to the eye during the period that it is implanted
in the eye (e.g. the treatment period). In an exemplary embodiment,
the disease is glaucoma and the therapeutic agent is a
prostaglandin or derivative thereof. In certain embodiments, the
implant is a punctual plug configured for insertion through a human
lacrimal punctum into a corresponding lacrimal canaliculus and
retention in the canaliculus. In an exemplary embodiment, the
sustained release formulation of the therapeutic agent is released
over a period of from about 4 weeks to about 12 weeks in a
therapeutic dose sufficient to reduce intraocular pressure of the
eye. In various embodiments, the therapeutic dose of the agent is
sufficient to decrease intraocular pressure by at least 4 mm Hg
from baseline (e.g., "normal").
[0088] In certain embodiments is provided a method for treating a
patient diagnosed with Open Angle Glaucoma (OAG) or Ocular
Hypertension (OH) in an eye. In this instance lacrimal implants are
provided for insertion into the upper and/or lower punctum of the
eye. Each lacrimal implant comprises a sustained release
formulation of a therapeutic agent for treating OAG and/or OH,
wherein the sustained release formulation can be released in a
therapeutically effective amount for at least 4 weeks and up to 12
weeks or longer. In one embodiment, the lacrimal implant is
inserted at least in the upper punctum. In one aspect this
therapeutically effective agent is latanoprost. In this instance of
treating OAG and/or OH the IOP is reduced. In an exemplary
embodiment, the methods of the invention provide a reduction in IOP
of at least about 4 mm Hg, at least about 5 mm Hg, at least about 6
mm Hg or at least about 7 mm Hg from baseline during the treatment
period.
[0089] In certain embodiments, a method for treating a patient
diagnosed with Open Angle Glaucoma (OAG) or Ocular Hypertension
(OH) in an eye is provided wherein a first lacrimal implant
comprising a sustained release formulation of the therapeutic agent
is inserted into a upper or lower punctum and a second lacrimal
implant that does not comprise the therapeutic agent is inserted
into the open punctum of the eye (i.e. the upper or lower punctum
that does not contain the first lacrimal implant). The second
lacrimal implant is also referred to herein as a "blank" implant.
In one embodiment the therapeutic agent is released in a
therapeutically effective dose from the first lacrimal implant on a
sustained release basis over at least four (4) weeks. In another
aspect, the therapeutic agent is released in a therapeutically
effective dose from the first lacrimal implant on a sustained
release basis over at least twelve (12) weeks.
[0090] In certain other embodiments, a method for treating a
patient diagnosed with Open Angle Glaucoma (OAG) or Ocular
Hypertension (OH) in an eye is provided wherein the IOP of the eye
is measured to obtain a baseline IOP before treatment and wherein a
lacrimal implant comprising a sustained release formulation is
inserted into a punctum. In exemplary embodiments the IOP is
reduced by at least 5.5 mm Hg from baseline at week 6, reduced by
at least 4.0 mm Hg from baseline at week 12, or reduced by at least
5.0 mm Hg from baseline at week 12.
[0091] In an exemplary embodiment, the method of the invention
utilizes latanoprost-eluting punctal implants. Previous methods of
delivering latanoprost to the eye using a latanoprost-eluting
punctal implant have met with varied and minimal success. For
example, as show in FIG. 16, in an eye implanted with a single
latanoprost-eluting plug in the lower punctum, the reduction in IOP
is minimal, and is substantially identical across a range of
latanoprost loadings: from 3.5 .mu.g to 95 .mu.g, the IOP does not
decrease even though more latanoprost is being delivered by the
plugs with higher latanoprost loading. See, FIG. 17. Thus, it is
surprising that the methods of the present invention, in which
either an eye has a latanoprost-eluting punctal implant in both the
upper and lower punctum, a blank and latanoprost-eluting punctual
implant in either the upper and lower punctum, or in certain
instances a latanoprost-eluting punctal implant in the upper
punctum and no implant in the bottom punctum, would yield a
statistically significant reduction in IOP after about two weeks.
See Example 6 and Table 8
[0092] Also disclosed herein are exemplary structures of ocular
implants of use in the methods of the invention for treating
various diseases and disorders. Exemplary structures include
lacrimal implants for at least partial insertion through the
lacrimal punctum and into its associated canaliculus. Various
embodiments further provide an insertion tool for placing a
lacrimal implant into a lacrimal punctum. Also disclosed herein are
exemplary implants including therapeutic agents incorporated
throughout the device, within one or more section of the device, or
in a therapeutic agent core, e.g., a localized therapeutic agent
core. The devices of the invention are of use for treating various
diseases.
[0093] In the various embodiments of methods of the invention,
implanting a lacrimal implant of the invention through the lacrimal
punctum and into its associated canaliculus, in various
embodiments, inhibits or blocks tear flow therethrough. In various
embodiments, a device inhibiting or blocking tear flow is of use to
treat dry eye. In an exemplary embodiment, the insertion of the
lacrimal implant allows for the delivery of a therapeutic agent. In
various embodiments, the delivery is sustained delivery. Exemplary
therapeutic agents incorporated into the implants of the invention
are of use to treat the eye, or they can be of use more broadly
systemic therapies. For example, using a device of the invention,
the therapeutic agent can be delivered to a nasal passage, to an
inner ear system, or to other passages or systems for treatment of
various diseases including, but not limited to, eye infection, eye
inflammation, glaucoma, other ocular disease, other ocular
disorder, a sinus or allergy disorder, dizziness or a migraine. The
devices of the invention are of use for systemic delivery of one or
more therapeutic agents in an amount having therapeutic
efficacy.
[0094] Those of ordinary skill in the art will understand that the
following detailed description of the present invention is
illustrative only and is not intended to be in any way limiting.
Other embodiments of the present invention will readily suggest
themselves to such skilled persons having benefit of this
disclosure. Reference will now be made in detail to implementations
of the present invention as illustrated in the accompanying
drawings. The same reference indicators will be used throughout the
drawings and the following detailed description to refer to the
same or like parts.
B) Definitions
[0095] As used herein, the terms "a" or "an" are used, as is common
in patent documents, to include one or more than one, independent
of any other instances or usages of "at least one" or "one or
more."
[0096] As used herein, the term "or" is used to refer to a
nonexclusive or, such that "A or B" includes "A but not B," "B but
not A," and "A and B," unless otherwise indicated.
[0097] As used herein, the term "about" is used to refer to an
amount that is approximately, nearly, almost, or in the vicinity of
being equal to or is equal to a stated amount, e.g., the state
amount plus/minus about 5%, about 4%, about 3%, about 2% or about
1%.
[0098] As used herein, an "axis" refers to a general direction
along which a member extends. According to this definition, the
member is not required to be entirely or partially symmetric with
respect to the axis or to be straight along the direction of the
axis. Thus, in the context of this definition, any member disclosed
in the present application characterized by an axis is not limited
to a symmetric or a straight structure.
[0099] In this document, the term "proximal" refers to a location
relatively closer to the cornea of an eye, and the term "distal"
refers to a location relatively further from the cornea and
inserted deeper into a lacrimal canaliculus.
[0100] In the appended claims, the terms "including" and "in which"
are used as the plain-English equivalents of the respective terms
"comprising" and "wherein." Also, in the following claims, the
terms "including" and "comprising" are open-ended, that is, a
system, assembly, device, article, or process that includes
elements in addition to those listed after such a term in a claim
are still deemed to fall within the scope of that claim. Moreover,
in the following claims, the terms "first," "second," and "third,"
etc. are used merely as labels, and are not intended to impose
numerical requirements on their objects.
[0101] As used herein, the term "adverse event" refers to any
undesirable clinical event experienced by a patient undergoing a
therapeutic treatment including a drug and/or a medical device,
whether in a clinical trial or a clinical practice. Adverse events
include a change in the patient's condition or laboratory results,
which has or could have a deleterious effect on the patient's
health or well-being. For example, adverse events include but are
not limited to: device malfunction identified prior to placement,
device malposition, device malfunction after placement, persistent
inflammation, endophthalmitis, corneal complications (corneal
edema, opacification, or graft decompensation), chronic pain, iris
pigmentation changes, conjunctival hyperemia, eyelash growth
(increased length, thickness, pigmentation, and number of lashes),
eyelid skin darkening, intraocular inflammation (iritis/uveitis),
macular edema including cystoid macular edema, blurred vision,
burning and stinging, foreign body sensation, itching, punctate
epithelial keratopathy, dry eye, excessive tearing, eye pain, lid
crusting, lid discomfort/pain, lid edema, lid erythema,
photophobia, VA decrease, conjunctivitis, diplopia, discharge from
the eye, retinal artery embolus, retinal detachment, vitreous
hemorrhage from diabetic retinopathy, upper respiratory tract
infection/cold/flu, chest pain/angina pectoris, muscle/joint/back
pain, and rash/allergic skin reaction, eye pruritus, increase in
lacrimation, ocular hyperemia and punctate keratitis. In an
exemplary embodiment, use of the device and method of the invention
results in one or more of: (i) occurrence of fewer adverse events;
or (ii) adverse events of less severity, than those occurring with
the use of a therapeutic agent in drop form, e.g., when the
therapeutic agent is administered via drops in essentially the same
unit dosage as that delivered by a device as set forth herein.
[0102] As used herein, the phrase "consisting essentially of"
limits a composition to the specified materials or steps and those
additional, undefined components that do not materially affect the
basic and novel characteristic(s) of the composition.
[0103] As used herein, the term "continuous" or "continuously"
means essentially unbroken or uninterrupted. For example,
continuously administered active agents are administered over a
period of time essentially without interruption.
[0104] As used herein, the term "diameter" encompasses a broad
meaning. For example, with respect to a member having a circular
cross section, the term "diameter" has the conventional meaning and
refers to a straight line through the center of the circle
connecting two points on the circumference. When the cross section
is not a circle, the term "diameter" in the present disclosure
refers to the characteristic diameter of the cross section. The
"characteristic diameter" refers to the diameter of a circle that
has the same surface area as the cross section of the element. In
the present application, "diameter" is interchangeable with
"characteristic diameter."
[0105] As used herein, the term "eye" refers to any and all
anatomical tissues and structures associated with an eye. The eye
is a spherical structure with a wall having three layers: the outer
sclera, the middle choroid layer and the inner retina. The sclera
includes a tough fibrous coating that protects the inner layers. It
is mostly white except for the transparent area at the front, the
cornea, which allows light to enter the eye. The choroid layer,
situated inside the sclera, contains many blood vessels and is
modified at the front of the eye as the pigmented iris. The
biconvex lens is situated just behind the pupil. The chamber behind
the lens is filled with vitreous humour, a gelatinous substance.
The anterior and posterior chambers are situated between the cornea
and iris, respectively and filled with aqueous humour. At the back
of the eye is the light-detecting retina. The cornea is an
optically transparent tissue that conveys images to the back of the
eye. It includes avascular tissue to which nutrients and oxygen are
supplied via bathing with lacrimal fluid and aqueous humour as well
as from blood vessels that line the junction between the cornea and
sclera. The cornea includes one pathway from the permeation of
drugs into the eye. Other anatomical tissue structures associated
with the eye include the lacrimal drainage system, which includes a
secretory system, a distributive system and an excretory system.
The secretory system comprises secretors that are stimulated by
blinking and temperature change due to tear evaporation and reflex
secretors that have an efferent parasympathetic nerve supply and
secrete tears in response to physical or emotional stimulation. The
distributive system includes the eyelids and the tear meniscus
around the lid edges of an open eye, which spread tears over the
ocular surface by blinking, thus reducing dry areas from
developing.
[0106] As used herein, the term "implant" refers to a structure
that can be configured to contain or be impregnated with a drug,
for example via a drug core or a drug matrix, such as those as
disclosed in this patent document and in WO 07/115,261, which is
herein incorporated by reference in its entirety, and which is
capable of releasing a quantity of active agent, such as
latanoprost or other intraocular pressure-reducing therapeutic
agent(s), into tear fluid for a sustained release period of time
when the structure is implanted at a target location along the path
of the tear fluid in the patient. The terms "implant," "plug,"
"punctal plug," and "punctal implant" are meant herein to refer to
similar structures. Likewise, the terms "implant body" and "plug
body" are meant herein to refer to similar structures. The implants
described herein may be inserted into the punctum of a subject, or
through the punctum into the canaliculus. The implant may be also
the drug core or drug matrix itself, which is configured for
insertion into the punctum without being housed in a carrier such
as a punctal implant occluder, for example having a polymeric
component and a latanoprost or other intraocular pressure-reducing
therapeutic agent(s) component with no additional structure
surrounding the polymeric component and latanoprost or other
intraocular pressure-reducing therapeutic agent(s) component.
[0107] As used in exemplary embodiments herein, "loss of efficacy"
(LoE) is defined as an IOP increase to baseline (post-washout) IOP
in either or both eyes while wearing a latanoprost punctal plug
delivery system (L-PPDS) continuously from Day 0. Subjects were
followed for at least 4 weeks before the subject could complete the
study due to LoE and LoE was confirmed at 2 sequential visits.
[0108] As used herein, a "pharmaceutically acceptable vehicle" is
any physiologically acceptable vehicle known to those of ordinary
skill in the art useful in formulating pharmaceutical compositions.
Suitable vehicles include polymeric matrices, sterile distilled or
purified water, isotonic solutions such as isotonic sodium chloride
or boric acid solutions, phosphate buffered saline (PBS), propylene
glycol and butylene glycol. Other suitable vehicular constituents
include phenylmercuric nitrate, sodium sulfate, sodium sulfite,
sodium phosphate and monosodium phosphate. Additional examples of
other suitable vehicle ingredients include alcohols, fats and oils,
polymers, surfactants, fatty acids, silicone oils, humectants,
moisturizers, viscosity modifiers, emulsifiers and stabilizers. The
compositions may also contain auxiliary substances, i.e.
antimicrobial agents such as chlorobutanol, parabans or organic
mercurial compounds; pH adjusting agents such as sodium hydroxide,
hydrochloric acid or sulfuric acid; and viscosity increasing agents
such as methylcellulose. An exemplary final composition is sterile,
essentially free of foreign particles, and has a pH that allows for
patient comfort and acceptability balanced with a pH that is
desirable for optimum drug stability. An exemplary
"pharmaceutically acceptable vehicle is an "ophthalmically
acceptable vehicle" as used herein refers to any substance or
combination of substances which are non-reactive with the compounds
and suitable for administration to patient. In an exemplary
embodiment, the vehicle is an aqueous vehicle suitable for topical
application to the patient's eyes. In various embodiments, the
vehicle further includes other ingredients which may be desirable
to use in the ophthalmic compositions of the present invention
include antimicrobials, preservatives, co-solvents, surfactants and
viscosity building agents.
[0109] In various embodiments, the "pharmaceutically acceptable
vehicle" includes more than one therapeutic agent.
[0110] As used herein, the term "punctum" refers to the orifice at
the terminus of the lacrimal canaliculus, seen on the margins of
the eyelids at the lateral extremity of the lacus lacrimalis.
Puncta (plural of punctum) function to reabsorb tears produced by
the lacrimal glands. The excretory part of the lacrimal drainage
system includes, in flow order of drainage, the lacrimal puncta,
the lacrimal canaliculi, the lacrimal sac and the lacrimal duct.
From the lacrimal duct, tears and other flowable materials drain
into a passage of the nasal system. The lacrimal canaliculi include
an upper (superior) lacrimal canaliculus and a lower (inferior)
lacrimal canaliculus, which respectively terminate in an upper and
lower lacrimal punctum. The upper and lower punctum are slightly
elevated at the medial end of a lid margin at the junction of the
ciliary and lacrimal portions near a conjunctival sac. The upper
and lower punctum are generally round or slightly ovoid openings
surrounded by a connective ring of tissue. Each of the puncta leads
into a vertical portion of their respective canaliculus before
turning more horizontal at a canaliculus curvature to join one
another at the entrance of the lacrimal sac. The canaliculi are
generally tubular in shape and lined by stratified squamous
epithelium surrounded by elastic tissue, which permits them to be
dilated.
[0111] The terms "subject" and "patient" refer to animals such as
mammals, including, but not limited to, primates (e.g., humans),
cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the
like. In many embodiments, the subject or patient is a human.
[0112] An "intraocular pressure-reducing therapeutic agent" can
comprise a drug and may be any of the following or their
equivalents, derivatives or analogs, including anti-glaucoma
medications (e.g. adrenergic agonists, adrenergic antagonists (beta
blockers), carbonic anhydrase inhibitors (CAIs, systemic and
topical), therapeutic agent(s) such as prostaglandins,
antiprostaglandins, prostaglandin precursors, including
antiglaucoma drugs including beta-blockers such as timolol,
betaxolol, levobunolol, atenolol (see U.S. Pat. No. 4,952,581);
adrenergic agonists including clonidine derivatives, such as
apraclonidine or brimonidine (see U.S. Pat. No. 5,811,443); and
prostaglandin analogues such as bimatoprost, travoprost,
tafluprost, latanoprost, etc. In an exemplary embodiment, the
therapeutic agent is already marketed for glaucoma, and
commercially available preparations thereof can be used. Further
therapeutic agents include carbonic anhydrase inhibitors such as
acetazolamide, dorzolamide, brinzolamide, methazolamide,
dichlorphenamide, diamox; and the like.
[0113] The term "topical" refers to any surface of a body tissue or
organ. A topical formulation is one that is applied to a body
surface, such as an eye, to treat that surface or organ. Topical
formulations as used herein also include formulations that can
release therapeutic agents into the tears to result in topical
administration to the eye.
[0114] As used herein, the term "treating" or "treatment" of a
state, disease, disorder, injury or condition as used herein is
understood to mean one or more of (1) preventing or delaying the
appearance of clinical symptoms of the state, disease, disorder,
injury or condition developing in a mammal that may be afflicted
with or predisposed to the state, disease, disorder, injury or
condition but does not yet experience or display clinical or
subclinical symptoms of the state, disease, disorder, injury or
condition, (2) inhibiting the state, disease, disorder, injury or
condition, i.e., arresting or reducing the development of the
disease or at least one clinical or subclinical symptom thereof, or
(3) relieving the state, disease, disorder, injury or condition,
i.e., causing regression of the state, disease, disorder, injury or
condition or at least one of its clinical or subclinical symptoms.
In an exemplary embodiment, the present invention provides a method
of treating glaucoma or ocular hypertension including contacting an
effective intraocular pressure reducing amount of a composition
with the eye in order to reduce eye pressure and to maintain the
pressure on a reduced level for a sustained period, e.g., at least
about 1, 2, 3, 4, 5, 6, 7 8, 9, 10, 11 or 12 weeks.
[0115] The term "delivering", as used herein, shall be understood
to mean providing a therapeutically effective amount of a
pharmaceutically active agent to a particular location within a
host causing a therapeutically effective concentration of the
pharmaceutically active agent at the particular location.
[0116] As used herein, the term "diameter" encompasses a broad
meaning. For example, with respect to a member having a circular
cross section, the term "diameter" has the conventional meaning and
refers to a straight line through the center of the circle
connecting two points on the circumference. When the cross section
is not a circle, the term "diameter" in the present disclosure
refers to the characteristic diameter of the cross section. The
"characteristic diameter" refers to the diameter of a circle that
has the same surface area as the cross section of the element. In
the present application, "diameter" is interchangeable with
"characteristic diameter."
[0117] Some embodiments of the invention provide the use of
latanoprost or another active agent or agents for treatment of
diabetic retinopathy, uveitis, intraocular inflammation, keratitis,
dry eye, macular edema including cystoid macular edema, infection,
macular degeneration, blurred vision, herpetic conjunctivitis,
blepharitis, retinal or choroidal neovascularizaton, and other
proliferative eye diseases. In some embodiments, the invention
provides the use of an anti-glaucoma drug for treatment of the
above diseases. In certain embodiments, the use of a prostaglandin
or prostaglandin analogue for treatment of the above diseases is
provided.
[0118] "Prostaglandin derivatives", as used herein refers to
compounds having the basic prostaglandin structure of 20 carbon
atoms and a 5-carbon ring. Exemplary prostaglandin derivatives of
use in the present invention are of the PGI.sub.2, PGE.sub.2 and
PGF.sub.2.alpha. types. The structure can be augmented by
incorporating or eliminating functional groups (e.g., HO, carbonyl,
ether, ester, carboxylic acid, halide) or by adding carbon
atom-based radicals (e.g., Me, Et, i-Pr, etc.). See for example,
U.S. Pat. No. 7,910,767. In some embodiments, the prostaglandin
derivative is a derivative of PGA, PGB, PGD, PGE and PGF, in which
the omega chain has been modified with the common feature of
containing a ring structure. See, U.S. Pat. No. 5,296,504. The
prostaglandin derivatives of use in the invention are synthesized
de novo or derived from modification of naturally occurring
prostaglandins.
C) Drug Delivery System
[0119] Applicants herein disclose a method for treating open angle
glaucoma (OAG) and/or ocular hypertension (OH) in an eye of a
patient utilizing a lacrimal implant comprising a sustained release
formulation to deliver the therapeutic agent to the eye. The
treatment of these eye diseases relies on a drug delivery system
for administering the therapeutic agent, wherein the therapeutic
agent may be a known drug for reducing IOP or a newly developed
drug. The drug delivery system comprises 1) the therapeutic agent,
2) the lacrimal implant and 3) sustained release formulations while
taking into account the specific disease being treated.
[0120] Applicants provide herein, for the first time, methods for
treating OAG and/or OH wherein a therapeutically effective dose of
the therapeutic agent (e.g. latanoprost) is administered from the
present lacrimal implants over the treatment period (e.g. 4-12
weeks) wherein the IOP is reduced over the treatment period by a
clinically meaningful amount (e.g. about 5 mm Hg from baseline.) In
this instance, no additional treatment, except for the therapeutic
agent eluted from the implants, was needed to reduce IOP by a
clinically meaningful amount.
[0121] For ease of understanding the invention, the drug delivery
system and each of the components will be described in detail
followed by methods and clinical applications for treating OAG
and/or OH wherein intraocular pressure (IOP) is reduced.
1) Therapeutic Agents
[0122] Generally, pharmaceutically active agents or drugs useful in
the methods of the present invention can be any compound,
composition of matter, or mixtures thereof that can be delivered
from an implant, such as those described herein, to produce a
beneficial and useful result to, for example, the eye, especially
an agent effective in obtaining a desired local or systemic
physiological or pharmacological effect.
[0123] Examples of such agents include, but are not limited to,
anesthetics and pain killing agents such as lidocaine and related
compounds, benzodiazepam and related compounds and the like;
anti-cancer agents such as 5-fluorouracil, adriamycin and related
compounds and the like; anti-fungal agents such as fluconazole and
related compounds and the like; anti-viral agents such as trisodium
phosphomonoformate, trifluorothymidine, acyclovir, ganciclovir,
DDI, AZT and the like; cell transport/mobility impending agents
such as colchicine, vincristine, cytochalasin B and related
compounds and the like; antiglaucoma drugs (e.g. adrenergic
agonists, adrenergic antagonists (beta blockers), carbonic
anhydrase inhibitors (CAIs, systemic and topical),
parasympathomimetics, prostaglandins and hypotensive lipids, and
combinations thereof), antimicrobial agent (e.g., antibiotic,
antiviral, antiparacytic, antifungal, etc.), a corticosteroid or
other anti-inflammatory (e.g., an NSAID or other analgesic and pain
management compounds), a decongestant (e.g., vasoconstrictor), an
agent that prevents of modifies an allergic response (e.g., an
antihistamine, cytokine inhibitor, leucotriene inhibitor, IgE
inhibitor, immunomodulator), a mast cell stabilizer, cycloplegic,
mydriatic or the like.
[0124] Other agents that can be incorporated into implants of use
in the invention include antihypertensives; decongestants such as
phenylephrine, naphazoline, tetrahydrazoline and the like;
immunological response modifiers such as muramyl dipeptide and
related compounds and the like; peptides and proteins such as
cyclosporin, insulin, growth hormones, insulin related growth
factor, heat shock proteins and related compounds and the like;
steroidal compounds such as dexamethasone, prednisolone and related
compounds and the like; low solubility steroids such as
fluocinolone acetonide and related compounds and the like; carbonic
anhydrase inhibitors; diagnostic agents; antiapoptosis agents; gene
therapy agents; sequestering agents; reductants such as glutathione
and the like; antipermeability agents; antisense compounds;
antiproliferative agents; antibody conjugates; antidepressants;
blood flow enhancers; antiasthmatic drugs; antiparasiticagents;
non-steroidal anti inflammatory agents such as ibuprofen and the
like; nutrients and vitamins: enzyme inhibitors: antioxidants;
anticataract drugs; aldose reductase inhibitors; cytoprotectants;
cytokines, cytokine inhibitors, and cytokin protectants; uv
blockers; mast cell stabilizers; anti neovascular agents such as
antiangiogenic agents, e.g., matrix metalloprotease inhibitors and
the like.
[0125] Representative examples of additional pharmaceutically
active agent for use herein include, but are not limited to,
neuroprotectants such as nimodipine and related compounds and the
like; antibiotics such as tetracycline, chlortetracycline,
bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline,
chloramphenicol, gentamycin, erythromycin and the like;
anti-infectives; antibacterials such as sulfonamides,
sulfacetamide, sulfamethizole, sulfisoxazole; nitrofurazone, sodium
propionate and the like; antiallergenics such as antazoline,
methapyriline, chlorpheniramine, pyrilamine, prophenpyridamine and
the like; anti-inflammatories such as hydrocortisone,
hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone,
medrysone, methylprednisolone, prednisolone 21-phosphate,
prednisolone acetate, fluoromethalone, betamethasone, triminolone
and the like; miotics; anti-cholinesterase such as pilocarpine,
eserine salicylate, carbachol, di-isopropyl fluorophosphate,
phospholine iodine, demecarium bromide and the like; miotic agents;
mydriatics such as atropine sulfate, cyclopentolate, homatropine,
scopolamine, tropicamide, eucatropine, hydroxyamphetamine and the
like; svmpathomimetics such as epinephrine and the like; and
prodrugs such as, for example, those described in Design of
Prodrugs, edited by Hans Bundgaard, Elsevier Scientific Publishing
Co., Amsterdam, 1985. In addition to the foregoing agents, other
agents suitable for treating, managing, or diagnosing conditions in
a mammalian organism may be entrapped in the copolymer and
administered using the drug delivery systems of the current
invention. Once again, reference may be made to any standard
pharmaceutical textbook such as, for example, Remington's
Pharmaceutical Sciences for pharmaceutically active agents.
[0126] Any pharmaceutically acceptable form of the foregoing
therapeutically active agent may be employed in the practice of the
present invention, e.g., the free base; free acid; pharmaceutically
acceptable salts, esters or amides thereof, e.g., acid additions
salts such as the hydrochloride, hydrobromide, sulfate, bisulfate,
acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,
borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate,
maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate,
lactobionate, and lauryl sulfate salts and the like; alkali or
alkaline earth metal salts such as the sodium, calcium, potassium
and magnesium salts and the like; hydrates; enantiomers; isomers;
stereoisomers; diastereoisomers; tautomers; polymorphs, mixtures
thereof, prodrugs thereof or racemates or racemic mixtures
thereof.
[0127] Additional agents that can be used with the present methods
utilizing lacrimal implants include, but are not limited to, drugs
that have been approved under Section 505 of the United States
Federal Food, Drug, and Cosmetic Act or under the Public Health
Service Act, some of which can be found at the U.S. Food and Drug
Administration (FDA) website
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index. The
present lacrimal implants can also be used with drugs listed in the
Orange Book, either in paper or in electronic form, which can be
found at the FDA Orange Book website
(http://www.fda.gov/cder/ob/)), that has or records the same date
as, earlier date than, or later date than, the filing date of this
patent document. For example, these drugs can include, among
others, dorzolamide, olopatadine, travoprost, bimatoprost,
latanoprost, cyclosporin, brimonidine, moxifloxacin, tobramycin,
brinzolamide, aciclovir timolol maleate, ketorolac tromethamine,
prednisolone acetate, sodium hyaluronate, nepafenac, bromfenac,
diclofenac, flurbiprofen, suprofenac, binoxan, patanol,
dexamethasone/tobramycin combination, moxifloxacin, or
acyclovir.
[0128] Further discussion of drugs or other agents can be found in
commonly-owned U.S. Patent Application Publication No.
2009/0104248, U.S. Patent Application Publication No. 2010/0274204,
and U.S. Patent Application Publication No. 2009/0105749, which are
herein incorporated by reference in its entirety.
Prostaglandins
[0129] Prostaglandins are regarded as potent ocular hypertensives;
however, evidence accumulated in the last decade shows that some
prostaglandins are highly effective ocular hypotensive agents and
are ideally suited for the long-term medical management of glaucoma
(see, for example, Bito, L. Z. Biological Protection with
Prostaglandins Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc.,
1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the
Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H.
eds., New York, Grune & Stratton, 1984, pp. 477-505). Such
prostaglandins include PGF2.alpha., PGF.sub.1.alpha., PGE.sub.2,
and certain lipid-soluble esters, such as C.sub.1 to C.sub.5 alkyl
esters, e.g. 1-isopropyl ester, of such compounds.
[0130] Thus, in certain embodiments, the therapeutic agent is a
prostaglandin, including derivatives thereof. Prostaglandins are
derivatives of prostanoic acid. Various types of prostaglandins are
known, depending on the structure and substituents carried on the
alicyclic ring of the prostanoic acid skeleton. Further
classification is based on the number of unsaturated bonds in the
side chains indicated by numerical subscripts after the generic
type of prostaglandin (e.g., prostaglandin E.sub.1 (PGE.sub.1),
prostaglandin E.sub.2 (PGE.sub.2)), and on the configuration of the
substituents on the alicyclic ring indicated by .alpha. or .beta.
(e.g. prostaglandin F.sub.2.alpha. (PGF.sub.2.alpha.)). Any of
these prostaglandins are of use in the present invention.
[0131] An exemplary therapeutic agent for use in the methods
described herein is latanoprost. Latanoprost is a prostaglandin
F.sub.2.alpha. analogue. Its chemical name is isopropyl-(Z)-7
[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-
-5-heptenoate. Its molecular formula is C.sub.26H.sub.40O.sub.5 and
its chemical structure is:
##STR00001##
[0132] Latanoprost is a colorless to slightly yellow oil that is
very soluble in acetonitrile and freely soluble in acetone,
ethanol, ethyl acetate, isopropanol, methanol and octanol. It is
practically insoluble in water.
[0133] Latanoprost is believed to reduce intraocular pressure (IOP)
by increasing the outflow of aqueous humor. Studies in animals and
man suggest that the main mechanism of action is increased
uveoscleral outflow of aqueous fluid from the eyes. Latanoprost is
absorbed through the cornea where the isopropyl ester prodrug is
hydrolyzed to the acid form to become biologically active. Studies
in man indicate that the peak concentration in the aqueous humor is
reached about two hours after topical administration.
[0134] Xalatan.RTM. latanoprost ophthalmic solution is a
commercially available product indicated for the reduction of
elevated IOP in patients with open-angle glaucoma or ocular
hypertension. The amount of latanoprost in the commercially
available product Xalatan.RTM. is approximately 1.5
micrograms/drop, which is the recommended daily total dose of
latanoprost to one eye. As described above, eye drops, though
effective, can be inefficient and require multiple applications to
maintain the therapeutic benefit. Low patient compliance compounds
these effects.
[0135] In various embodiments, the prostaglandin is latanoprost. In
an illustrative embodiment, the unit dosage format includes from 40
.mu.g to 100 .mu.g of the therapeutic agent. In an exemplary
embodiment, the implant includes about 46 .mu.g or about 95 .mu.g
of latanoprost.
[0136] In an exemplary embodiment, the implant of the invention is
a member of a pair of implants. In various embodiments, the pair of
implants is configured as a unit dosage. In various embodiments,
the implant is formatted as a unit dosage of an antiglaucoma agent.
In an exemplary embodiment, the antiglaucoma agent is a
prostaglandin. In various embodiments, the prostaglandin is
latanoprost. In an illustrative embodiment, the unit dosage format
includes from 40 .mu.g to 100 .mu.g of the therapeutic agent. In an
exemplary embodiment, the unit dosage is 141 .mu.g of latanoprost.
In an exemplary embodiment, one implant includes about 46 .mu.g of
latanoprost and the other includes about 95 .mu.g of latanoprost.
In an exemplary embodiment, the unit dosage is a unit dosage for
both eyes, including four implants as described herein.
[0137] In an exemplary embodiment, the implant of the invention is
a member of a pair of implants. In various embodiments, the pair of
implants is configured as a unit dosage. In various embodiments,
the implant is formatted as a unit dosage of an antiglaucoma agent.
In an exemplary embodiment, the antiglaucoma agent is a
prostaglandin. In various embodiments, the prostaglandin is
latanoprost. In an illustrative embodiment, the unit dosage format
includes from 40 .mu.g to 100 .mu.g of the therapeutic agent. In an
exemplary embodiment, the unit dosage is 190 .mu.g of latanoprost.
In an exemplary embodiment, each implant includes about 95 .mu.g of
latanoprost. In an exemplary embodiment, the unit dosage is a unit
dosage for both eyes, including four implants as described
herein.
[0138] In an exemplary embodiment, the implant of the invention is
a member of a pair of implants. In various embodiments, the pair of
implants is configured as a unit dosage. In various embodiments,
the implant is formatted as a unit dosage of an antiglaucoma agent.
In an exemplary embodiment, the antiglaucoma agent is a
prostaglandin. In various embodiments, the prostaglandin is
latanoprost. In an illustrative embodiment, the unit dosage format
includes from 40 .mu.g to 100 .mu.g of the therapeutic agent. In an
exemplary embodiment, the unit dosage is 95 .mu.g of latanoprost.
In an exemplary embodiment, a first implant includes about 95 .mu.g
of latanoprost and a second implant does not include latanoprost
(e.g. a blank implant). In an exemplary embodiment, the unit dosage
is a unit dosage for both eyes, including four implants as
described herein.
[0139] In an alternative embodiment, the implant of the invention
is a single implant configured as a unit dosage. In various
embodiments, the implant is formatted as a unit dosage of an
antiglaucoma agent. In an exemplary embodiment, the antiglaucoma
agent is a prostaglandin. In various embodiments, the prostaglandin
is latanoprost. In an illustrative embodiment, the unit dosage
format includes from 40 .mu.g to 100 .mu.g of the therapeutic
agent. In an exemplary embodiment, the unit dosage is 95 .mu.g of
latanoprost. In an exemplary embodiment, a first implant includes
about 95 .mu.g of latanoprost and is inserted into the upper
punctum while no implant is inserted into the lower punctum. In an
exemplary embodiment, the unit dosage is a unit dosage for both
eyes, including two implants as described herein.
[0140] Actual dosage levels of the pharmaceutically active agent(s)
in the drug delivery systems of use in the present invention may be
varied to obtain an amount of the pharmaceutically active agent(s)
that is effective to obtain a desired therapeutic response for a
particular system and method of administration. The selected dosage
level therefore depends upon such factors as, for example, the
desired therapeutic effect, the route of administration, the
desired duration of treatment, and other factors. The total daily
dose of the pharmaceutically active agent(s) administered to a host
in single or divided doses can vary widely depending upon a variety
of factors including, for example, the body weight, general health,
sex, diet, time and route of administration, rates of absorption
and excretion, combination with other drugs, the severity of the
particular condition being treated, etc. In certain embodiments,
the amounts of pharmaceutically active agent(s) present in the drug
delivery systems of the present invention can range from about 0.1%
w/w to about 60% w/w. In one embodiment, the amounts of
pharmaceutically active agent(s) present in the present drug
delivery systems can range from about 1% w/w to about 50% w/w.
[0141] The therapeutic agents are formulated as a sustained release
formulation and incorporated into the lacrimal implants. This
sustained release formulation may either be in the form of a drug
core or dispersed throughout the lacrimal implant. In this instance
the lacrimal implant may be saturated and/or impregnated with the
therapeutic agent. However, before describing the sustained release
formulations the lacrimal implants will first be described in
detail.
2) Lacrimal Implants
[0142] The implant can be one of any number of different designs
that releases latanoprost or other intraocular pressure-reducing
therapeutic agent(s) for a sustained period of time. The
disclosures of the following patent documents, which describe
example implant structure or processing embodiments for use in the
methods of embodiments of the current invention and methods of
making those implants, are incorporated herein by reference in
their entirety: U.S. Application Ser. No. 60/871,864 (filed Dec.
26, 2006 and entitled Nasolacrimal Drainage System Implants for
Drug Therapy); U.S. application Ser. No. 11/695,537 (filed Apr. 2,
2007 and entitled Drug Delivery Methods, Structures, and
Compositions for Nasolacrimal System); U.S. U.S. application Ser.
No. 12/332,219 (filed Dec. 10, 2008 and entitled Drug Delivery
Methods, Structures, and Compositions for Nasolacrimal System);
U.S. Application Ser. No. 60/787,775 (filed Mar. 31, 2006 and
entitled Nasolacrimal Drainage System Implants for Drug Therapy);
U.S. application Ser. No. 11/695,545 (filed Apr. 2, 2007 and
entitled Nasolacrimal Drainage System Implants for Drug Therapy);
U.S. Application Ser. No. 60/585,287 (filed Jul. 2, 2004 and
entitled Treatment Medium Delivery Device and Methods for Delivery
of Such Treatment Mediums to the Eye Using Such a Delivery Device);
U.S. application Ser. No. 11/571,147 (filed Dec. 21, 2006 and
entitled Treatment Medium Delivery Device and Methods for Delivery
of Such Treatment Mediums to the Eye Using Such a Delivery Device);
U.S. Application Ser. No. 60/970,696 (filed Sep. 7, 2007 and
entitled Expandable Nasolacrimal Drainage System Implants); U.S.
Application Ser. No. 60/974,367 (filed Sep. 21, 2007 and entitled
Expandable Nasolacrimal Drainage System Implants); U.S. Application
Ser. No. 60/970,699 (filed Sep. 7, 2007 and entitled Manufacture of
Drug Cores for Sustained Release of Therapeutic Agents); U.S.
Application Ser. No. 60/970,709 (filed Sep. 7, 2007 and entitled
Nasolacrimal Drainage System Implants for Drug Delivery); U.S.
Application Ser. No. 60/970,720 (filed Sep. 7, 2007 and entitled
Manufacture of Expandable Nasolacrimal Drainage System Implants);
U.S. Application Ser. No. 60/970,755 (filed Sep. 7, 2007 and
entitled Prostaglandin Analogues for Implant Devices and Methods);
U.S. Application Ser. No. 60/970,820 (filed Sep. 7, 2007 and
entitled Multiple Drug Delivery Systems and Combinations of Drugs
with Punctal Implants); U.S. Application Ser. No. 61/066,223 (filed
Feb. 18, 2008 and entitled Lacrimal Implants and Related Methods);
U.S. Application Ser. No. 61/049,347 (filed Apr. 30, 2008 and
entitled Lacrimal Implants and Related Methods); U.S. Application
Ser. No. 61/033,211 (filed Mar. 3, 2008 and entitled Lacrimal
Implants and Related Methods); U.S. Application Ser. No. 61/049,360
(filed Apr. 30, 2008 and entitled Lacrimal Implants and Related
Methods); U.S. Application Ser. No. 61/052,595 (filed May 12, 2008
and entitled Lacrimal Implants and Related Methods); U.S.
Application Ser. No. 61/075,309 (filed Jun. 24, 2008 and entitled
Lacrimal Implants and Related Methods); U.S. Application Ser. No.
61/154,693 (filed Feb. 23, 2009 and entitled Lacrimal Implants and
Related Methods); U.S. Application Ser. No. 61/209,036 (filed Mar.
2, 2009 and entitled Lacrimal Implants and Related Methods); U.S.
Application Ser. No. 61/209,630 (filed Mar. 9, 2009 and entitled
Lacrimal Implants and Related Methods); U.S. Application Ser. No.
61/036,816 (filed Mar. 14, 2008 and entitled Lacrimal Implants and
Related Methods); U.S. Application Ser. No. 61/271,862 (filed Jul.
27, 2009 and entitled Lacrimal Implants and Related Methods); U.S.
Application Ser. No. 61/252,057 (filed Oct. 15, 2009 and entitled
Lacrimal Implants and Related Methods); U.S. application Ser. No.
12/710,855 (filed Feb. 23, 2010 and entitled Lacrimal Implants and
Related Methods); U.S. Application Ser. No. 60/871,867 (filed Dec.
26, 2006 and entitled Drug Delivery Implants for Inhibition of
Optical Defects); U.S. application Ser. No. 14/521,543 (filed Dec.
31, 2009 and entitled Drug Delivery Implants for Inhibition of
Optical Defects); U.S. Application Ser. No. 61/052,068 (filed May
9, 2008 and entitled Sustained Release Delivery of Latanoprost to
Treat Glaucoma); U.S. Application Ser. No. 61/052,113 (filed May 9,
2008 and entitled Sustained Release Delivery of Latanoprost to
Treat Glaucoma); U.S. Application Ser. No. 61/108,777 (filed Oct.
27, 2008 and entitled Sustained Release Delivery of Latanoprost to
Treat Glaucoma); U.S. application Ser. No. 12/463,279 (filed May 8,
2009 and entitled Sustained Release Delivery of Active Agents to
Treat Glaucoma and Ocular Hypertension); U.S. Application Ser. No.
61/049,337 (filed Apr. 30, 2008 and entitled Lacrimal Implants and
Related Methods); U.S. application Ser. No. 12/432,553 (filed Apr.
29, 2009 and entitled Composite Lacrimal Insert and Related
Methods); U.S. Application Ser. No. 61/049,317 (filed Apr. 30, 2008
and entitled Drug-Releasing Polyurethane Lacrimal Insert); U.S.
application Ser. No. 12/378,710 (filed Feb. 17, 2009 and entitled
Lacrimal Implants and Related Methods); U.S. Application Ser. No.
61/075,284 (filed Jun. 24, 2008 and entitled Combination Treatment
of Glaucoma); U.S. application Ser. No. 12/490,923 (filed Jun. 24,
2009 and entitled Combination Treatment of Glaucoma); U.S.
Application Ser. No. 61/134,271 (filed Jul. 8, 2008 and entitled
Lacrimal Implant Body Including Comforting Agent); U.S. application
Ser. No. 12/499,605 (filed Jul. 8, 2009 and entitled Lacrimal
Implant Body Including Comforting Agent); U.S. Application Ser. No.
61/057,246 (filed May 30, 2008 and entitled Surface Treatment of
Implants and Related Methods); U.S. Application Ser. No. 61/132,927
(filed Jun. 24, 2008 and entitled Surface Treated Implantable
Articles and Related Methods); U.S. application Ser. No. 12/283,002
(filed Sep. 5, 2008 and entitled Surface Treated Implantable
Articles and Related Methods); U.S. application Ser. No. 12/231,989
(filed Sep. 5, 2008 and entitled Lacrimal Implants and Related
Methods); U.S. Application Ser. No. 61/049,317 (filed Apr. 30, 2008
and entitled Drug-Releasing Polyurethane Lacrimal Insert); U.S.
application Ser. No. 12/231,986 (filed Sep. 5, 2008 and entitled
Drug Cores for Sustained Release of Therapeutic Agents); U.S.
Application Ser. No. 61/050,901 (filed May 6, 2008 and entitled
Punctum Plug Detection); U.S. application Ser. No. 12/231,987
(filed Sep. 5, 2008 and entitled Lacrimal Implant Detection); U.S.
Application Ser. No. 61/146,860 (filed Jan. 23, 2009 and entitled
Sustained Release Delivery of One or More Anti-Glaucoma Agents);
U.S. Application Ser. No. 61/152,909 (filed Feb. 16, 2009 and
entitled Sustained Release Delivery of One or More Anti-Glaucoma
Agents); U.S. Application Ser. No. 61/228,894 (filed Jul. 27, 2009
and entitled Sustained Release Delivery of One or More
Anti-Glaucoma Agents); U.S. Application Ser. No. 61/277,000 (filed
Sep. 18, 2009 and entitled Drug Cores for Sustained Ocular Release
of Therapeutic Agents); U.S. application Ser. No. 12/692,452 (filed
Jan. 22, 2010 and entitled Sustained Release Delivery of One or
More Agents); U.S. Application Ser. No. 61/283,100 (filed Nov. 27,
2009 and entitled Lacrimal Implants Including Split and Insertable
Drug Core); International Application Serial No. PCT/US2010/058129
(filed Nov. 26, 2010, published as WO 2011/066479 and entitled
Lacrimal Implants Including Split and Insertable Drug Core); U.S.
Application Ser. No. 61/139,456 (filed Dec. 19, 2008 and entitled
Substance Delivering Punctum Implants and Methods); U.S.
application Ser. No. 12/643,502 (filed Dec. 21, 2009 and entitled
Substance Delivering Punctum Implants and Methods); U.S.
application Ser. No. 10/825,047 (filed Apr. 15, 2004 and entitled
Drug Delivery via Punctal Plug); U.S. application Ser. No.
12/604,202 (filed Oct. 22, 2009 and entitled Drug Delivery via
Ocular Implant); International Application Serial No.
PCT/US2005/023848 (filed Jul. 1, 2005, published as WO 2006/014434
and entitled Treatment Medium Delivery Device and Methods for
Delivery); International Application Serial No. PCT/US2007/065792
(filed Apr. 2, 2007, published as WO 2007/115261 and entitled Drug
Delivery Methods, Structures, and Compositions for Nasolacrimal
System); and International Application Serial No. PCT/US2007/065789
(filed Apr. 2, 2007, published as WO 2007/115259 and entitled
Nasolacrimal Drainage System Implants for Drug Therapy).
Occlusive Element
[0143] In an exemplary embodiment, the methods of the invention use
an implant having an occlusive element. An occlusive element can be
mounted to and expandable with the retention structure, described
below, to inhibit tear flow. An occlusive element may inhibit tear
flow through the lumen, and the occlusive element may cover at
least a portion of the retention structure to protect the lumen
from the retention structure. The occlusive element comprises an
appropriate material that is sized and shaped so that the implant
can at least partially inhibit, even block, the flow of fluid
through the hollow tissue structure, for example lacrimal fluid
through the canaliculus. The occlusive material may be a thin
walled membrane of a biocompatible material, for example silicone,
that can expand and contract with the retention structure. The
occlusive element is formed as a separate thin tube of material
that is slid over the end of the retention structure and anchored
to one end of the retention structure as described above.
Alternatively, the occlusive element can be formed by dip coating
the retention structure in a biocompatible polymer, for example
silicone polymer. The thickness of the occlusive element can be in
a range from about 0.01 mm to about 0.15 mm, and often from about
0.05 mm to 0.1 mm.
Retention
[0144] In various embodiments of the methods of the invention, an
implant including a retention structure is employed to retain the
implant in the punctum or canaliculus. The retention structure is
attached to or integral with the implant body. The retention
structure comprises an appropriate material that is sized and
shaped so that the implant can be easily positioned in the desired
tissue location, for example, the punctum or canaliculus. In some
embodiments, the drug core may be attached to the retention
structure via, at least in part, the sheath. In some embodiments,
the retention structure comprises a hydrogel configured to expand
when the retention structure is placed in the punctum. The
retention structure can comprise an attachment member having an
axially oriented surface. In some embodiments, expansion of the
hydrogel can urge against the axially oriented surface to retain
the hydrogel while the hydrogel is hydrated. In some embodiments,
the attachment member can comprise at least one of a protrusion, a
flange, a rim, or an opening through a portion of the retention
structure. In some embodiments, the retention structure includes an
implant body portion size and shape to substantially match an
anatomy of the punctum and canaliculus.
[0145] The retention structure may have a size suitable to fit at
least partially within the canalicular lumen. The retention
structure can be expandable between a small profile configuration
suitable for insertion and a large profile configuration to anchor
the retention structure in the lumen, and the retention structure
can be attached near the distal end of the drug core. In specific
embodiments, the retention structure can slide along the drug core
near the proximal end when the retention structure expands from the
small profile configuration to the large profile configuration. A
length of the retention structure along the drug core can be
shorter in the large profile configuration than the small profile
configuration.
[0146] In some embodiments, the retention structure is resiliently
expandable. The small profile may have a cross section of no more
than about 0.2 mm, and the large profile may have a cross section
of no more than about 2.0 mm. The retention structure may comprise
a tubular body having arms separated by slots. The retention
structure can be disposed at least partially over the drug
core.
[0147] In some embodiments, the retention structure is mechanically
deployable and typically expands to a desired cross sectional
shape, for example with the retention structure comprising a super
elastic shape memory alloy such as Nitinol.TM.. Other materials in
addition to Nitinol.TM. can be used, for example resilient metals
or polymers, plastically deformable metals or polymers, shape
memory polymers, and the like, to provide the desired expansion. In
some embodiments polymers and coated fibers available from
Biogeneral, Inc. of San Diego, Calif. may be used. Many metals such
as stainless steels and non-shape memory alloys can be used and
provide the desired expansion. This expansion capability permits
the implant to fit in hollow tissue structures of varying sizes,
for example canaliculae ranging from 0.3 mm to 1.2 mm (i.e. one
size fits all). Although a single retention structure can be made
to fit canaliculae from 0.3 to 1.2 mm across, a plurality of
alternatively selectable retention structures can be used to fit
this range if desired, for example a first retention structure for
canaliculae from 0.3 to about 0.9 mm and a second retention
structure for canaliculae from about 0.9 to 1.2 mm. The retention
structure has a length appropriate to the anatomical structure to
which the retention structure attaches, for example a length of
about 3 mm for a retention structure positioned near the punctum of
the canaliculus. For different anatomical structures, the length
can be appropriate to provide adequate retention force, e.g. 1 mm
to 15 mm lengths as appropriate.
[0148] Although the implant body may be attached to one end of the
retention structure as described above, in many embodiments the
other end of the retention structure is not attached to the implant
body so that the retention structure can slide over the implant
body including the sheath body and drug core while the retention
structure expands. This sliding capability on one end is desirable
as the retention structure may shrink in length as the retention
structure expands in width to assume the desired cross sectional
width. However, it should be noted that many embodiments may employ
a sheath body that does not slide in relative to the core.
[0149] In many embodiments, the retention structure can be
retrieved from tissue. A projection, for example a hook, a loop, or
a ring, can extend from a portion of the implant body to facilitate
removal of the retention structure.
[0150] In some embodiments the sheath and retention structure can
comprise two parts.
[0151] In certain embodiments, the lacrimal implants used with the
present methods have exceptional retention properties, and are
retained in the punctum and canaliculus for a period that is
enhanced relative to a commercially available plug (FIG. 9) based
upon the percentage of eyes in which an implant was implanted
retaining the implant over a selected time period. In other
embodiments, the retention properties of the present lacrimal
implants of FIG. 33 were evaluated demonstrating superior retention
rates over a period of weeks. See, FIGS. 34-39.
[0152] In an exemplary embodiment, the method of the invention uses
a lacrimal implant configured to remain implanted in a punctum for
at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks,
7 weeks, 8, weeks, 9 weeks 10 weeks, 11 weeks, or at least about 12
weeks or more. In an exemplary embodiment, the lacrimal implant is
configured to be retained by the puncta for the duration of the
intended sustained release of the therapeutic agent. In various
embodiments, the duration of the intended sustained release of the
therapeutic agent is at least about 1 week, 2 weeks, 3 weeks, 4
weeks, 5 weeks, 6 weeks, 7 weeks, 8, weeks, 9 weeks 10 weeks, 11
weeks, or at least about 12 weeks or more. In various embodiments
at least about 95%, at least about 90%, at least about 85% or at
least about 80% of the implanted implants are retained for the
duration of the intended controlled release of the therapeutic
agent. In an exemplary embodiment, the implant is retained by the
puncta for a length of time to show therapeutic efficacy.
[0153] In various embodiments, the present invention provides for
the use of implants having structural features that enhance the
retention of the implant in a puncta. Amongst other features, the
heel of the present implant (e.g., 330) is configured to come to
rest in the lacrimal canaliculus ampulla (e.g., 252), effectively
locking the implant into place. However, the Applicants have
recognized that to prevent rotation and relative movement of the
implanted device, which plays a role in the displacement of the
device, a first member was needed to maintain the heel in the
ampula. Thus, the first member, e.g., 305, is configured to
stabilize the punctal plug within the lacrimal canaliculus, prevent
rotation and maintain positioning of the plug when the surrounding
tissue moves.
[0154] FIGS. 3-6 illustrate exemplary embodiments of lacrimal
implants of use in the methods of the invention. The exemplary
implants are insertable through a lacrimal punctum 212, 214 and
into its associated canaliculus 208, 210. Exemplary lacrimal
implants of use in the present invention comprise a first member, a
second member and a heel, such as the first member 305, the second
member 310 and the third member or heel 330 depicted in FIG. 3A.
Exemplary lacrimal implants further comprise a bore that is formed
in the heel, for example, the bore 385 formed in the third member
or heel 330 in FIG. 3A. In some embodiments, exemplary lacrimal
implants further comprise a cavity 458 (e.g., lacrimal implants
illustrated in FIG. 4A).
[0155] Referring to FIG. 3A, where a perspective view of an
exemplary lacrimal implant 300 of use in the present methods is
depicted, the first member 305 is characterized by a first axis A
and the second member 310 is characterized by a second axis B.
[0156] The third member or heel 330 is configured to connect the
first member 305 and the second member 310 at a first angle
.theta..sub.1, where .theta..sub.1 is defined by the first axis A
with respect to the second axis B. For instance, in FIG. 3A, the
first angle .theta..sub.1 refers to the angle originating at the
first axis A and turning counterclockwise from the first axis A to
the second axis B. In some embodiments, the first axis A and the
second axis B are in the same plane and intersect each other. In
some embodiments, the first axis A is in a plane other than the
plane of the second axis B, and the first axis A and the second
axis B do not intersect. In such embodiments, the first angle
.theta..sub.1 refers to the angle defined by a parallel line of the
first axis A with respect to the second axis B. This parallel line
of the first axis A lies in the same plane as the second axis and
intersects with the second axis.
[0157] In some embodiments, the first angle .theta..sub.1 is from
about 30 degrees to about 150 degrees, from about 45 degrees to
about 135 degrees, or from about 75 degrees to about 105 degrees.
For example, in some embodiments, the first angle .theta..sub.1 is
approximately 90 degrees.
[0158] In some embodiments, the overall dimension of the implant
along the first axis is from about 4 mm to about 8 mm. In an
exemplary embodiment, the overall dimension along the first axis is
about 5 mm to about 7 mm. In various embodiments, the overall
dimension along the first axis is about 6.3 mm.
[0159] In various embodiments, the overall dimension along the
second axis B is from about 1 mm to about 3 mm, e.g., from about
1.2 mm to about 1.9 mm.
[0160] In some embodiments, the overall dimension along the first
axis is approximately 6.3 mm and the overall dimension along the
second axis is approximately 1.2 mm. In various embodiments, the
overall dimension along the first axis is approximately 6.3 mm and
the overall dimension along the second axis is approximately 1.9
mm. In some embodiments, the overall dimension along the first axis
is approximately 4.8 mm and the overall dimension along the second
axis is approximately 1.9 mm.
First Member 305
[0161] In some embodiments, the first member 305 is configured to
extend into a canaliculus, while the second member 310 is
configured to reside in the vertical portion 220, 222 of the
canaliculus and to extend to the opening of, or out of the opening
of, the associated puncta. When a lacrimal implant 300 of such
configuration is inserted into a canaliculus, the intersection of
the first axis A and the second axis B resides generally at a
curvature of the canaliculus, such as the canaliculus curvature 250
in FIG. 2. In some embodiments, the first member 305 and the second
member 310 are connected at the first angle, and that angle is at
least about 45 degree, thereby forming an angled intersection
between the first member and the second member. In various
embodiments, when the lacrimal implant 300 is positioned in the
lacrimal canaliculus, at least a portion of the angled intersection
is biased against a canaliculus curvature of the lacrimal
canaliculus. In this embodiment, the lacrimal implant 300 uses
anatomical structures to facilitate the retention of the implanted
lacrimal implant 300.
[0162] FIG. 3B depicts a side view of an exemplary lacrimal implant
300 of the invention. In some embodiments, the first member 305
includes an intermediate segment 315, a tip segment or tip 325, and
a forward segment 320 in between the forward segment and tip
segment. While the intermediate segment 315 is configured to be
connected to the second member 310 by the third member or heel 330,
the tip segment or tip 325 is configured to be inserted through a
punctum prior to the other two segments of the first member 305 and
prior to the other members of the lacrimal implant 300.
[0163] In some embodiments, the intermediate segment 315, the
forward segment 320 and the tip segment or tip 325 are
distinguishable from each other in general by their shapes. For
example, in some embodiments, the intermediate segment 315 has a
generally cylindrical shape with a diameter that is larger than the
diameter of the tip segment or tip 325. In various embodiments, the
forward segment 320 is tapered and has a conical shape, such that
the forward segment 320 connects the intermediate segment 315 at
one end and the tip segment or tip 325 at the other end. In some
embodiments, the transition from the intermediate segment 315 to
the forward segment 320 or the transition from the forward segment
320 to the tip segment or tip 325 is gradual and smooth such that
no distinguishable edge exists at the transition.
[0164] In some embodiments, the intermediate segment 315 has a
cylindrical shape. In various embodiments, the intermediate segment
has a circular cross section, an elliptic cross section, or a
polygonal cross section. The intermediate segment 315 is of any
useful combination of length and diameter.
[0165] In some embodiments, the intermediate segment 315 has a
diameter that is from about 0.4 mm to about 0.8 mm. For example, in
some embodiments the diameter of the intermediate segment 315 is
from about 0.53 mm to about 0.63 mm. In some embodiments, the
intermediate segment 315 has a length along the first axis A that
is from about 0.5 mm to about 3.5 mm. For example, in some
embodiments the length of the intermediate segment 315 is from
about 1 mm to about 2.8 mm.
[0166] In some embodiments, the tip segment or tip 325 is
substantially a semi-sphere, or a portion of a semi-sphere. In
exemplary embodiments, the semi-sphere, or portion therapy, has a
radius that is from about 0.05 mm to about 0.3 mm. For example, in
some embodiments, the radius of the tip segment or tip 325 is
approximately 0.20 mm.
[0167] In some embodiments, the forward segment 320 has a conical
configuration, tapering from the diameter of the intermediate
segment 315 as it approaches the tip segment or tip 325. In some
embodiments, the forward segment 320 is short and is tapered
steeply, thus forming a wider taper angle. The forward segment 320
can also be long and tapered more gradually, thus forming a
narrower taper angle. The tapering angle .theta..sub.3 is
illustrated in FIG. 3E. In some embodiments, the tapering angle
.theta..sub.3 is from about 2.degree. to about 10.degree.. For
example, in some embodiments the tapering angle .theta..sub.3 is
from about 3.8.degree. to about 7.8.degree.. In some embodiments,
.theta..sub.3 is about 7.8.degree.. In some embodiments, the
forward segment 320 has a length along the first axis A that is
from about 1 mm to about 5 mm. For example in some embodiments the
length of forward segment 320 is from about 1.7 mm to about 3.5
mm.
Second Member 310
[0168] Referring to FIG. 3B, in some embodiments of implants of use
in the present method, the second member 310 includes an upright
segment 335 that extends from the third member or heel 330
generally along the direction of the second axis B. In various
embodiments, the second member 310 further includes a head segment
340 that attaches to the upright segment 335 at an end opposite to
the third member or heel 330. In some embodiments, the second
member 310 is configured such that the upright segment 335 resides
in the vertical portion of the canaliculus while the head segment
340 contacts the tissue surrounding the exterior of the punctum
when the lacrimal implant 300 is positioned in the lacrimal
canaliculus. In an exemplary embodiment, illustrated in FIGS.
3A-3F, the upright segment 335 has a cylindrical shape and the head
segment 340 has an oval or oblong configuration. However, it will
be appreciated that any other suitable shapes or configurations can
be used and are within the scope of the present invention. For
example, in various embodiments, the upright segment 335 is
configured to be a conical; the head segment 340 is configured to
have a circular, elliptical or polygonal cross section.
[0169] In some embodiments, the upright segment 335 has a
characteristic diameter that is from about 0.7 mm to about 0.9 mm.
For example, in some embodiments, the characteristic diameter of
the upright segment 335 is about 0.8 mm.
[0170] In some embodiments, the upright segment 335 has a length in
the direction of the second axis B that is from about 0.7 mm to
about 1.5 mm. For example, in some embodiments the length of
upright segment 335 along the direction of the second axis B is
about 0.9 mm.
[0171] Generally, the head segment 340 has a cross section
characterized by a minor axis and a major axis. The minor axis and
the major axis refer to the shortest characteristic diameter and
the longest characteristic diameter of the cross section,
respectively. As such, the minor axis is equal to or less than the
major axis. For instance, in some embodiments where the head
segment 340 has a circular cross section, the minor axis and the
major axis are of equal length. In various embodiments, the head
segment 340 has an oval or oblong cross section, and the minor axis
is shorter than the major axis. In some embodiments, the head
segment 340 is elongated in a direction that is parallel to the
first axis A. The major axis indicates the extension of the first
member 305 and facilitates positioning of the lacrimal implant 300
in the punctum and canalinculus. In some embodiments, the major
axis is from about 1.5 mm to about 2.5 mm. In various embodiments,
the minor axis is from about 1 mm to about 1.5 mm. For example, in
some embodiments, the major axis and the minor axis head segment
340 are approximately 1.9 mm and 1.3 mm respectively. In some
embodiments, the head segment 340 has a thickness in the direction
of the second axis that is from about 0.2 mm to about 0.4 mm. For
example, in some embodiments, the thickness of the head segment 340
in the direction of the second axis is approximately 0.3 mm.
[0172] Referring still to FIG. 3B, exemplary head segment 340
comprises an under-surface 350 facing towards the third member or
heel 330 and an outer-surface 355 that faces away from the third
member or heel 330. Exemplary head segment 340 further comprises an
edge surface 345 that couples the under-surface 350 and the
outer-surface 355. The distance between the under-surface 350 and
the outer-surface 355 can be readily varied. In some embodiments,
the distance is from about 0.2 mm to about 0.4 mm.
[0173] In some embodiments, the outer-surface 355 is smaller than
the under-surface 350 and is substantially flat. In various
embodiments, the edge surface 345 is tapered, curved, angular, or
multifaceted. In some embodiments, the edge surface 345 has a
radius of curvature that is from about 0.2 mm to about 0.7 mm. In
some embodiments, the under-surface 350 is in general flat and is
configured to contact the exterior tissue surrounding the punctum
when the lacrimal implant 300 is positioned in the lacrimal
canaliculus.
Third Member or Heel 330
[0174] In some embodiments, the third member or heel 330 includes
an upper surface 360, a lower surface 365, and side surfaces 370.
In the illustrated embodiments, the bore 385 extends from the upper
surface 360 into the third member or heel 330. In some embodiments,
the upper surface 360 and the lower surface 365 are substantially
flat and separated from each other by a distance. Such distance is
readily variable and is typically about 0.3 mm to about 0.7 mm. For
instance, in some embodiments, the upper surface 360 and the lower
surface 365 are separated by a distance that is from about 0.4 mm
to 0.6 mm (e.g., about 0.53 mm). In some embodiments, the upper
surface 360 extends beyond the intersection with the second member
310. In some embodiments, the upper surface 360 extends beyond the
intersection with the second member 310 for a distance that is from
about 0.3 to about 0.6 mm. The upper surface 360 can also be joined
with the side surfaces 370. In various embodiments, upper surface
360 and side surfaces 370 are joined by a curved intersection 380.
In some embodiments, the curved intersection 380 has a radius of
curvature that is from about 0.04 mm to about 0.08 mm.
[0175] Referring now to FIGS. 3D and 3F, in some embodiments, the
third member or heel 330 includes a heel connecting segment 375
configured to couple the third member or heel 330 to the first
member 305, or to the intermediate segment 315 of the first member
305. The heel connecting segment 375 is of readily variable shape,
including flat or curved structures. In FIG. 3F, a width of the
heel connecting segment 375 in the direction of the second axis B
varies along the direction of the first axis A. For example, the
heel connecting segment 375 has a smaller width at or near the side
surfaces 370 than the diameter of the intermediate segment 315 of
the first member 305. In some embodiments, at or near the
intersection with the intermediate segment 315, the heel connecting
segment 375 increases the width and thus forms a notch as depicted
in FIG. 3F. It will be appreciated that the notch can be either
deeper or shallower along both the first axis A and the second axis
B before it meets the first member 305 or the second member
310.
[0176] A notch is not a required feature in the implants of the
present invention. In some embodiments, the heel connecting segment
375 has the same dimension as the diameter of the intermediate
segment 315. For example, the thickness of the third member or heel
330 along the second axis B is equal to the diameter of the
intermediate segment 315 of the first member 305. For example, in
some embodiments, both the thickness of the third member or heel
330 in the direction of the second axis B and the diameter of the
intermediate segment 315 are from about 0.53 mm to about 0.63 mm.
In such configurations, the third member or heel 330 couples with
the intermediate segment 315 without forming a notch, as
illustrated by the alternative heel connecting segment 675 in FIG.
6.
[0177] By way of illustration, the third member or heel 330
depicted in FIGS. 3A-3F is substantially parallel to the first axis
A of the first member 305. It would be appreciated that this is
unnecessary. In some embodiments, the third member or heel 330 can
form an angle with relation to the first axis A.
Bore 385
[0178] Exemplary structures of the bore 385 are detailed in FIGS.
3E and 3F, where a cross sectional view and a partial enlarged
cross sectional view of the lacrimal implant 300 are provided. The
bore 385 is configured to receive a tip or other protrusion of an
external insertion tool for facilitating insertion of the lacrimal
implant 300 into a lacrimal punctum. See FIG. 7. The configuration,
including size, shape, angle (O.sub.2) and position of the bore in
the heel are readily adjustable to facilitate the mating of the
insertion tool with the bore, the flexibility of the heel, or the
retention of the lacrimal implants. Depending on the purpose or use
of the implant and the materials used for making the heel, the
characteristics of the bore noted above are readily varied.
Configurations of the bore 385 disclosed herein are illustrative
and any other suitable configurations are within the scope of the
present invention.
[0179] In FIG. 3F, an exemplary bore 385 is characterized by a
third axis C and a second angle .theta..sub.2 that is defined by
the first axis with respect to the third axis A in a similar way as
the first angle .theta..sub.1. In some embodiments, the second
angle .theta..sub.2 is from about 15.degree. to about 90.degree..
For example, in some embodiments, the second angle .theta..sub.2 is
about 45.degree..
[0180] In some embodiments, the bore 385 has a depth along the
direction of the third axis C that is from about 0.3 mm to about
0.7 mm. For example, in some embodiments the depth of the bore 385
is approximately 0.4 mm and in some embodiments is approximately
0.6 mm. The bore 385 may include a bore shaft 390 that is generally
cylindrical, with a circular, elliptical, oval, or polygonal cross
section. The bore 385 may further include a bore tip 395 at which
the bore shaft 390 terminates. An exemplary bore tip 395 generally
has a semispherical configuration. In some embodiments, the bore
shaft 390 has a characteristic diameter that is from about 0.1 mm
to about 0.3 mm. In some embodiments, the characteristic diameter
of the bore is approximately 0.17 mm. As will be appreciated, the
shapes, sizes, orientations disclosed in the present application
are illustrative, and any other suitable shapes, sizes, or
orientations are within the scope of the present application. In
addition, it will be appreciated that the opening of the bore can
be positioned closer to the second member or closer to the edge of
the heel.
Cavity 458
[0181] FIG. 4A-4C illustrates an exemplary lacrimal implant 400
that is insertable through a lacrimal punctum 212, 214 and into its
associated canaliculus 208, 210. In FIG. 4A, the lacrimal implant
400 comprises a cavity 458 that is configured to house a
therapeutic agent core, also referred to herein as a drug core, or
other materials for release into an eye or surrounding tissues for
treatment of various ocular, sinus or other diseases.
[0182] In the illustrated exemplary embodiment, the cavity 458 is
formed in the head segment 340 and has an opening through the
outer-surface 355. The cavity 458 can be shallow such that it stays
within the head segment 340. The cavity 458 can be also deeper and
extend beyond the head segment 340 and into the upright segment
335. Illustrated exemplary cavity 458 is in general substantially
cylindrical with a circular cross section. Any other suitable
configuration is within the scope of the present application. For
example, in some embodiments, the cavity 458 has a truncated
spherical configuration, or has a cylindrical configuration with an
oblong or a polygonal cross section.
[0183] In some embodiments, the cavity 458 has a depth in the
direction of the second axis B that is about from 0.2 mm to about
1.4 mm. For example, in some embodiments, the depth of the cavity
458 is approximately 1.2 mm. In some embodiments, the cavity 458
has a diameter that is from about 0.3 mm to about 0.7 mm. For
example, in some embodiments the diameter of the cavity 458 is from
about 0.42 mm to about 0.55 mm. In an exemplary embodiment, the
cavity 458 extends into the upright segment 335, and the diameter
of the cavity 458 is smaller than the diameter of the upright
segment 335.
[0184] Referring to FIG. 4C, the cavity 458 includes a bottom 482.
In various embodiments, the bottom 482 is rounded. In various
embodiments, the rounded bottom has a radius of curvature that is
from about 0.03 mm to about 0.07 mm.
[0185] FIG. 5 depicts exemplary configurations of the cavity 458.
In FIG. 5, the cavity 458 includes a lip 584 or other retaining
structure positioned at the opening of the cavity 458. The lip 584
or the other retaining structure are optionally configured to
partially enclose the cavity 458, e.g, prevent a therapeutic agent
core or other materials from moving out of the cavity 458. In some
embodiments, the lip 584 is a square cross sectional annulus that
extends down from the outer-surface 355 into the cavity 458 and
extends inwardly towards the center of the opening of the cavity
458. In some embodiments, the lip 584 is of a tab configuration and
includes a plurality of spaced lips that extend inwardly into the
opening of the cavity 458. The lip 584 may extend downwardly from
about 0.02 mm to about 0.1 mm and inwardly from about 0.02 mm to
about 0.1 mm. For example, in some embodiments, the lip 584 extends
about 0.05 mm downwardly or inwardly.
Formation of Lacrimal Implants
[0186] Exemplary lacrimal implants of use in methods of the present
invention are made of various materials including plastic, rubber,
polymer, or composite. Exemplary lacrimal implants of the present
invention formed from one or more material including plastic,
rubber, polymer, composites, or other appropriate materials. In
some embodiments, the lacrimal implants are formed from liquid
silicone rubber. For instance, in exemplary embodiments, lacrimal
implants are formed from a material marketed as NuSil 4840 liquid
silicone rubber, NuSil 4870, or a mixture including such a liquid
silicone rubber. Examples of such a mixture include a material
marketed as 6-4800, which comprises NuSil 4840 with from about 1%
to about 5%, e.g., from about 2% to about 4% 6-4800.
[0187] In some embodiments, the lacrimal implant is formed from
biodegradable materials, for instance, biodegradable elastic
materials including cross-linked polymers, such as poly (vinyl
alcohol). In some embodiments, the lacrimal implant can comprise a
co-polymer, such as silicone/polyurethane co-polymer,
silicone/urethane, silicone/poly (ethylene glycol) (PEG), and
silicone/2hydroxyethyl methacrylate (HEMA). As discussed in
commonly-owned Utkhede et al., U.S. Patent Publication No.
2009/0104243, entitled "DRUG CORES FOR SUSTAINED RELEASE OF
THERAPEUTIC AGENTS," filed Sep. 5, 2008, which is herein
incorporated by reference in its entirety, urethane-based polymer
and copolymer materials allow for a variety of processing methods
and bond well to one another.
[0188] The hardness of the material is selected to facilitate or
alter the retention of the lacrimal implant within the lacrimal
punctum and its associated canaliculus. Accordingly, in some
embodiments, a material having a durometer rating of from about 20D
to about 80D, e.g., about 30D to about 70D, e.g., from about 40D to
about 60D is of use to adjust parameters such as patient comfort
and retention. For example, in some embodiments, the durometer
rating of the material used to form the lacrimal implants is
approximately 40D. Materials other than those exemplified above
providing a durometer rating for the lacrimal implants within the
stated ranges, and particularly that is about 40D are also of use.
In some embodiments, a harder material or softer material is
utilized for the entire lacrimal implant or for portions thereof.
In such case, the lacrimal implants are formed from the materials
that provide a durometer rating of about 70D.
[0189] In some embodiments, the lacrimal implants of use in the
present methods are formed of multiple materials, where certain
members or portions of the lacrimal implants are formed with
materials having different properties. For example, in some
embodiments the first member 305 is formed of a harder durometer
rated material while the second member 310 is formed of a softer
durometer rated material. In some embodiments, the first member 305
is formed of a softer durometer rated material while the second
member 310 is formed of a harder durometer rated material. In some
embodiments the third member or heel 330 is formed of a harder
durometer rated material than one or more parts of the remainder of
the second member 310. In various embodiments, the third member or
heel 330 is formed of a softer durometer rated material than the
remainder of the second member 310.
[0190] In certain embodiments, the implant comprises a contrast
agent to aid in detection of the inserted lacrimal implant. See, US
Patent Publication No. 2009/0099626, filed Sep. 5, 2008 entitled
LACRIMAL IMPLANT DETECTION. In one embodiment, the contrast agent
is a dye or pigment. In another embodiment, a green colorant is
added during the manufacturing process of the lacrimal implant. In
certain embodiments, this green colorant is premixed with the NuSil
liquid silicone rubber to form a green lacrimal implant.
[0191] Exemplary implants of use in the invention can be formed by
methods known in the art, including, but not limited to, machining
a blank to the desired shape and size and molding the material
forming the implant.
Insertion Tools
[0192] Installing the lacrimal implant of use in the invention can
be facilitated by the use of an insertion tool. For example, in
some embodiments the lacrimal implants and/or the inserter tool may
include features or components that are found in U.S. Patent
Application Publication No. 2009/0104248, U.S. Patent Application
Publication No. 2010/0274204, U.S. Patent Application Publication
No. 2009/0105749 and International Patent Application Publication
No. WO 2011/066479, both of which are incorporated herein by
reference in their entirety.
[0193] Turning to FIG. 7, an exemplary insertion tool is shown
engaged with an implant of the invention through meeting of pin 760
and insertion of the lacrimal implants into a lacrimal punctum. The
lacrimal implants include the exemplary embodiments disclosed
above, variations thereof, or any similar structures.
3) Sustained Release Formulations
[0194] Conventional drug delivery involving frequent periodic
dosing is not ideal or practical in many instances. For example,
with more toxic drugs, conventional periodic dosing can result in
unfavorably high initial drug levels at the time of dosing,
followed by low drug levels between doses often times below levels
of therapeutic value. Likewise, conventional periodic dosing may
not be practical or therapeutically effective in certain instances
such as with pharmaceutical therapies targeting areas of the inner
eye or brain in need of treatment such as the retina. Accordingly,
in certain embodiments, the lacrimal implant further comprises one
or more therapeutic agents within its structure. In certain
embodiments, the therapeutic agent is dispersed throughout the
device (e.g. providing a saturated or impregnated implant). In
other certain embodiments, the therapeutic agent is located at one
or more distinct locations or zones of the implant. In an exemplary
embodiment, the therapeutic agent is located in a cavity of the
device and the component holding the therapeutic agent is referred
to as a drug core. This drug core may comprise additional component
such as an impermeable sheath to prevent migration of the
therapeutic drug through the lacrimal implant and/or provide
direction for the drug migration.
[0195] In certain embodiments, in which the agent is dispersed
throughout the device, the rate and location of release of the
agent is controlled by coating at least a component of the device
with a material that is impermeable to the drug. In an exemplary
embodiment, essentially the entire device is coated with the
material with the exception of one or more gaps in the material
through which the agent can elute into the eye or surrounding
tissue. An exemplary coating is a Parylene coating (See, US Patent
Publication No. 2008/0181930, herein incorporated by
reference).
[0196] In one embodiment, the lacrimal implant of the invention is
configured as a sustained release device, releasing the
incorporated therapeutic agent in a therapeutically effective
manner, e.g., at a rate that provides a therapeutically effective
dosage for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 7 weeks, 8, weeks, 9 weeks 10 weeks, 11 weeks, or
at least about 12 weeks or more. In an exemplary embodiment, the
lacrimal implant is configured to be retained by the puncta for the
duration of the intended controlled release of the therapeutic
agent. In various embodiments, the duration of the intended
controlled release of the therapeutic agent is at least about 1
week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8,
weeks, 9 weeks 10 weeks, 11 weeks, or at least about 12 weeks or
more. In various embodiments at least 95% of the implanted implants
are retained for the duration of the intended controlled release of
the therapeutic agent. In an exemplary embodiment, the implant is
retained by the puncta for a length of time to show therapeutic
efficacy.
[0197] In an exemplary embodiment, the implant is formatted as a
unit dosage of the therapeutic agent. In various embodiments, the
implant is formatted as a unit dosage of an antiglaucoma agent. In
an exemplary embodiment, the antiglaucoma agent is a
prostaglandin.
Therapeutic Agent (Drug) Core
[0198] In an exemplary embodiment, the methods of the invention
utilize an implant including a distinct therapeutic agent core or
integrated drug or other agent disposed in at least one of the
first member 305 or the second member 310 of the implant body, to
provide a sustained release of a therapeutic agent. For instance,
the drug core or integrated drug or other agent disposed may be
disposed in the cavity 458 of the lacrimal implant 400 to provide a
sustained drug or other therapeutic agent release.
[0199] An exemplary implant of use in the methods of the invention
is configured to deliver a therapeutic agent to one or more of an
eye, nasal passage or inner ear system. In various embodiments, the
drug is delivered systemically to the subject through the eye. A
therapeutic agent core can comprise one or more therapeutic agents,
and in some examples, one or more matrix materials to provide
sustained release of the drug or other agents.
[0200] In various embodiments, the therapeutic agent core is
inserted into cavity 458.
[0201] In various examples, the distinct drug core or integrated
drug or other agent includes at least about 20 micrograms, at least
about 40 micrograms, at least about 45 micrograms, at least 80
micrograms, or at least 95 micrograms of a drug (e.g.,
latanoprost), such as is further discussed in commonly-owned
Butuner et al., U.S. Patent Publication No. 2009/0280158, entitled
"SUSTAINED RELEASE DELIVERY OF ACTIVE AGENTS TO TREAT GLAUCOMA AND
OCULAR HYPERTENSION," filed May 8, 2009, and commonly-owned
Butuner, U.S. Patent Publication No. US 2010/0209477, entitled
"SUSTAINED RELEASE DELIVERY OF ONE OR MORE AGENTS," filed Jan. 22,
2010, both of which are incorporated by reference in their
entirety, including their descriptions of drug or other agent
concentration and formulations.
[0202] The drug core can comprise one or more biocompatible
materials capable of providing a sustained release of the one or
more drugs or agents. The drug core can comprise a matrix including
a substantially non-biodegradable silicone matrix with dissolvable
inclusions of the drugs or agents located therein. The drug core
can include other structures that provide sustained release of the
drugs or agents, for example a biodegradable matrix, a porous drug
core, a liquid drug core or a solid drug core. A matrix that
includes the drugs or agents can be formed from either
biodegradable or non-biodegradable polymers. In some examples, a
non-biodegradable drug core can include silicone, acrylates,
polyethylenes, polyurethane, polyurethane, hydrogel, polyester
(e.g., DACRON.TM. from E.I. Du Pont de Nemours and Company,
Wilmington, Del.), polypropylene, polytetrafluoroethylene (PTFE),
expanded PTFE (ePTFE), polyether ether ketone (PEEK), nylon,
extruded collagen, polymer foam, silicone rubber, polyethylene
terephthalate, ultra high molecular weight polyethylene,
polycarbonate urethane, polyurethane, polyimides, stainless steel,
nickel-titanium alloy (e.g., Nitinol), titanium, stainless steel,
cobalt-chrome alloy (e.g., ELGILOY.TM. from Elgin Specialty Metals,
Elgin, Ill.; CONICHROME.TM. from Carpenter Metals Corp.,
Wyomissing, Pa.). In some examples, a biodegradable drug core can
comprise one or more biodegradable polymers, such as protein,
hydrogel, polyglycolic acid (PGA), polylactic acid (PLA),
poly(L-lactic acid) (PLLA), poly(L-glycolic acid) (PLGA),
polyglycolide, poly-L-lactide, poly-D-lactide, poly(amino acids),
polydioxanone, polycaprolactone, polygluconate, polylactic
acid-polyethylene oxide copolymers, modified cellulose, collagen,
polyorthoesters, polyhydroxybutyrate, polyanhydride,
polyphosphoester, poly(alpha-hydroxy acid) and combinations
thereof. In some examples, the drug core can comprise a hydrogel
polymer.
[0203] The therapeutic agent can be present in the device in a
formulation with a pharmaceutically acceptable carrier, e.g.,
excipients, suspending agents, diluents, fillers, salts, buffers,
stabilizers, solubilizers, solvents, dispersion media, coatings,
isotonic agents, and other materials known in the art. The
pharmaceutical formulation optionally includes potentiators,
complexing agents, targeting agents, stabilizing agents,
cosolvents, pressurized gases, or solubilizing conjugates.
[0204] Exemplary excipients include sugars such as lactose,
sucrose, mannitol, or sorbitol; cellulose preparations such as,
maize starch, wheat starch, rice starch, potato starch, gelatin,
gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose,
sodium caroxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
Preferred excipients include lactose, gelatin, sodium carboxymethyl
cellulose, and low molecular weight starch products.
[0205] Exemplary suspending agents that can serve as valve
lubricants in pressurized pack inhaler systems are desirable. Such
agents include oleic acid, simple carboxylic acid derivatives, and
sorbitan trioleate.
[0206] Exemplary diluents include water, saline, phosphate-buffered
citrate or saline solution, and mucolytic preparations. Other
diluents that can be considered include alcohol, propylene glycol,
and ethanol; these solvents or diluents are more common in oral
aerosol formulations. Physiologically acceptable diluents that have
a tonicity and pH compatible with the alveolar apparatus are
desirable. Preferred diluents include isotonic saline, phosphate
buffered isotonic solutions whose tonicity have been adjusted with
sodium chloride or sucrose or dextrose or mannitol.
[0207] Exemplary fillers include glycerin, propylene glycol,
ethanol in liquid or fluid preparations. Suitable fillers for dry
powder inhalation systems include lactose, sucrose, dextrose,
suitable amino acids, and derivatives of lactose. Preferred fillers
include glycerin, propylene glycol, lactose and certain amino
acids.
[0208] Exemplary salts include those that are physiologically
compatible and provide the desired tonicity adjustment. Monovalent
and divalent salts of strong or weak acids are desirable. Preferred
salts include sodium chloride, sodium citrate, ascorbates, sodium
phosphates.
[0209] Exemplary buffers include phosphate or citrate buffers or
mixed buffer systems of low buffering capacity. Preferred buffers
include phosphate or citrate buffers.
[0210] Table 1 shows exemplary drug insert silicones that may be
used and associated cure properties, according to embodiments of
the present invention. The drug core insert matrix material can
include a base polymer comprising dimethyl siloxane, such as
MED-4011, MED 6385 and MED 6380, each of which is commercially
available from NuSil. The base polymer can be cured with a cure
system such as a platinum-vinyl hydride cure system or a tin-alkoxy
cure system, both commercially available from NuSil. In many
embodiments, the cure system may comprise a known cure system
commercially available for a known material, for example a known
platinum vinyl hydride cure system with known MED-4011. In a
specific embodiment shown in Table 1, 90 parts of MED-4011 can be
combined with 10 parts of the crosslinker, such that the
crosslinker comprises 10% of the mixture. A mixture with MED-6385
may comprise 2.5% of the crosslinker, and mixtures of MED-6380 may
comprise 2.5% or 5% of the crosslinker.
TABLE-US-00001 TABLE 1 Drug Insert Silicone Selections Crosslinker
Material Base Polymer Cure System Percent MED-4011 Dimethyl
siloxane Platinum vinyl 10% Silica filler hydride system material
10% MED-6385 Dimethyl siloxane Tin-Alkoxy 2.5% 2.5% Diatomaceous
earth filler material MED-6380 Dimethyl siloxane Tin-Alkoxy 2.5 to
5% without filler material
[0211] It has been determined according to the present invention
that the cure system and type of silicone material can affect the
curing properties of the solid drug core insert, and may
potentially affect the yield of therapeutic agent from the drug
core matrix material. In specific embodiments, curing of MED-4011
with the platinum vinyl hydride system can be inhibited with high
concentrations of drug/prodrug, for example over 20% drug, such
that a solid drug core may not be formed. In specific embodiments,
curing of MED-6385 or MED 6380 with the tin alkoxy system can be
slightly inhibited with high concentrations, e.g. 20%, of
drug/prodrug. This slight inhibition of curing can be compensated
by increasing the time or temperature of the curing process. For
example, embodiments of the present invention can make drug cores
comprising 40% drug and 60% MED-6385 with the tin alkoxy system
using appropriate cure times and temperatures. Similar results can
be obtained with the MED-6380 system the tin-alkoxy system and an
appropriate curing time or temperature. Even with the excellent
results for the tin alkoxy cure system, it has been determined
according to the present invention that there may be an upper
limit, for example 50% drug/prodrug or more, at which the
tin-alkoxy cure system may not produce a solid drug core. In many
embodiments, the latanoprost or other intraocular pressure-reducing
therapeutic agent(s) in the solid drug core may be at least about
5%, for example a range from about 5% to 50%, and can be from about
20% to about 40% by weight of the drug core.
[0212] In a specific embodiment, drug cores with two different
concentrations of Latanoprost are utilized in the method of the
invention.
[0213] In one embodiment of the present methods an implant with a
drug core with 46 .mu.g of Latanoprost was inserted into a lacrimal
implant, See Table 2.
TABLE-US-00002 TABLE 2 Latanoprost Punctal Plug Delivery System
(PPDS) Composition (46 .mu.g) L-PPDS, 46 .mu.g Material Specific
Formulation or ID Description with DMPC Latanoprost Chirogate
International GMP grade, neat oil 46.0 .mu.g Everlight Chemical
Industrial Corporation Silicone NuSil MED-6385 (MAF 970) Two part
medical grade formulation Part A - proprietary silicone 60.1 .mu.g
formulation Part B - stannous octoate 0.70 nL Crosslinker NuSil
MED5-6382 (MAF 1289) Only crosslinker is used from kit 2.1 nL
Dimyristoyl Nippon Fine Chemical GMP grade, white solid 8.6 .mu.g
Phosphatidylcholine (DMPC) Tubing Polyimide Polyimide tube length
(0.0155'' 0.95 mm inner diameter, with 0.0010'' wall - medical
grade) Cyanoacrylate Loctite .RTM. 4305 .TM. Medical grade ethyl
cyanoacrylate ~0.3 .mu.g adhesive with photoinitiator
[0214] In another embodiment, a drug core with 95 .mu.g of
Latanoprost was made and inserted into a lacrimal implant, see
Table 3.
TABLE-US-00003 TABLE 3 Latanoprost Punctal Plug Delivery System
(PPDS) Composition (95 .mu.g) L-PPDS, 95 .mu.g Material Specific
Formulation or ID Description with DMPC Latanoprost Everlight
Chemical Industrial GMP grade, neat oil 95.0 .mu.g Corporation
Silicone NuSil MED-6385 (MAF 970) Two part medical grade
formulation Part A - proprietary silicone 124.7 .mu.g formulation
Part B - stannous octoate 0.70 nL Crosslinker NuSil MED5-6382 (MAF
1289) Only crosslinker is used from kit 4.8 nL Dimyristoyl Nippon
Fine Chemical GMP grade, white solid 17.8 .mu.g Phosphatidylcholine
(DMPC) Tubing Polyimide Polyimide tube length (0.0220'' 0.95 mm
inner diameter, with 0.0010'' wall - medical grade) Cyanoacrylate
Loctite .RTM. 4305 .TM. Medical grade ethyl cyanoacrylate ~0.3
.mu.g adhesive with photoinitiator
[0215] Further discussion of drug-releasing or other
agent-releasing drug cores can be found in commonly-owned Utkhede
et al., U.S. Patent Publication No. 2009/0104243, entitled "DRUG
CORES. FOR SUSTAINED RELEASE OF THERAPEUTIC AGENTS," filed Sep. 5,
2008, which is herein incorporated by reference in its
entirety.
Sheath Body
[0216] In certain embodiments, the implant of use in the methods of
the invention includes a therapeutic agent core which is encased in
a sheath body. The sheath body can comprise appropriate shapes and
materials to control the migration of latanoprost or other
anti-glaucoma agents from the drug core. In some embodiments, the
sheath body houses the drug core and can fit snugly against the
core. The sheath body is made from a material that is substantially
impermeable to the therapeutic agent so that the rate of migration
of the agent may be largely controlled by the exposed surface area
of the drug core that is not covered by the sheath body. In certain
embodiments, migration of the therapeutic agent through the sheath
body can be about one tenth of the migration of the therapeutic
agent through the exposed surface of the drug core, or less, often
being one hundredth or less. In other words, the migration of the
therapeutic agent through the sheath body is at least about an
order of magnitude less that the migration of the therapeutic agent
through the exposed surface of the drug core. Suitable sheath body
materials include polyimide, polyethylene terephthalate
(hereinafter "PET"). The sheath body has a thickness, as defined
from the sheath surface adjacent the core to the opposing sheath
surface away from the core, from about 0.00025'' to about 0.0015''.
The total diameter of the sheath that extends across the core
ranges from about 0.2 mm to about 1.2 mm. The core may be formed by
dip coating the core in the sheath material. Alternatively or in
combination, the sheath body can comprise a tube and the core
introduced into the sheath, for example as a liquid or solid that
can be slid, injected or extruded into the sheath body tube. The
sheath body can also be dip coated around the core, for example dip
coated around a pre-formed core.
[0217] The sheath body can be provided with additional features to
facilitate clinical use of the implant. For example, the sheath may
receive a drug core that is exchangeable while the implant body,
retention structure and sheath body remain implanted in the
subject. The sheath body is often rigidly attached to the retention
structure as described above, and the core is exchangeable while
the retention structure retains the sheath body. In specific
embodiments, the sheath body can be provided with external
protrusions that apply force to the sheath body when squeezed and
eject the core from the sheath body. Another drug core can then be
positioned in the sheath body. In many embodiments, the sheath body
or retention structure may have a distinguishing feature, for
example a distinguishing color, to show placement such that the
placement of the sheath body or retention structure in the
canaliculus or other body tissue structure can be readily detected
by the subject. The retention element or sheath body may comprise
at least one mark to indicate the depth of placement in the
canaliculus such that the retention element or sheath body can be
positioned to a desired depth in the canaliculus based on the at
least one mark.
Formation of the Therapeutic Agent Cores
[0218] Those of skill in the art will be familiar with various
methods useful for making the drug cores and inserting into the
lacrimal implant to complete the present drug delivery system
described as being of use in the methods disclosed herein.
Particular methods are described in the above-identified patent
documents, the disclosures of which are incorporated herein by
reference in their entirety.
[0219] For example, drug cores as described above may be fabricated
with different cross sectional sizes of between about 0.006 inches
and 0.025 inches. Drug concentrations in the core may be about 5%,
10%, 20%, 30%, 40% or 50% in a silicone matrix. These drug cores
can be made with a syringe tube and cartridge assembly, mixing the
therapeutic agent(s) with silicone, and injecting the mixture into
a polyimide tube which is cut to desired lengths and sealed. The
length of the drug cores can be approximately 0.80 to 0.95 mm, or
any length designed to fit within the cavity of the present
lacrimal implants.
[0220] Syringe Tube and Cartridge Assembly: 1. Polyimide tubing of
various diameters (for example 0.006 inches, 0.0125 inches and
0.025 inches) can be cut to 15 cm length. 2. The polyimide tubes
can be inserted into a Syringe Adapter. 3. The polyimide tube can
be adhesive bonded into luer adapter (Loctite, low viscosity UV
cure). 4. The end of the assembly can then be trimmed. 5. The
cartridge assembly can be cleaned using distilled water and then
with methanol and dried in oven at 60 degrees C.
[0221] The therapeutic agent can be mixed with silicone.
Therapeutic agent(s) may be provided as a 1% solution in
methylacetate. The appropriate amount of solution can be placed
into a dish and using a nitrogen stream, the solution can be
evaporated until only the therapeutic agent(s) remains. The dish
with the therapeutic agent(s) oil can be placed under vacuum for 30
minutes. This therapeutic agent(s) can then be combined with
silicone, with three different concentrations of therapeutic
agent(s) (5%, 10% and 20%) in silicone NuSil 6385 being injected
into tubing of different diameters (0.006 in, 0.012 in and 0.025
inches) to generate 3.times.3 matrixes. The tube can then be
injected: 1. The cartridge and polyimide tubes assembly can be
inserted into a 1 ml syringe. 2. One drop of catalyst (MED-6385
Curing Agent) can be added in the syringe. 3. Excess catalyst can
be forced out of the polyimide tube with clean air. 4. The syringe
can then be filled with silicone drug matrix. 5. The tube can then
be injected with drug matrix until the tube is filled or the
syringe plunger becomes too difficult to push. 6. The distal end of
the polyimide tube can be closed off and pressure can be maintained
until the silicone begins to solidify. 7. Allow to cure at room
temperature for 12 hours. 8. Place under vacuum for 30 minutes. 9.
The tube can then be place in the correct size trim fixture
(prepared in house to hold different size tubing) and drug inserts
can be cut to length (0.80-0.95 mm).
[0222] In certain embodiments, the drug core formulations of Table
2 and 3 are made using a cold extrusion method described in US
Patent Publication No. 2009/0104243 entitled DRUG CORES FOR
SUSTAINED RELEASE OF THERAPEUTIC AGENTS. Filed Sep. 5, 2008, the
entirety of which is incorporated herein by reference. See, Example
3.
[0223] In this instance, the silicone and latanoprost are prepared
as described above. When latanoprost, which is in a liquid physical
state at about room temperature (22.degree. C.), and thus is also
in a liquid physical state at human body temperature (37.degree.
C.), is used, the agent and the matrix material can be mixed by
techniques that bring about a high degree of dispersion of the
liquid latanoprost droplets in the matrix material in which it can
be substantially insoluble. Mixing techniques should provide for a
dispersion of the droplet within the matrix material, such that
when curing takes place, the liquid therapeutic agent is present as
relatively small, relatively homogeneously dispersed discrete
droplets within the matrix of solid silicone material.
[0224] In this cold extrusion method, the mixture of latanoprost
and silicone can be injected into the tubing (e.g. sheath body)
wherein the mixture is at a subambient temperature. A syringe, for
example a 1 ml syringe, can be connected to the syringe tube and
cartridge assembly. A drop of catalyst appropriate for the
silicone, for example MED-6385 curing agent, can be placed into the
syringe and the syringe is then filled with the uncured mixture of
silicone and latanoprost. The mixture, i.e., mixture of the uncured
silicone and latanoprost still liquid enough to flow or pump, can
be chilled to subambient temperatures. For example, the mixture can
be chilled to temperatures of less than 20.degree. C. For example,
the mixtures can be chilled to 0.degree. C., or to -25.degree. C.
In a particular embodiment, the mixture is chilled to between about
zero and 5.degree. C.
[0225] The polyimide tube is injected with the drug/matrix mixture
until the tube is filled. The tube and associated apparatus can
also be chilled to maintain the subambient temperature of the
mixture throughout the process of filling or injecting the sheath
with the mixture. In various embodiments, the polyimide tube, or
sheath, is filled with the drug matrix mixture under pressure, for
example through use of a high pressure pump. For instance, the
drug/matrix mixture, such as can be obtained in mixtures of
latanoprost with MED-6385 Part A to which amounts of catalyst Part
B have been added, can be pumped into the tube under at least about
40 psi pressure. The tube can be filled at any suitable rate, but
preferably, at rates of less than about 0.5 linear cm/sec. Without
wishing to be bound by a theory, it is believed that filling the
tube relatively rapidly under a relatively high head of pressure
can reduce the degree of phase separation of the substantially
immiscible latanoprost oil and silicone monomer material, such that
upon polymerization ("curing") to provide the final silicone
polymeric product, the latanoprost droplets are finely dispersed in
the solid matrix in which they are only slightly soluble.
[0226] Curing takes place in the presence of the catalyst ("Part
B") of the NuSil MED-6385, and can be carried out at temperatures
of at least about 40.degree. C., at relative humidity (RH) of at
least about 80%, or both. Curing can be initiated directly after
filling the tube and clamping the ends of the filled tube to
prevent the formation of voids and loss of the precursor material
from the tube ends.
[0227] After curing, which can be complete in about 16-24 hours at
40.degree. C. and 80% RH, the clamps can be removed from the ends
of the tubing, as the silicone is fully set up. The tubing can then
be cut into sections of suitable length for use as drug cores, for
example, lengths of about 1 mm.
[0228] When the extrusion is carried out at subambient
temperatures, small and more uniform inclusions of the therapeutic
agent can result. For example, when the agent is latanoprost, a
liquid at room temperature, extrusion at -5.degree. C. provides
significantly smaller and more uniform inclusion droplets. In an
example, cold extrusion yielded a drug core comprising a silicone
matrix with latanoprost droplets of average diameter of 6 .mu.m,
with a standard deviation of diameter of 2 .mu.m. In comparison, an
extrusion carried out at room temperature yielded a drug core
comprising a silicone matrix with latanoprost droplets of average
diameter of 19 .mu.m, with a standard deviation of droplet diameter
of 19 .mu.m. It is apparent that the cold extrusion technique
provides smaller, more uniform inclusions than does extrusion at
room temperature. This in turn results in a more uniform
concentration of drug throughout the core, or the insert containing
the core.
[0229] The final step in making the present lacrimal implants
comprises inserting the drug core, cut to an appropriate length and
sealed on one end, into the cavity of the lacrimal implant. This
can be done manually or with the aid of a machine.
D) Release of Latanoprost or Other Intraocular Pressure-Reducing
Therapeutic Agent(s) at Effective Levels
[0230] The rate of release of latanoprost or other intraocular
pressure-reducing therapeutic agent(s) can be related to the
concentration of latanoprost or other intraocular pressure-reducing
therapeutic agent(s) dissolved in the drug core. In some
embodiments, the drug core comprises non-therapeutic agents that
are selected to provide a desired solubility of the latanoprost or
other intraocular pressure-reducing therapeutic agent(s) in the
drug core. The non-therapeutic agent of the drug core can comprise
polymers as described herein, and additives. A polymer of the core
can be selected to provide the desired solubility of the
latanoprost or other intraocular pressure-reducing therapeutic
agent(s) in the matrix. For example, the core can comprise hydrogel
that may promote solubility of hydrophilic treatment agent. In some
embodiments, functional groups can be added to the polymer to
provide the desired solubility of the latanoprost or other
intraocular pressure-reducing therapeutic agent(s) in the matrix.
For example, functional groups can be attached to silicone
polymer.
[0231] Additives may be used to control the concentration of
latanoprost or other intraocular pressure-reducing therapeutic
agent(s) by increasing or decreasing solubility of the latanoprost
or other intraocular pressure-reducing therapeutic agent(s) in the
drug core so as to control the release kinetics of the latanoprost
or other intraocular pressure-reducing therapeutic agent(s). The
solubility may be controlled by providing appropriate molecules or
substances that increase or decrease the content of latanoprost or
other intraocular pressure-reducing therapeutic agent(s) in the
matrix. The latanoprost or other intraocular pressure-reducing
therapeutic agent(s) content may be related to the hydrophobic or
hydrophilic properties of the matrix and latanoprost or other
intraocular pressure-reducing therapeutic agent(s). For example,
surfactants and salts can be added to the matrix and may increase
the content of hydrophobic latanoprost in the matrix. In addition,
oils and hydrophobic molecules can be added to the matrix and may
increase the solubility of hydrophobic treatment agent in the
matrix.
[0232] Instead of or in addition to controlling the rate of
migration based on the concentration of latanoprost or other
intraocular pressure-reducing therapeutic agent(s) dissolved in the
matrix, the surface area of the drug core can also be controlled to
attain the desired rate of drug migration from the core to the
target site. For example, a larger exposed surface area of the core
will increase the rate of migration of the treatment agent from the
drug core to the target site, and a smaller exposed surface area of
the drug core will decrease the rate of migration of the
latanoprost or other intraocular pressure-reducing therapeutic
agent(s) from the drug core to the target site. The exposed surface
area of the drug core can be increased in any number of ways, for
example by any of castellation of the exposed surface, a porous
surface having exposed channels connected with the tear or tear
film, indentation of the exposed surface, protrusion of the exposed
surface. The exposed surface can be made porous by the addition of
salts that dissolve and leave a porous cavity once the salt
dissolves. Hydrogels may also be used, and can swell in size to
provide a larger exposed surface area. Such hydrogels can also be
made porous to further increase the rate of migration of the
latanoprost or other intraocular pressure-reducing therapeutic
agent(s).
[0233] Further, an implant may be used that includes the ability to
release two or more drugs in combination, such as the structure
disclosed in U.S. Pat. No. 4,281,654. For example, in the case of
glaucoma treatment, it may be desirable to treat a patient with
multiple prostaglandins or a prostaglandin and a cholinergic agent
or an adrenergic antagonist (beta blocker), such as Alphagan.RTM.,
or latanoprost and a carbonic anhydrase inhibitor.
[0234] In addition, drug impregnated meshes may be used such as
those disclosed in U.S. Patent Publication No. 2002/0055701 or
layering of biostable polymers as described in U.S. Patent
Publication No. 2005/0129731, the disclosures of which are
incorporated herein in their entirety. Certain polymer processes
may be used to incorporate latanoprost or other intraocular
pressure-reducing therapeutic agent(s) into the devices of the
present invention; such as so-called "self-delivering drugs" or
PolymerDrugs (Polymerix Corporation, Piscataway, N.J.) are designed
to degrade only into therapeutically useful compounds and
physiologically inert linker molecules, further detailed in U.S.
Patent Publication No. 2005/0048121, hereby incorporated by
reference in its entirety. Such delivery polymers may be employed
in the devices of the present invention to provide a release rate
that is equal to the rate of polymer erosion and degradation and is
constant throughout the course of therapy. Such delivery polymers
may be used as device coatings or in the form of microspheres for a
drug depot injectable (such as a reservoir of the present
invention). A further polymer delivery technology may also be
configured to the devices of the present invention such as that
described in U.S. Patent Publication No. 2004/0170685, and
technologies available from Medivas (San Diego, Calif.).
[0235] In specific embodiments, the drug core matrix comprises a
solid material, for example silicone, that encapsulates inclusions
of the latanoprost or other intraocular pressure-reducing
therapeutic agent(s). The drug comprises molecules which are very
insoluble in water and slightly soluble in the encapsulating drug
core matrix. The inclusions encapsulated by the drug core can be
micro-particles having dimensions from about 1 micrometer to about
100 micrometers across. The drug inclusions can comprise droplets
of oil, for example latanoprost oil. The drug inclusions can
dissolve into the solid drug core matrix and substantially saturate
the drug core matrix with the drug, for example dissolution of
latanoprost oil into the solid drug core matrix. The drug dissolved
in the drug core matrix is transported, often by diffusion, from
the exposed surface of the drug core into the tear film. As the
drug core is substantially saturated with the drug, in many
embodiments the rate limiting step of drug delivery is transport of
the drug from the surface of the drug core matrix exposed to the
tear film. As the drug core matrix is substantially saturated with
the drug, gradients in drug concentration within the matrix are
minimal and do not contribute significantly to the rate of drug
delivery. As surface area of the drug core exposed to the tear film
is nearly constant, the rate of drug transport from the drug core
into the tear film can be substantially constant. Naturally
occurring surfactants may affect the solubility of the latanoprost
or other intraocular pressure-reducing therapeutic agent(s) in
water and molecular weight of the drug can affect transport of the
drug from the solid matrix to the tear. In many embodiments, the
latanoprost or other intraocular pressure-reducing therapeutic
agent(s) is nearly insoluble in water and has a solubility in water
of about 0.03% to 0.002% by weight and a molecular weight from
about 400 grams/mol. to about 1200 grams/mol.
[0236] In many embodiments the latanoprost or other intraocular
pressure-reducing therapeutic agent(s) has a very low solubility in
water, for example from about 0.03% by weight to about 0.002% by
weight, a molecular weight from about 400 grams per mole (g/mol) to
about 1200 g/mol, and is readily soluble in an organic solvent.
Latanoprost is a liquid oil at room temperature, and has an aqueous
solubility of 50 micrograms/mL in water at 25 degrees C., or about
0.005% by weight and a M.W. of 432.6 g/mol.
[0237] Naturally occurring surfactants in the tear film, for
example surfactant D and phospholipids, may affect transport of the
drug dissolved in the solid matrix from the core to the tear film.
In some embodiments the drug core can be configured in response to
the surfactant in the tear film to provide sustained delivery of
latanoprost or other intraocular pressure-reducing therapeutic
agent(s) into the tear film at therapeutic levels. For example,
empirical data can be generated from a patient population, for
example 10 patients whose tears are collected and analyzed for
surfactant content. Elution profiles in the collected tears for a
drug that is sparingly soluble in water can also be measured and
compared with elution profiles in buffer and surfactant such that
an in vitro model of tear surfactant is developed. An in vitro
solution with surfactant based on this empirical data can be used
to adjust the drug core in response to the surfactant of the tear
film.
[0238] The drug cores may also be modified to utilize carrier
vehicles such as nanoparticles or microparticles depending on the
size of the molecule to be delivered such as latent-reactive
nanofiber compositions for composites and nanotextured surfaces
(Innovative Surface Technologies, LLC, St. Paul, Minn.),
nanostructured porous silicon, known as BioSilicon.RTM., including
micron sized particles, membranes, woven fivers or micromachined
implant devices (pSividia, Limited, UK) and protein nanocage
systems that target selective cells to deliver a drug
(Chimeracore).
[0239] In many embodiments, the drug insert comprises of a
thin-walled polyimide tube sheath with a drug core comprising
latanoprost dispersed in Nusil 6385 (MAF 970), a medical grade
solid silicone that serves as the matrix for drug delivery. The
distal end of the drug insert is sealed with a cured film of solid
Loctite 4305 medical grade adhesive. The drug insert may be placed
within the bore of the punctal implant, the Loctite 4305 adhesive
does not come into contact with either tissue or the tear film. The
inner diameter of the drug insert can be 0.32 mm; and the length
can be 0.95 mm. At least four latanoprost concentrations in the
finished drug product can be employed: Drug cores can comprise 3.5,
7, 14 or 21 micrograms latanoprost, with percent by weight
concentrations of 5, 10, 20, or 30% respectively. Assuming an
overall elution rate of approximately 100 ng/day, the drug core
comprising 14 micrograms of latanoprost is configured to deliver
drug for approximately at least 100 days, for example 120 days. The
overall weight of the drug core, including latanoprost or other
intraocular pressure-reducing therapeutic agent(s), can be about 70
micrograms. The weight of the drug insert including the polyimide
sleeve can be approximately 100 micrograms. In an embodiment, the
drug core can comprise 46 micrograms of latanoprost, and in another
embodiment, the drug core can comprise 95 micrograms of
latanoprost.
[0240] In many embodiments, the drug core may elute with an initial
elevated level of latanoprost or other intraocular
pressure-reducing therapeutic agent(s) followed by substantially
constant elution of the latanoprost or other intraocular
pressure-reducing therapeutic agent(s). In many instances, an
amount of latanoprost or other intraocular pressure-reducing
therapeutic agent(s) released daily from the core may be below the
therapeutic levels and still provide a benefit to the patient. An
elevated level of eluted latanoprost or other intraocular
pressure-reducing therapeutic agent(s) can result in a residual
amount of latanoprost or other intraocular pressure-reducing
therapeutic agent(s) or residual effect of the latanoprost or other
intraocular pressure-reducing therapeutic agent(s) that is combined
with a sub-therapeutic amount of latanoprost or other intraocular
pressure-reducing therapeutic agent(s) to provide relief to the
patient. In embodiments where therapeutic level is about 80 ng per
day, the device may deliver about 100 ng per day for an initial
delivery period. The extra 20 ng delivered per day can have a
beneficial effect when latanoprost or other intraocular
pressure-reducing therapeutic agent(s) is released at levels below
the therapeutic level, for example at 60 ng per day. As the amount
of drug delivered can be precisely controlled, an initial elevated
dose may not result in complications or adverse events to the
patient.
E) Clinical Use of the Drug Delivery System to Treat Glaucoma
and/or Ocular Hypertension
[0241] Ocular hypertension (OH) and primary open angle glaucoma
(POAG) are caused by a build-up of aqueous humor in the anterior
chamber primarily due to the eye's inability to properly drain
aqueous fluid. The ciliary body, situated at the root of the iris,
continuously produces aqueous humor. It flows into the anterior
chamber and then drains via the angle between the cornea and iris
through the trabecular meshwork and into a channel in the sclera.
In the normal eye, the amount of aqueous humor being produced is
equal to the amount that is draining out. However, in an eye in
which this mechanism is compromised, intraocular pressure (IOP)
rises. Elevated IOP represents a major risk factor for glaucomatous
field loss. Results from several studies indicate that early
intervention targeted at lowering intraocular pressure retards the
progression of optic nerve damage and loss of visual fields that
lead to decreased vision and blindness.
[0242] As described above, first line treatment for treating OAG
and/or OH is the use of eye drops, such as Xalatan. However,
numerous studies have been published showing high noncompliance by
patients using eye drops for treatment of various ocular disorders.
One study showed only 64% of patients used the eye drops as
directed (Winfield A J, et al. A study of the causes of
non-compliance by patients prescribed eyedrops. Br J Ophthalmol.
1990 August; 74(8):477-80). Another study showed that 41% of
patients using eye drops for glaucoma missed six or more doses over
a 30-day period (Norell S E, Granstrom P A. Self-medication with
pilocarpine among outpatients in a glaucoma clinic. Br J
Ophthalmol. 1980 February; 64(2):137-41).
[0243] In certain embodiments, the invention described herein
provides methods to treat glaucoma that avoid the problem of
noncompliance associated with eye drop administration. In some
embodiments, the methods of the invention reduce patient
noncompliance significantly compared to eye drop administration,
e.g., by at least about 10%, at least about 20%, at least about
30%, at least about 40%, at least about 50%, at least about 60%, at
least about 70%, at least about 80%, or at least about 90%. In some
embodiments, overall patient noncompliance with the methods
described herein is about 5%, about 10%, about 15%, about 20%, or
about 25%.
[0244] Patient noncompliance may occur if an implant of the
invention is intentionally removed by a patient or if the patient
does not seek reinsertion of the implant after such implant has
been unintentionally lost from the punctum of the patient. Patient
compliance is considered to be met if the implant is intentionally
removed and the patient seeks reinsertion within less than about 48
hours. Patient compliance is also considered to be met if the
implant is intentionally removed and the patient seeks reinsertion
within less than about 24 hours of removal or loss of the
implant.
[0245] Implicit in the methods to treat OAG and/or OH to avoid
patient non-compliance is the comparable efficacy of the present
drug delivery system comprising lacrimal implants to the use of eye
drops. Lacrimal implants to treat ocular disease have been in
development for many years by the applicants and others with
limited success. However, applicants demonstrate for the first time
herein a clinically meaningful reduction in IOP over the treatment
period (e.g. between 4 weeks and 12 weeks) using the present
lacrimal implants to administer latanoprost.
[0246] In certain embodiments, the invention described herein
provides methods to treat glaucoma, elevated intraocular pressure,
and glaucoma-associated elevated intraocular pressure with a
therapeutic agent. Examples of glaucoma treatable according to the
present invention include primary open angle glaucoma, normal
intraocular tension glaucoma, hypersecretion glaucoma, ocular
hypertension, acute angle-closure glaucoma, chronic closed angle
glaucoma, combined-mechanism glaucoma, corticosteroid glaucoma,
amyloid glaucoma, neovascular glaucoma, malignant glaucoma,
capsular glaucoma, plateau iris syndrome and the like.
[0247] In one embodiment, the present disclosure provides methods
of treating a patient with open angle glaucoma (OAG) and/or ocular
hypertension (OH) in an eye. In a further embodiment, the present
disclosure provides methods of treating a patient with Open Angle
Glaucoma (OAG) or Ocular Hypertension (OH) in an eye by reducing
intraocular pressure (IOP) in the eye.
[0248] In certain embodiments the treatment period is at least four
(4) weeks, and can be up to twelve (12) week or longer, wherein the
therapeutic agent is released in a therapeutically effective dose
from a lacrimal implant on a sustained basis over the treatment
period.
[0249] In one embodiment, the implants and methods of the invention
provide a 90-day course of treatment. In other embodiments, the
implants and methods of the invention provide a 60-day course of
treatment. In still other embodiments, the implants and methods of
the invention provide a 45-day course of treatment. In still other
embodiments, the implants and methods of the invention provide a
30-day course of treatment, depending upon the disease to be
treated and the therapeutic agent to be delivered. Other
embodiments include four weeks, five weeks, six weeks, seven weeks,
eight weeks, nine weeks, ten weeks, eleven weeks, or twelve weeks
of treatment.
[0250] In certain embodiments, the methods comprise reducing the
intraocular pressure (IOP) during the treatment period. In one
embodiment, reduction in intraocular pressure (IOP) is between
about 10% and 24% from baseline over the treatment period. In
particular embodiments, the percentage reduction or decrease in
intraocular pressure (IOP) is approximately 23%, approximately 22%,
approximately 21%, or approximately 20% from baseline. In other
particular embodiments, the present methods result in a percentage
reduction or decrease in intraocular pressure (IOP) of at least
24%, at least 23%, at least 22%, at least 21%, at least 20%, at
least 15%, or at least 10% from baseline.
[0251] In certain embodiments, the methods of the invention result
in a reduction in intraocular pressure from baseline over a
treatment period of about 4, mm Hg, about 5 mm Hg, about 6 mm Hg,
or about 7 mm Hg. In certain embodiments, the methods of the
invention result in a reduction in intraocular pressure from
baseline of at least 4 mm Hg, at least 5 mm Hg, at least 6 mm Hg,
or at least 7 mm Hg. In some embodiments, intraocular pressure is
reduced to less than or equal to 24 mm Hg, less than or equal to 23
mm Hg, less than or equal to 22 mm Hg, less than or equal to 21 mm
Hg, less than or equal to 20 mm Hg, less than or equal to 19 mm Hg,
less than or equal to 18 mm Hg, or less than or equal to 17 mm Hg,
or less than or equal to 16 mm Hg, less than or equal to 15 mm Hg,
less than or equal to 14 mm Hg, or less than or equal to 13 mm
Hg.
[0252] In one embodiment, the invention provides a method of
treating glaucoma and/or ocular hypertension with a punctal plug
delivering a therapeutic agent effective against these conditions
in a sustained release manner. The release occurs at a rate and in
an amount sufficient to be therapeutically useful. In various
embodiments, the therapeutic agent is a prostaglandin, e.g.,
latanoprost.
[0253] In an exemplary embodiment, the condition treated is primary
open-angle glaucoma (POAG) and ocular hypertension (OH) with a
punctual plug of the invention in which a sustained release
formulation of a prostaglandin derivative is provided. In this
method one to four punctual plugs may be inserted per patient.
Exemplary punctal plugs are formulated with from about 40 .mu.g to
about 115 .mu.g of prostaglandin. In various embodiments, the
prostaglandin is latanoprost. In various embodiments, the plugs are
formulated with either 46 .mu.g or 95 .mu.g of latanoprost (See,
Tables 2 and 3) so that a dosage which is a member selected from 46
.mu.g, 92 .mu.g, 95 .mu.g, 141 .mu.g or 190 .mu.g is administered
to each eye. In one embodiment 141 .mu.g of latanoprost was
administered to an individual eye. In another embodiment, 190 .mu.g
of latanoprost was administered to an individual eye. In another
embodiment, 95 .mu.g of latanoprost was administered to an
individual eye. A patient may have the same amount of latanoprost
administered to each eye or the patient may have a different amount
administered to each eye.
[0254] The implants described herein may be inserted into the
superior (upper) punctum, the inferior (lower) punctum, or both,
and may be inserted into one or both eyes of the subject. Without
wishing to be bound by a theory, the data presented in the figures
and examples appear to demonstrate that the placement and
configuration of the lacrimal implants may contribute to the
reduction of IOP over the treatment period. In previously published
studies, the lacrimal implants were only inserted into the lower
punctum, and those studies, despite dose escalation (FIG. 16) and
with a constant elution of drug over the treatment period (FIG. 17)
were unable to show significant reduction in IOP over the treatment
period. See Example 2. Thus, in certain embodiments at least the
upper punctum is inserted with a present lacrimal implant.
Surprisingly though, this lacrimal implant need not comprise a
therapeutic agent (See Example 6 and FIGS. 19 and 27). In this
instance a blank lacrimal implant is inserted into the upper
punctum and a lacrimal implant comprising a therapeutic agent (e.g.
95 .mu.g of latanoprost) is inserted into the lower punctum. This
configuration demonstrated a mean reduction in IOP from baseline of
5.17 mm Hg at week twelve (FIG. 23 and Table 8), while previous
studies with no lacrimal implant in the upper punctum and the same
concentration of latanoprost in the lower puntum lacrimal implant
demonstrated only a reduction of less than about 4.0 mm Hg from
baseline at week 2 (FIG. 16).
[0255] In certain embodiments, the method for treating OAG and/or
OH comprises inserting a lacrimal implant into at least the upper
punctum. In one embodiment, the lacrimal implant comprises a
therapeutic agent (e.g. latanoprost). In another embodiment, the
lacrimal implant does not comprise a therapeutic agent for treating
OAG and/or OH. In this instance, a lacrimal implant is inserted
into the lower punctum comprising a therapeutic agent (e.g.
latanoprost).
[0256] Thus, the present methods comprise inserting at least a
lacrimal implant into an upper punctum wherein a number of
different configurations are contemplated resulting in significant
reduction of IOP over the treatment period. In one embodiment, the
method for treating OAG and/or OH comprises inserting a lacrimal
implant into the upper punctum comprising a therapeutic agent and
inserting a lacrimal implant into the lower punctum comprising a
therapeutic agent. In another embodiment, the method of treating
OAG and/or OH comprises inserting a lacrimal implant into the upper
punctum that does not comprise a therapeutic agent for lowering IOP
and inserting a lacrimal implant into the lower punctum that
comprises a therapeutic agent for treating OAG and/or OH. In yet
another embodiment, the present method for treating OAG and/or OH
comprises inserting a lacrimal implant into the upper punctum
comprising a therapeutic agent wherein no lacrimal implant is
inserted into the lower punctum. In each of the above embodiments,
reference to an upper and lower punctum is referring to the same
eye. Each eye may have the same configuration of lacrimal implant
inserted or different; each eye is treated separately for OAG
and/or OH.
[0257] In a particular embodiment, the method of treating OAG
and/or OH in an eye comprises providing a first lacrimal implant
comprising a sustained release formulation of a therapeutic agent
for treating OAG or OH; providing a second lacrimal implant that
does not comprise the therapeutic agent; and inserting the first
and second lacrimal implant through an upper and lower punctum into
a lacrimal canaliculus of the same eye wherein the therapeutic
agent is released in a therapeutically effective dose from the
first lacrimal implant on a sustained basis over at least four (4)
weeks. In one aspect, the therapeutic agent is latanoprost. In
another aspect, the dose of latanoprost administered to the eye is
about 95 .mu.g. In yet another aspect, the therapeutic agent is
released in a therapeutically effective dose from the first
lacrimal implant on a sustained basis over at least twelve (12)
weeks. In this particular embodiment, it was surprisingly found
that the IOP was reduced by about 5.0 mm Hg at week 4 and about at
least 4.0 mm Hg at week 12.
[0258] In another particular embodiment, the method of treating OAG
and/or OH in an eye comprises providing a lacrimal implant
comprising a sustained release formulation of a therapeutic agent
for treating OAG or OH; and inserting the lacrimal implant through
an upper punctum into a lacrimal canaliculus of the eye wherein the
therapeutic agent is released in a therapeutically effective dose
from the first lacrimal implant on a sustained basis over at least
four (4) weeks. In one aspect, the therapeutic agent is
latanoprost. In another aspect, the dose of latanoprost
administered to the eye is about 95 .mu.g. In yet another aspect,
the therapeutic agent is released in a therapeutically effective
dose from the first lacrimal implant on a sustained basis over at
least twelve (12) weeks. In this particular embodiment, it was
surprisingly found that the IOP was reduced by about at least 4.0
mm Hg at week 4 and about at least 4.0 mm Hg at week 12.
[0259] In some embodiments, the therapeutic agent is released to
the eye over a sustained period of time. In an embodiment, the
sustained period of time is at least about 28 days, about 45 days,
about 60 days or at least about 90 days. In some embodiments, the
method comprises inserting through a punctum an implant having a
body and a drug core so that the drug core is retained near the
punctum. In some embodiments, the method comprises inserting
through a punctum an implant having a body dispersed throughout
with a therapeutic agent. In some embodiments, an exposed surface
of the drug core or agent dispersed body located near the proximal
end of the implant contacts the tear or tear film fluid and the
latanoprost or other intraocular pressure-reducing therapeutic
agent(s) migrates from the exposed surface to the eye over a
sustained period of time while the drug core and body is at least
partially retained within the punctum. In an exemplary embodiment,
a method of treating an eye with latanoprost or other intraocular
pressure-reducing therapeutic agent(s) is provided, the method
comprising inserting through a punctum into a canalicular lumen an
implant having an optional retention structure so that the implant
body is anchored to a wall of the lumen by the retention structure.
The implant releases effective amounts of latanoprost or other
intraocular pressure-reducing therapeutic agent(s) from a drug core
or other agent supply into a tear or tear film fluid of the eye. In
some embodiments, the drug core may be removed from the retention
structure while the retention structure remains anchored within the
lumen. A replacement drug core can then be attached to the
retention structure while the retention structure remains anchored.
At least one exposed surface of the replacement drug core releases
latanoprost or other intraocular pressure-reducing therapeutic
agent(s) at therapeutic levels over a sustained period.
[0260] A replacement implant, or in other embodiments, a
replacement drug core which can in some embodiments be attached to
or include its own retention structure, can be attached to the
retention structure approximately every 30 days, approximately
every 60 days or approximately every 90 days to result in
continuous release of the drug to the eye for a period of time of
approximately 180 days, approximately 270 days, approximately 360
days, approximately 450 days, approximately 540 days, approximately
630 days, approximately 720 days, approximately 810 days or
approximately 900 days. In some embodiments, a replacement implant
can be inserted into the punctum approximately every 30 days,
approximately every 60 days or approximately every 90 days to
achieve release of the drug to the eye for extended periods of
time, including up to about 180 days, about 270 days, about 360
days, about 450 days, about 540 days, about 630 days, about 720
days, about 810 days or about 900 days.
[0261] In other embodiments, a method for treating an eye with
latanoprost or other intraocular pressure-reducing therapeutic
agent(s) is provided, the method comprising inserting a drug core
or other implant body at least partially into at least one punctum
of the eye. The drug core may or may not be associated with a
separate implant body structure. The drug core or agent-impregnated
implant body provides sustained release delivery of latanoprost or
other intraocular pressure-reducing therapeutic agent(s) at
therapeutic levels. In some embodiments, the sustained release
delivery of latanoprost or other intraocular pressure-reducing
therapeutic agent(s) continues for up to 90 days.
[0262] In exemplary embodiments, a method for treating an eye with
latanoprost or other intraocular pressure-reducing therapeutic
agent(s) is provided, the method comprising inserting a distal end
of an implant into at least one punctum and into at least one
lacrimal canaliculus of the eye. In some embodiment, a retention
structure of the implant is fitted so as to inhibit expulsion of
the implant. The expansion of the retention structure can help to
occlude a flow of tear fluid through the punctum. In some
embodiments, the implant is configured such that, when implanted,
at least 45 degree angled intersection exists between a first axis,
defined by a proximal end of the implant, and a second axis,
defined by the distal end of the implant, to inhibit expulsion of
the implant. Latanoprost or other intraocular pressure-reducing
therapeutic agent(s) is delivered from a proximal end of the
implant to the tear fluid adjacent the eye. Delivery of the
latanoprost or other intraocular pressure-reducing therapeutic
agent(s) is inhibited distally of the proximal end.
[0263] The methods of the invention provide sustained release of
latanoprost or other intraocular pressure-reducing therapeutic
agent(s). In some embodiments, the active agent is released from
the implant for at least four weeks, at least five weeks, at least
six weeks, at least seven weeks, at least eight weeks, at least
nine weeks, at least ten weeks, at least eleven weeks, at least
twelve weeks, at least thirteen weeks, at least fourteen weeks, at
least fifteen weeks, or at least sixteen weeks. In some
embodiments, the therapeutic agent is latanoprost. In an
embodiment, the latanoprost or other intraocular pressure-reducing
therapeutic agent(s) is released for at least twelve weeks. In an
exemplary embodiment, the methods of treatment according to the
present invention comprise an adjunctive therapy with a
latanoprost-delivering eye drop solution, for example,
Xalatan.RTM..
[0264] The amount of latanoprost or other intraocular
pressure-reducing therapeutic agent(s) associated with the implant
may vary depending on the desired therapeutic benefit and the time
during which the device is intended to deliver the therapy. Since
the devices of the present invention present a variety of shapes,
sizes and delivery mechanisms, the amount of drug associated with
the device will depend on the particular disease or condition to be
treated, and the dosage and duration that is desired to achieve the
therapeutic effect. Generally, the amount of latanoprost or other
intraocular pressure-reducing therapeutic agent(s) is at least the
amount of drug that, upon release from the device, is effective to
achieve the desired physiological or pharmacological local or
systemic effects.
[0265] Certain embodiments of the implants of the present invention
can be configured to provide, in combination with each other or
separately, delivery of latanoprost or other intraocular
pressure-reducing therapeutic agent(s) at daily rates that are
greater than or equivalent to the therapeutically effective drop
form of treatment. Other embodiments of the implants of the present
invention can be configured to provide, in combination with each
other or separately, delivery of latanoprost or other intraocular
pressure-reducing therapeutic agent(s) at daily rates that enable
comparable clinical outcomes to that of daily administered eye
drops. Other embodiments of the implants of the present invention
can be configured to provide delivery of latanoprost or other
intraocular pressure-reducing therapeutic agent(s) at daily rates
that exceed the therapeutically effective drop form of
treatment.
[0266] For comparison purposes, standard treatment, i.e., the
recommended daily total dose, with drops, such as Xalatan.RTM.
drops, delivers about 1.5 micrograms of latanoprost to the eye all
at once, assuming a 35 microliter drop volume. In embodiments of
the present invention, the sustained release of at least 1.5
micrograms of latanoprost per day can be administered. For example,
in an embodiment, a sustained release ophthalmic drug delivery
system is configured to release, on a sustained basis over the
course of 24 hours to the eye, a total amount of latanoprost from a
combination of a first lacrimal implant, located in a lower punctum
of the eye, and a second lacrimal implant, located in an upper
punctum of the same eye, that is greater than or equal to the
recommended daily total dose of latanoprost that is in Xalatan.RTM.
drops (i.e., eye drop form). In other embodiments, at least two
times the recommended daily total dose of latanoprost that is in
Xalatan.RTM. drops may be release by a combination of the first
lacrimal implant and the second lacrimal implant that are in the
lower punctum and the upper punctum, respectively, of the same eye.
In an embodiment, both eyes of the patient may be treated with two
lacrimal implants at the same time.
[0267] Methods of inserting and removing the implant are known to
those of skill in the art. For instance, tools for insertion and
removal/extraction of implants are described in U.S. Patent
Publication No. 2009/0105749 (filed Sep. 5, 2008 and entitled
Insertion and Extraction Tools for Lacrimal Implants), the
disclosure of which is incorporated herein in its entirety.
Generally, for placement, the size of a punctal implant to be used
may be determined by using suitable magnification or, if provided,
using a sizing tool that accompanies the punctal implant. The
patient's punctum may be dilated if necessary to fit the punctal
implant. A drop of lubricant may be applied if necessary to
facilitate placement of the implant into the punctum. Using an
appropriate placement instrument, the implant may be inserted into
the superior or inferior punctum of the eye. After placement, the
cap of the implant may be visible. This process may be repeated for
the patient's other eye. For removal of the implant, small surgical
forceps may be used to securely grasp the implant at the tube
section below the cap. Using a gentle tugging motion the implant
may be gently retrieved.
F) Kits
[0268] The present invention also provides methods that utilize
kits that, in an exemplary embodiment, include one, two, three or
four implants of use in the methods of the invention. In an
exemplary embodiment, the implants are sterilized. In various
embodiments, there is also provided an insertion tool. An exemplary
insertion tool of use in this embodiment is set forth herein. In
various embodiments, at least one implant is engaged with the
insertion tool by engaging the pin of the tool (760) with the bore
of the implant (385). In various embodiments, the tool is
sterilized. In an exemplary embodiment, the elements of the kit are
packaged together with one or more of a set of instructions for
installing the implant in the punctum, a topical anesthetic, an
administration device for the topical anesthetic or another
component of use in installing the implant in the punctum.
G) Specific Embodiments
[0269] E1. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye, comprising: providing
a unit dosage of about 95 .mu.g of latanoprost to an eye over a
treatment period, wherein the latanoprost is administered from a
lacrimal implant comprising a sustained release formulation of the
95 ug of latanoprost and the latanoprost is released in a
therapeutically effective dose from the lacrimal implant over the
treatment period, with the proviso that the lacrimal implant is
inserted into an upper punctum of the eye and a lower punctum of
the eye is open or has inserted a blank lacrimal implant that does
not comprise latanoprost.
[0270] E2. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye, comprising: providing
a unit dosage of about 95 .mu.g of latanoprost to an eye over a
treatment period, wherein the latanoprost is administered from a
lacrimal implant comprising a sustained release formulation of the
95 .mu.g of latanoprost and the latanoprost is released in a
therapeutically effective dose from the lacrimal implant over the
treatment period, with the proviso that the lacrimal implant is
inserted into a lower punctum and a blank lacrimal implant that
does not comprise latanoprost is inserted in an upper punctum.
[0271] E3. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: providing a unit dosage of
about 95 .mu.g of latanoprost to an eye over a treatment period of
at least 4 weeks, wherein the latanoprost is administered from a
lacrimal implant comprising a sustained release formulation of the
95 .mu.g of latanoprost and the latanoprost is released in a
therapeutically effective dose from the lacrimal implant over the
treatment period, wherein the IOP is reduced by at least 4 mm Hg
from a baseline at week 4.
[0272] E4. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: providing a unit dosage of
about 95 .mu.g of latanoprost to an eye over a treatment period of
at least 8 weeks, wherein the latanoprost is administered from a
lacrimal implant comprising a sustained release formulation of the
95 .mu.g of latanoprost and the latanoprost is released in a
therapeutically effective dose from the lacrimal implant over the
treatment period, wherein the IOP is reduced by at least 4 mm Hg
from a baseline at week 8.
[0273] E5. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: providing a unit dosage of
about 95 .mu.g of latanoprost to an eye over a treatment period of
at least 12 weeks, wherein the latanoprost is administered from a
lacrimal implant comprising a sustained release formulation of the
95 .mu.g of latanoprost and the latanoprost is released in a
therapeutically effective dose from the lacrimal implant over the
treatment period, wherein the IOP is reduced by at least 4 mm Hg
from a baseline at week 12.
[0274] E6. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: providing a unit dosage of
about between 140 and 200 .mu.g of latanoprost to an eye over a
treatment period of at least 4 weeks, wherein the latanoprost is
administered from a lacrimal implant comprising a sustained release
formulation of the latanoprost and the latanoprost is released in a
therapeutically effective dose from the lacrimal implant over the
treatment period, wherein the IOP is reduced by at least 5 mm Hg
from a baseline at week 4.
[0275] E7. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: providing a unit dosage of
about between 140 and 200 .mu.g of latanoprost to an eye over a
treatment period of at least 8 weeks, wherein the latanoprost is
administered from a lacrimal implant comprising a sustained release
formulation of the latanoprost and the latanoprost is released in a
therapeutically effective dose from the lacrimal implant over the
treatment period, wherein the IOP is reduced by at least 5 mm Hg
from a baseline at week 8.
[0276] E8. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: providing a unit dosage of
about between 140 and 200 .mu.g of latanoprost to an eye over a
treatment period of at least 12 weeks, wherein the latanoprost is
administered from a lacrimal implant comprising a sustained release
formulation of the latanoprost and the latanoprost is released in a
therapeutically effective dose from the lacrimal implant over the
treatment period, wherein the IOP is reduced by at least 5 mm Hg
from a baseline at week 12.
[0277] E9. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: providing a unit dosage of
about 190 .mu.g of latanoprost to an eye over a treatment period of
at least 4 weeks, wherein the latanoprost is administered from a
lacrimal implant comprising a sustained release formulation of the
latanoprost and the latanoprost is released in a therapeutically
effective dose from the lacrimal implant over the treatment period,
wherein the IOP is reduced by at least 5 mm Hg from a baseline at
week 4.
[0278] E10. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: providing a unit dosage of
about 190 .mu.g of latanoprost to an eye over a treatment period of
at least 8 weeks, wherein the latanoprost is administered from a
lacrimal implant comprising a sustained release formulation of the
latanoprost and the latanoprost is released in a therapeutically
effective dose from the lacrimal implant over the treatment period,
wherein the IOP is reduced by at least 5 mm Hg from a baseline at
week 8.
[0279] E11. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: providing a unit dosage of
about 190 .mu.g of latanoprost to an eye over a treatment period of
at least 12 weeks, wherein the latanoprost is administered from a
lacrimal implant comprising a sustained release formulation of the
latanoprost and the latanoprost is released in a therapeutically
effective dose from the lacrimal implant over the treatment period,
wherein the IOP is reduced by at least 4 mm Hg from a baseline at
week 12.
[0280] E12. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: providing a unit dosage of
about 141 .mu.g of latanoprost to an eye over a treatment period of
at least 8 weeks, wherein the latanoprost is administered from a
lacrimal implant comprising a sustained release formulation of the
latanoprost and the latanoprost is released in a therapeutically
effective dose from the lacrimal implant over the treatment period,
wherein the IOP is reduced by at least 5 mm Hg from a baseline at
week 8.
[0281] E13. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye, comprising: (a)
providing a first lacrimal implant comprising a sustained release
formulation of a therapeutic agent for treating OAG or OH; (b)
providing a second lacrimal implant that does not comprise the
therapeutic agent; and (c) inserting the first and second lacrimal
implant through an upper and lower punctum into a lacrimal
canaliculus of the same eye wherein the therapeutic agent is
released in a therapeutically effective dose from the first
lacrimal implant on a sustained basis over at least four (4)
weeks.
[0282] E14. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye, comprising: (a)
providing a first lacrimal implant comprising a sustained release
formulation of a therapeutic agent for treating OAG or OH; (b)
providing a second lacrimal implant that does not comprise the
therapeutic agent; and (c) inserting the first and second lacrimal
implant through an upper and lower punctum into a lacrimal
canaliculus of the same eye wherein the therapeutic agent is
released in a therapeutically effective dose from the first
lacrimal implant on a sustained basis over at least eight (8)
weeks.
[0283] E15. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye, comprising: (a)
providing a first lacrimal implant comprising a sustained release
formulation of a therapeutic agent for treating OAG or OH; (b)
providing a second lacrimal implant that does not comprise the
therapeutic agent; (c) inserting the first and second lacrimal
implant through an upper and lower punctum into a lacrimal
canaliculus of the same eye; and (d) releasing the therapeutic
agent from the first lacrimal implant as a therapeutically
effective dose on a sustained basis over at least twelve (12)
weeks.
[0284] E16. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: (a) measuring the IOP of the
patient to obtain a baseline IOP before treatment; (b) providing a
therapeutic agent for treating OAG or OH as a sustained release
formulation; (c) delivering the sustained release formulation to
the eye using a lacrimal implant comprising the sustained release
formulation; and (d) releasing the therapeutic agent to the eye on
a sustained basis over at least 8 weeks wherein the IOP is reduced
by at least 4 mmHg from baseline at week 8.
[0285] E17. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: (a) measuring the IOP of the
patient to obtain a baseline IOP before treatment; (b) providing a
therapeutic agent for treating OAG or OH as a sustained release
formulation; (c) delivering the sustained release formulation to
the eye using a lacrimal implant comprising the sustained release
formulation; and (d) releasing the therapeutic agent to the eye on
a sustained basis over at least 12 weeks wherein the IOP is reduced
by at least 4.0 mmHg from baseline at week 12.
[0286] E18. A method of treating a patient with Open Angle Glaucoma
(OAG) or Ocular Hypertension (OH) in an eye by reducing intraocular
pressure (IOP) in the eye, comprising: (a) measuring the IOP of the
patient to obtain a baseline IOP before treatment; (b) providing a
therapeutic agent for treating OAG or OH as a sustained release
formulation; (c) delivering the sustained release formulation to
the eye using a lacrimal implant comprising the sustained release
formulation; and (d) releasing the therapeutic agent to the eye on
a sustained basis over at least 12 weeks wherein the IOP is reduced
by at least 5.0 mmHg from baseline at week 12.
[0287] E19. A lacrimal implant comprising a unit dosage of about 95
.mu.g of latanoprost for use in the treatment of Open Angle
Glaucoma (OAG) or Ocular Hypertension (OH) in an eye, wherein the
latanoprost is administered from the lacrimal implant comprising a
sustained release formulation of the 95 ug of latanoprost and the
latanoprost is released in a therapeutically effective dose from
the lacrimal implant over a treatment period, with the proviso that
the lacrimal implant is inserted into an upper punctum of the eye
and a lower punctum of the eye is open or has inserted a blank
lacrimal implant that does not comprise latanoprost.
[0288] E20. A lacrimal implant comprising a unit dosage of about 95
.mu.g of latanoprost for use in the treatment of Open Angle
Glaucoma (OAG) or Ocular Hypertension (OH) in an eye, wherein the
latanoprost is administered from the lacrimal implant comprising a
sustained release formulation of the 95 .mu.g of latanoprost and
the latanoprost is released in a therapeutically effective dose
from the lacrimal implant over the treatment period, with the
proviso that the lacrimal implant is inserted into a lower punctum
and a blank lacrimal implant that does not comprise latanoprost is
inserted in an upper punctum.
[0289] E21. A lacrimal implant comprising a unit dosage of about 95
.mu.g of latanoprost for use in the treatment of Open Angle
Glaucoma (OAG) or Ocular Hypertension (OH) in an eye by reducing
intraocular pressure (IOP) in the eye, wherein the latanoprost is
administered from a lacrimal implant comprising a sustained release
formulation of the 95 .mu.g of latanoprost and the latanoprost is
released in a therapeutically effective dose from the lacrimal
implant over a treatment period of at least 4 weeks, wherein the
IOP is reduced by at least 4 mm Hg from a baseline at week 4.
[0290] E22. A lacrimal implant comprising a unit dosage of about 95
.mu.g of latanoprost for use in the treatment of Open Angle
Glaucoma (OAG) or Ocular Hypertension (OH) in an eye by reducing
intraocular pressure (IOP) in the eye, wherein the latanoprost is
administered from a lacrimal implant comprising a sustained release
formulation of the 95 .mu.g of latanoprost and the latanoprost is
released in a therapeutically effective dose from the lacrimal
implant over a treatment period of at least 8 weeks, wherein the
IOP is reduced by at least 4 mm Hg from a baseline at week 8.
[0291] E23. A lacrimal implant comprising a unit dosage of about 95
.mu.g of latanoprost for use in the treatment of Open Angle
Glaucoma (OAG) or Ocular Hypertension (OH) in an eye by reducing
intraocular pressure (IOP) in the eye, wherein the latanoprost is
administered from a lacrimal implant comprising a sustained release
formulation of the 95 .mu.g of latanoprost and the latanoprost is
released in a therapeutically effective dose from the lacrimal
implant over a treatment period of at least 12 weeks, wherein the
IOP is reduced by at least 4 mm Hg from a baseline at week 12.
[0292] E24. A lacrimal implant drug delivery system comprising a
unit dosage of about between 140 and 200 .mu.g of latanoprost for
use in the treatment of Open Angle Glaucoma (OAG) or Ocular
Hypertension (OH) in an eye by reducing intraocular pressure (IOP)
in the eye, comprising: providing the unit dosage of about between
140 and 200 .mu.g of latanoprost to an eye over a treatment period
of at least 4 weeks, wherein the latanoprost is administered from a
lacrimal implant comprising a sustained release formulation of the
latanoprost and the latanoprost is released in a therapeutically
effective dose from the lacrimal implant over the treatment period,
wherein the IOP is reduced by at least 5 mm Hg from a baseline at
week 4.
[0293] E25. A lacrimal implant drug delivery system comprising a
unit dosage of about between 140 and 200 .mu.g of latanoprost for
use in the treatment of Open Angle Glaucoma (OAG) or Ocular
Hypertension (OH) in an eye by reducing intraocular pressure (IOP)
in the eye, comprising: providing the unit dosage of about between
140 and 200 .mu.g of latanoprost to an eye over a treatment period
of at least 8 weeks, wherein the latanoprost is administered from a
lacrimal implant comprising a sustained release formulation of the
latanoprost and the latanoprost is released in a therapeutically
effective dose from the lacrimal implant over the treatment period,
wherein the IOP is reduced by at least 5 mm Hg from a baseline at
week 8.
[0294] E26. A lacrimal implant drug delivery system comprising a
unit dosage of about between 140 and 200 .mu.g of latanoprost for
use in the treatment of Open Angle Glaucoma (OAG) or Ocular
Hypertension (OH) in an eye by reducing intraocular pressure (IOP)
in the eye, comprising: providing the unit dosage of about between
140 and 200 .mu.g of latanoprost to an eye over a treatment period
of at least 12 weeks, wherein the latanoprost is administered from
a lacrimal implant comprising a sustained release formulation of
the latanoprost and the latanoprost is released in a
therapeutically effective dose from the lacrimal implant over the
treatment period, wherein the IOP is reduced by at least 5 mm Hg
from a baseline at week 12.
[0295] E27. A lacrimal implant drug delivery system comprising a
unit dosage of about 190 .mu.g of latanoprost for use in the
treatment of Open Angle Glaucoma (OAG) or Ocular Hypertension (OH)
in an eye by reducing intraocular pressure (IOP) in the eye,
comprising: providing the unit dosage of about 190 .mu.g of
latanoprost to an eye over a treatment period of at least 4 weeks,
wherein the latanoprost is administered from a lacrimal implant
comprising a sustained release formulation of the latanoprost and
the latanoprost is released in a therapeutically effective dose
from the lacrimal implant over the treatment period, wherein the
IOP is reduced by at least 5 mm Hg from a baseline at week 4.
[0296] E28. A lacrimal implant drug delivery system comprising a
unit dosage of about 190 .mu.g of latanoprost for use in the
treatment of Open Angle Glaucoma (OAG) or Ocular Hypertension (OH)
in an eye by reducing intraocular pressure (IOP) in the eye,
comprising: providing the unit dosage of about 190 .mu.g of
latanoprost to an eye over a treatment period of at least 8 weeks,
wherein the latanoprost is administered from a lacrimal implant
comprising a sustained release formulation of the latanoprost and
the latanoprost is released in a therapeutically effective dose
from the lacrimal implant over the treatment period, wherein the
IOP is reduced by at least 5 mm Hg from a baseline at week 8.
[0297] E29. A lacrimal implant drug delivery system comprising a
unit dosage of about 190 .mu.g of latanoprost for use in the
treatment of Open Angle Glaucoma (OAG) or Ocular Hypertension (OH)
in an eye by reducing intraocular pressure (IOP) in the eye,
comprising: providing the unit dosage of about 190 .mu.g of
latanoprost to an eye over a treatment period of at least 12 weeks,
wherein the latanoprost is administered from a lacrimal implant
comprising a sustained release formulation of the latanoprost and
the latanoprost is released in a therapeutically effective dose
from the lacrimal implant over the treatment period, wherein the
IOP is reduced by at least 4 mm Hg from a baseline at week 12.
[0298] E30. A lacrimal implant drug delivery system comprising a
unit dosage of about 141 .mu.g of latanoprost for use in the
treatment of Open Angle Glaucoma (OAG) or Ocular Hypertension (OH)
in an eye by reducing intraocular pressure (IOP) in the eye,
comprising: providing the unit dosage of about 141 .mu.g of
latanoprost to an eye over a treatment period of at least 8 weeks,
wherein the latanoprost is administered from a lacrimal implant
comprising a sustained release formulation of the latanoprost and
the latanoprost is released in a therapeutically effective dose
from the lacrimal implant over the treatment period, wherein the
IOP is reduced by at least 5 mm Hg from a baseline at week 8.
[0299] E31. A lacrimal implant drug delivery system comprising a
sustained release formulation of a therapeutic agent for use in the
treatment of Open Angle Glaucoma (OAG) or Ocular Hypertension (OH)
in an eye, comprising: (a) providing a first lacrimal implant
comprising the sustained release formulation of a therapeutic agent
for treating OAG or OH; (b) providing a second lacrimal implant
that does not comprise the therapeutic agent; and (c) inserting the
first and second lacrimal implant through an upper and lower
punctum into a lacrimal canaliculus of the same eye wherein the
therapeutic agent is released in a therapeutically effective dose
from the first lacrimal implant on a sustained basis over at least
four (4) weeks.
[0300] E32. A lacrimal implant drug delivery system comprising a
sustained release formulation of a therapeutic agent for use in the
treatment of Open Angle Glaucoma (OAG) or Ocular Hypertension (OH)
in an eye, comprising: (a) providing a first lacrimal implant
comprising the sustained release formulation of a therapeutic agent
for treating OAG or OH; (b) providing a second lacrimal implant
that does not comprise the therapeutic agent; and (c) inserting the
first and second lacrimal implant through an upper and lower
punctum into a lacrimal canaliculus of the same eye wherein the
therapeutic agent is released in a therapeutically effective dose
from the first lacrimal implant on a sustained basis over at least
eight (8) weeks.
[0301] E33. A lacrimal implant drug delivery system comprising a
sustained release formulation of a therapeutic agent for use in the
treatment of Open Angle Glaucoma (OAG) or Ocular Hypertension (OH)
in an eye, comprising: (a) providing a first lacrimal implant
comprising the sustained release formulation of a therapeutic agent
for treating OAG or OH; (b) providing a second lacrimal implant
that does not comprise the therapeutic agent; (c) inserting the
first and second lacrimal implant through an upper and lower
punctum into a lacrimal canaliculus of the same eye; and (d)
releasing the therapeutic agent from the first lacrimal implant as
a therapeutically effective dose on a sustained basis over at least
twelve (12) weeks.
[0302] E34. A lacrimal implant drug delivery system comprising a
sustained release formulation of a therapeutic agent for use in the
treatment of Open Angle Glaucoma (OAG) or Ocular Hypertension (OH)
in an eye by reducing intraocular pressure (IOP) in the eye,
comprising: (a) measuring the IOP of the patient to obtain a
baseline IOP before treatment; (b) providing the therapeutic agent
for treating OAG or OH as a sustained release formulation; (c)
delivering the sustained release formulation to the eye using the
lacrimal implant comprising the sustained release formulation; and
(d) releasing the therapeutic agent to the eye on a sustained basis
over at least 8 weeks wherein the IOP is reduced by at least 4 mmHg
from baseline at week 8.
[0303] E35. A lacrimal implant drug delivery system comprising a
sustained release formulation of a therapeutic agent for use in the
treatment of Open Angle Glaucoma (OAG) or Ocular Hypertension (OH)
in an eye by reducing intraocular pressure (IOP) in the eye,
comprising: (a) measuring the IOP of the patient to obtain a
baseline IOP before treatment; (b) providing the therapeutic agent
for treating OAG or OH as a sustained release formulation; (c)
delivering the sustained release formulation to the eye using a
lacrimal implant comprising the sustained release formulation; and
(d) releasing the therapeutic agent to the eye on a sustained basis
over at least 12 weeks wherein the IOP is reduced by at least 4.0
mmHg from baseline at week 12.
[0304] E36. A lacrimal implant drug delivery system comprising a
sustained release formulation of a therapeutic agent for use in the
treatment of Open Angle Glaucoma (OAG) or Ocular Hypertension (OH)
in an eye by reducing intraocular pressure (IOP) in the eye,
comprising: (a) measuring the IOP of the patient to obtain a
baseline IOP before treatment; (b) providing the therapeutic agent
for treating OAG or OH as a sustained release formulation; (c)
delivering the sustained release formulation to the eye using a
lacrimal implant comprising the sustained release formulation; and
(d) releasing the therapeutic agent to the eye on a sustained basis
over at least 12 weeks wherein the IOP is reduced by at least 5.0
mmHg from baseline at week 12.
[0305] The following Examples are provided to illustrate exemplary
embodiments of the invention and are not to be construed as
limiting the scope of the present invention.
EXAMPLES
Example 1--Evaluation of Safety and Efficacy of the Latanoprost
Punctal Plug Delivery System (L-PPDS) Containing Latanoprost
[0306] A Phase II, open-label, clinical study was conducted in
human subjects with ocular hypertension (OH) or open-angle glaucoma
(OAG) to evaluate safety and efficacy of the latanoprost punctal
plug delivery system (L-PPDS).
[0307] The Phase II trial featured simultaneous placement of
punctal plugs in both the upper and lower puncta for delivery of a
daily drug load with a goal of enabling comparable clinical
outcomes to that of daily administered Xalatan.RTM. eye drops. The
overall objective was a mean reduction in IOP of 5 mm Hg or
greater. The primary endpoint in this Phase II study was a mean
change in IOP from baseline (measured as mm Hg) at 2 weeks.
Secondary endpoints were the mean change in IOP from baseline at 4
weeks and mean percentage change in IOP at 2 weeks and 4 weeks. A
total of 95 ITT (Intent to Treat) subjects were included in the
L-PPDS treatments in this study. The mean IOP as baseline was 25.8
mm HG for this group (with a range of baseline of 22.5 mm Hg to 33
mm Hg).
[0308] After 2 weeks of L-PPDS treatment, IOP showed a
statistically significant mean change from baseline of -6.2 mm Hg
(95% C.I. -6.8, -5.6). At the end of week 2, 73% of subjects showed
an IOP reduction vs. baseline of 5 mm Hg or greater and 51% of
subjects showed a reduction of 6 mm Hg or greater. The mean
percentage change in IOP from baseline at 2 weeks was -24.3%, which
was statistically significant (95% C.I. -26.7, -21.9).
[0309] After 4 weeks of L-PPDS treatment, IOP showed a
statistically significant mean change from baseline of -5.7 mm Hg
(95% C.I. -6.5, -4.9). At the end of 4 weeks, 60% of subjects
showed an IOP reduction vs. baseline of 5 mm Hg or greater and 47%
of subjects showed a reduction of 6 mm or greater. The mean
percentage change in IOP from baseline at 4 weeks was also
statistically significant at 22.3% (95% C.I. -25.4, -19.2).
[0310] Subjects were fitted with L-PPDS containing specified
latanoprost concentrations in the upper L-PPDS (46 .mu.g) and the
lower L-PPDS (95 .mu.g).
Study Procedures
[0311] During the screening visit, the subjects were fitted with
the trial punctal plugs for approximately 15 minutes to 2 hours to
assess fitting and eligibility. Pre-washout IOP measurements were
determined in each eye of the patient, and adverse device events
(ADEs) were also monitored. After the trial fitting, subjects began
the washout period in which subjects were discontinued from topical
prostaglandin therapy to assess IOP eligibility for a minimum of 4
weeks and to a maximum of 6 weeks.
[0312] After the washout, baseline IOP was measured in each eye of
a patient on two separate visits that were 2 to 4 days apart (Day
-2 and Day 0 study visits), after the patient had washed out of
previous topical prostaglandin therapy.
[0313] At the start of the study (Day 0), each patient had an
L-PPDS inserted bilaterally into each puncta of each eyes and
inspected thereafter at each visit. If an L-PPDS was spontaneously
extruded, one replacement L-PPDS per patient was allowed. The
L-PPDS were removed at the Week 4 visit.
[0314] After placement of the L-PPDS, subjects were monitored for
any treatment-emergent or adverse events (Aes) during the 4-week
treatment period. Subjects had weekly follow-up visits with the
last study visit at Week 4. Tear volume was measured by a Schirmer
test with anesthesia over 5 minutes at Day 0 and at the last visit.
Visual acuity was measured with best correction using a Snellen
chart at every visit. Biomicroscopy examinations were performed in
each eye at every visit, including an inspection of the L-PPDS
placement. Treatment-emergent ocular and systemic Aes and
concomitant medications were monitored at every visit with
standardized questioning techniques. Automated perimetry was
performed to measure visual fields at the last visit. A funduscopy
examination was performed at the last visit.
[0315] Goldmann IOP measurements (the average of 3 measurements)
were measured in each eye at every visit. The baseline IOP was
taken on two separate days, at least 48 hours apart. Specifically,
IOP measurements were taken at 8:30 am (.+-.30 minutes) at each
visit.
L-PPDS
[0316] Each L-PPDS for the upper puncta was of a proprietary
punctal plug design and had a latanoprost strength of 46 .mu.g.
Inactive components were medical grade silicone, polyimide tubing,
DMPC, cyanoacrylate medical grade adhesive, and 2% green colorant.
Each L-PPDS was supplied in a separate sterilized mylar foil
pouch.
[0317] Each L-PPDS for the lower puncta was of a proprietary
punctal plug design and had a latanoprost strength of 95 .mu.g.
Inactive components are medical grade silicone, polyimide tubing,
DMPC, cyanoacrylate medical grade adhesive, and 2% green colorant.
L-PPDS for the lower puncta were preloaded on an insertion tool.
Each L-PPDS and insertion tool were supplied in a tray contained in
a sterilized mylar foil pouch.
[0318] FIG. 13 shows the mean reduction in intraocular pressure
(IOP) from baseline in weeks during the treatment period. FIG. 14
shows the percent of subjects that recorded an IOP reduction of
.gtoreq.5 mm Hg from baseline, .gtoreq.6 mm Hg from baseline, and
.gtoreq.7 mm Hg from baseline, in weeks.
[0319] A secondary endpoint in the study was the percentage change
in average IOP from baseline at 2 weeks and 4 weeks for L-PPDS
treatment. FIG. 15 shows the mean reduction in IOP from baseline in
weeks during the treatment period. At 2 weeks, the percentage
change from baseline of -24.3% (95% C.I. -26.7, -21.9) was
statistically significant, and at 4 weeks, the percentage change
from baseline of -22.3% (95% C.I. -25.4, -19.2) was also
statistically significant.
[0320] The IOP reduction results are summarized in the Table 4:
TABLE-US-00004 TABLE 4 Mean change and % change in IOP in weeks for
L-PPDS containing latanoprost concentration of 141 .mu.g Mean
Change in IOP from % Change in IOP Baseline (95% C.I.) from
Baseline (95% C.I.) 2 weeks -6.2 (-6.8, -5.6) -24.3% (-26.7%,
-21.9%) (n = 70) 4 weeks -5.7 (-6.5, -4.9) -22.3% (-25.4%, -19.2%)
(n = 53)
Plug Retention Results
[0321] The lower punctal plug achieved 94% or greater retention per
subject across the duration of the 4 week study. The upper punctal
plug showed a retention rate of 40% per subject across the duration
of the study.
Assessment of Treatment Safety and Tolerability
[0322] The L-PPDS was well tolerated over the testing period. The
majority of AEs were ocular in nature, however, none were serious
AEs. The most frequently reported AE was mild to moderate tearing.
Few subjects experienced any discomfort related to the punctal
plugs with most subjects having either no awareness or mild
awareness of the punctal plugs by week 4.
Example 2--Comparison of Clinical Studies of the L-PPDS at
Different Dosages
[0323] A number of clinical studies have been conducted to assess
the safety, efficacy, and dosing for L-PPDS treatment in more than
300 human subjects with OH or OAG. These studies have investigated
the preliminary safety and efficacy of L-PPDS over the dose range
of 3.5 to 95 .mu.g per eye, primarily delivered via an L-PPDS
positioned in the lower puncta. See, for example,
ClinicalTrials.gov Identifier: NCT00967811, "An Open-Label, Phase 2
Study of Different Formulations (E1 and E2) of the Latanoprost
Punctal Plug Delivery System (L-PPDS) in Subjects With Ocular
Hypertension (OH) or Open-Angle Glaucoma (OAG)," Study Start Date:
August 2009, (other study ID number: PPL GLAU 07), incorporated
herein by reference; and ClinicalTrials.gov Identifier:
NCT01037036, "An Open-Label, Phase 2 Study of the Latanoprost
Punctal Plug Delivery System (L-PPDS) With Adjunctive Xalatan.RTM.
Eye Drops in Subjects With Ocular Hypertension (OH) or Open-Angle
Glaucoma (OAG)," Study Start Date: Dec. 17, 2009, (other study ID
number: PPL GLAU 08), incorporated herein by reference. Based on
the published clinical results for IOP reduction associated with
Xalatan.RTM. eye drops, the magnitude of mean IOP reductions has
been less than expected; however, results for L-PPDS show that some
subjects had IOP reductions that would be expected with
Xalatan.RTM.. All studies have occluded only one punctum per eye.
The overall mean IOP reduction for the L-PPDS was similar among
most of the studies (range -3 to -5 mmHg), regardless of
latanoprost concentration from 3.5 .mu.g to 95 .mu.g per eye.
Specifically, the mean IOP reduction according to the clinical
study described in Example 1 and the clinical studies of the L-PPDS
containing latanoprost concentrations of 44 .mu.g and 81 .mu.g, see
ClinicalTrials.gov Identifier: NCT00820300, "An Open-Label, Phase 2
Study of the Latanoprost Punctal Plug Delivery System (L-PPDS) in
Subjects With Ocular Hypertension (OH) or Open Angle Glaucoma
(OAG)," Study Start Date: January 2009, (other study ID number: PPL
GLAU 03), incorporated herein by reference, and two different 95
.mu.g formulations were compared, where the two 95 .mu.g
formulations (E1 and E2) were developed to deliver different
average daily doses, see ClinicalTrials.gov Identifier:
NCT00967811, "An Open-Label, Phase 2 Study of Different
Formulations (E1 and E2) of the Latanoprost Punctal Plug Delivery
System (L-PPDS) in Subjects With Ocular Hypertension (OH) or
Open-Angle Glaucoma (OAG)," Study Start Date: August 2009, (other
study ID number: PPL GLAU 07), incorporated herein by reference.
Table 5 summarizes the range of mean IOP change from baseline
during the first 4 weeks period of the L-PPDS treatments in the
clinical studies. Table 6 summarizes the IOP change (mm Hg) in
number (percent) of subjects in weeks 2 and 4.
TABLE-US-00005 TABLE 5 Mean IOP change from baseline in clinical
studies Study ID GLAU 11 GLAU 03 GLAU 07 (Example 1) L-PPDS 44
.mu.g 81 .mu.g 95 .mu.g E1 95 .mu.g E2 141 .mu.g Formulation (N =
57) (N = 53) (N = 42) (N = 41) (N = 95) Range of Mean -3.5 to -3.6
-3.0 to -3.4 -3.5 to -4.2 -3.9 to -4.7 -5.7 to -6.8 IOP Change from
Baseline: Weeks 1 to 4 (mmHg)
TABLE-US-00006 TABLE 6 IOP Changes in % Subjects Study ID GLAU 03
GLAU 07 GLAU 11 L-PPDS 44 .mu.g 81 .mu.g 95 .mu.g E1 95 .mu.g E2
141 .mu.g Formulation (N = 57) (N = 53) (N = 42) (N = 41) (N = 95)
Week 2 .gtoreq.5 31% 25% 31% 22% 73% .gtoreq.6 24% 16% 17% 17% 51%
.gtoreq.7 16% 4% 12% 15% 36% Week 4 .gtoreq.5 35% 29% 38% 31% 60%
.gtoreq.6 23% 22% 15% 21% 47% .gtoreq.7 8% 12% 13% 10% 28%
[0324] No mean IOP change of .gtoreq.5 mm Hg was observed within
the 4 weeks duration of treatments of L-PPDS containing latanoprost
concentrations of 44 .mu.g, 81 .mu.g, and 95 .mu.g. The mean IOP
reductions were significantly greater with L-PPDS containing a
combined latanoprost concentration of 141 .mu.g recorded in the
clinical study described in Example 1, compared with L-PPDS
containing lower lantanoprost doses. The mean IOP change from
baseline for L-PPDS with a combined latanoprost concentration of
141 .mu.g was substantial, from -5.7 mm Hg to -6.8 mm Hg.
Example 3--Method of Preparation L-PPDS (95 .mu.g) Cores
[0325] NuSil Silicone MED6385 part A was stirred for a minimum of 5
minutes, and 63 mg of which was weighed and transferred onto a
glass slide. To the same glass slide was added Latanoprost
(obtained from Everlight Chemical, Taipei, Taiwan) (48 mg),
dimyristoylphosphatidylcholine (DMPC) (9 mg) and NuSil Med6382
crosslinker (2.4 mL). Using a 0.5 .mu.L Hamilton Syringe, Nusil
MED6385 part B (0.348 .mu.L) was transferred directly onto a mini
spatula. The latanoprost, NuSil MED6382 crosslinker, NuSil Silicone
MED-6385 part B and DMPC were mixed together for 2-5 minutes to
form a homogenous mixture. The resulting mixture was combined with
NuSil Silicone MED6385 part A and was mixed for another 2 minutes
to form a homogenous mixture, which was immediately transferred
into a previously prepared syringe assembly. The syringe was then
attached to polyimide tubing (0.024'' OD) by way of an adapter. The
polyimide tubing was kept at a temperature of 4.degree. C. by way
of a cooling jacket. After 2 minutes, the mixture was injected into
the polyimide tubing by increasing the pressure of the system to 40
psi over 2.5 minutes. Once the mixture had extruded through the
polyimide tubing to the end, the tubing was cut and both ends were
clamped. The tube was placed into a humidity chamber at 40.degree.
C. and 80% relative humidity for 24-96 hours to cure the silicone,
and the tubing was cut into 1.0 mm lengths. Loctite 4305 (Henkel
Adhesives Technologies, Ltd.) was applied to the bottom end of the
cut tubing and cured for 20 seconds in a 100 W UV curing chamber.
These cores were then inserted into the cavity of punctal plugs
with the glued end positioned in the bottom of the cavity.
Example 4--PP DEV 05: A Device Evaluation Study to Further Assess
the Physical and Clinical Characteristics of Prototype Punctal Plug
Design Iterations
Study Objective
[0326] To evaluate the physical and clinical performance
characteristics of punctal plug design iterations.
Study Design
[0327] This is a multicenter, device assessment, feasibility study
to assess the physical and clinical performance characteristics of
prototype punctal plugs. Up to approximately 500 subjects will be
enrolled at 5-15 sites in the US. No drug treatment will be
administered. The study will evaluate the physical (handling) and
clinical (comfort, tearing, retention) characteristics of punctal
plug prototypes. The study will be iterative, with data monitored
on an ongoing basis and design modifications to the punctal plugs
made if further improvements are indicated. An investigational plug
detection aid may also be evaluated.
[0328] Subjects will be enrolled into 1 of 2 groups. Group 1 will
undergo two 12-week plug placement periods. Group 2 will undergo
two 2-week plug placement periods followed by one 12-week plug
placement period. Plug placement will be attempted in the lower and
upper puncta of both eyes. Placement must be successful in both the
upper and lower puncta of at least 1 eye for the subject to be
eligible for the study. The Sponsor will inform the sites in
advance in writing which plug iterations to use for each subject
for each placement period. For Group 1, study visits will occur at
Day 0, and Weeks 4, 8, 12, 16, 20 and 24, with plug placement at
the Day 0 and Week 12 visits. For Group 2, study visits will occur
at Day 0 and Weeks 1, 2, 3, 4, 8, 12 and 16, with plug placement at
Day 0, Week 2, and Week 4.
[0329] A subject who completes or is withdrawn from the Group 1 or
Group 2 treatment schedule may be re-enrolled into the study (to
either Group 1 or Group 2). A re-enrolled subject will be assigned
a new subject number and undergo screening procedures again.
[0330] Safety will be assessed throughout the study.
Study Population
[0331] Subjects will be male and female volunteers, age 50 years or
older. Main exclusion criteria will include: [0332] History of, or
active, lid disease requiring lid scrubs (e.g., moderate or severe
blepharitis, dacryocystitis, meibomianitis) [0333] Structural lid
abnormalities (e.g., ectropion, entropion) [0334] Active anterior
segment inflammatory disease [0335] Ocular allergies [0336]
Habitual eye rubbing [0337] Previous intolerance of punctal plugs
(e.g., inflammatory reaction, granuloma, dacryocystitis, etc. due
to punctal plug wear) [0338] Laser eye surgery within the last 3
months or incisional eye surgery within the last 6 months.
Study Devices
[0339] The punctal plugs will be placed bilaterally into the upper
and lower puncta using an investigational insertion tool provided
with the plug or ophthalmic forceps. The techniques for insertion
and removal are similar to the procedures for other commercial
punctal plugs.
Study Variables
[0340] Device Performance: [0341] Retention rates [0342] Insertion
success [0343] Ease of use
[0344] Tolerability [0345] Comfort [0346] Tearing
Safety
[0346] [0347] Adverse device events (ADEs) [0348] Biomicroscopy
Study Procedures and Assessments:
[0349] Device Performance: [0350] For subjects who provide
additional consent, photographs of the punctal plugs may be taken
after their placement to observe their location in the lid margin;
videography of punctal plug placement and removal procedures may be
performed for future physician training. In-person observational
physician training of punctal plug placement and removal procedures
may also occur.
[0351] Tolerability: [0352] Subjects will rate the acceptability of
tearing and comfort according to a visual analog scale at every
visit.
[0353] Safety: [0354] Biomicroscopy will be performed in each eye
and ADEs will be collected at every study visit.
Sample Size and Statistical Analyses:
[0354] [0355] The sample size is based on clinical judgment and is
believed to be sufficient to meet the study objectives. All study
variables will be summarized descriptively. ADEs will be coded
using the Medical Dictionary for Regulatory Activities (MedDRA) and
summarized descriptively by system organ class and preferred
term.
Example 5: GLAU 12: A Phase 2 Dose Evaluation Study for the
Latanoprost Punctal Plug Delivery System (L-PPDS) in Subjects With
Ocular Hypertension (OH) or Open-Angle Glaucoma (OAG)
[0356] The Phase II trial featured simultaneous placement of
punctal plugs in both the upper and lower puncta for delivery of a
daily drug load with a goal of enabling comparable clinical
outcomes to that of daily administered Xalatan.RTM. eyedrops. The
objective of this study was to evaluate the efficacy, safety and
duration of effect of the L-PPDS at two dose levels (141 .mu.g and
190 .mu.g).
[0357] Study PPL GLAU 11 (Example 1 and FIGS. 13-15) showed that
occlusion of both puncta with the L-PPDS at a total latanoprost
dose per eye of 141 .mu.g significantly reduced IOP for up to 4
weeks. This study, in which the left eye has the same dose as PPL
GLAU 11 and the right eye has a 95 .mu.g L-PPDS in both the upper
and lower puncta, is designed to replicate the results of PPL GLAU
11 and to assess the effect of a higher dose. In addition, this
study will run for 12 weeks to determine whether the effect
observed in PPL GLAU 11 is durable for a longer time period.
[0358] The latanoprost dose for the left eye (46 .mu.g L-PPDS in
the upper punctum and 95 .mu.g L-PPDS in the lower punctum) was
chosen in order to replicate the dose used in Study PPL GLAU 11.
The latanoprost dose for the right eye (95 .mu.g L-PPDS in both the
upper and lower puncta) was chosen because it is the highest dose
currently attainable.
[0359] The highest latanoprost dose in this study (190 .mu.g
delivered over 3 months) is equivalent to the amount in
approximately 127 drops of Xalatan. The prescribed Xalatan dose
over 3 months is 90 drops (1 drop/day), so 190 .mu.g latanoprost
delivered over 3 months represents a dose about one-third higher
than that for Xalatan drops.
Main Study Design
[0360] Subjects diagnosed with bilateral OH or OAG who are
treatment naive or managed with up to 2 glaucoma medications were
eligible for study screening. IOP eligibility was established at
baseline prior to enrollment in the study.
[0361] After eligibility was established, subjects received
treatment for 12 weeks as follows: [0362] Right eye: 95 .mu.g
L-PPDS inserted in the lower puncta and 95 .mu.g L-PPDS in the
upper puncta. [0363] Left eye: 95 .mu.g L-PPDS inserted in the
lower puncta and a 46 .mu.g L-PPDS in the upper puncta.
Addendum Study Design
[0364] The addendum study included subjects enrolled in the main
study who had a decrease in IOP of >5 mmHg from baseline at Day
7 in response to two 95 .mu.g L-PPDS and who retained both plugs in
at least 1 eye for at least 4 weeks in the first treatment cycle.
Eligible subjects started L-PPDS Cycle 2 (C2) within 30 days of
removal of L-PPDS in the main study. On C2 Day 0, subjects had 95
.mu.g L-PPDS inserted in the upper and lower puncta of both eyes
for 8 weeks (C2). At the end of C2, another set of 95 .mu.g L-PPDS
were inserted in the upper and lower puncta of both eyes for 4
weeks (Cycle 3 [C3]). Subjects were followed up for assessment of
safety and IOP effect with visits at 1, 2, 4, 6 and 8 weeks of C2,
and 1, 2 and 4 weeks of C3. Safety was monitored as in the main
study. Analysis of IOP effect was primarily based on change from
baseline in IOP measurements (the baseline value from the main
study was used to determine IOP change from baseline in subsequent
cycles) and between-cycle comparisons.
[0365] Treatment
[0366] Main Study
[0367] Investigational L-PPDS for the lower puncta of both eyes was
the L67 design with a latanoprost dose of 95 .mu.g. See, FIG. 33.
Investigational L-PPDS for the upper puncta was the L69 design with
a latanoprost dose of 95 .mu.g for the right eye, and the L72
design with a latanoprost dose of 46 .mu.g for the left eye.
[0368] The total latanoprost dose was 190 .mu.g for the right eye
and 141 .mu.g for the left eye.
[0369] At the Day 0 visit, subjects had the plugs inserted
bilaterally into the upper and lower puncta. If any plug
spontaneously extruded, it was to be replaced with an L67 95-.mu.g
L-PPDS, if possible. The number of replacements was limited to 2,
and once a subject lost plugs from both eyes, the subject was
withdrawn from the study. The LPPDS was removed at the Week 12
visit.
Addendum Study
[0370] Investigational L-PPDS for all puncta had a latanoprost dose
of 95 .mu.g. The total latanoprost dose was 190 .mu.g/eye. Subjects
underwent an 8-week L-PPDS treatment cycle (C2) followed by a
4-week L-PPDS treatment cycle (C3). If any plug spontaneously
extruded, it was to be replaced; however, once a subject lost a
plug from each eye in C2, the remaining L-PPDS were removed, and
the subject started C3. Once a subject lost a plug from each eye in
C3 the subject was withdrawn from the study.
[0371] Subjects were followed up for assessment of safety and IOP
effect. Safety was monitored with adverse events (AEs), IOP,
Snellen best-corrected visual acuity (BCVA) or pinhole visual
acuity (method should be consistent for a given subject throughout
the study), biomicroscopy, subject tearing and comfort assessments,
automated perimetry, and funduscopy. Analysis of IOP effect was
primarily based on change from baseline in IOP measurements.
[0372] To address the study objective of evaluating the safety and
IOP lowering effects of the L-PPDS, IOP results were compared to
baseline IOP. The IOP entry criteria included precautions to ensure
that washout (if applicable) is complete and baseline IOP is stable
(e.g., minimum 5 mmHg change from pre-screening and less than 3
mmHg difference in IOP between 2 baseline visits 2 days apart).
[0373] Providing different treatments to each of a subject's eyes
necessitated that the eyes be independent of each other for the
results to be valid.
Number of Subjects and Statistical Analyses
[0374] Approximately 55 subjects were enrolled to have 35 eyes
available for each treatment for the evaluable analysis. With a
sample size of 35 evaluable eyes in each treatment group, a 2-sided
95.0% confidence interval (CI) for the mean IOP change from
baseline extended 1.0 mm Hg from the observed mean, assuming that
the standard deviation was known to be 3.0 mm Hg and the CI is
based on the large sample z statistic. The standard deviation of
3.0 mm Hg used in the above sample size calculation was based on
results of the L-PPDS clinical studies conducted to date.
[0375] The primary efficacy variable was the change from baseline
in IOP measurements and the primary analysis time point will be at
4 weeks. Other IOP variables listed above were secondary efficacy
variables. For analyses using the intent-to-treat (ITT) data set,
all data from all subjects with at least 1 follow-up IOP
measurement were included. For analyses using the evaluable (EVAL)
data set, data from subjects or visits with significant protocol
deviations were excluded.
Inclusion Criteria
[0376] To be eligible for the study, subjects must fulfill all of
the following criteria:
[0377] Subjects who are men or women >18 years old.
[0378] Subjects diagnosed with bilateral OAG or OH. Subjects may be
treatment naive or managed with up to 2 medications (combination
products such as Cosopt.RTM. will be considered 2 medications).
[0379] For subjects on a topical prostaglandin treatment (as
monotherapy or in combination): Screening IOP is .ltoreq.21.0 mmHg.
[0380] Subjects who can be fitted with L-PPDS in all 4 puncta at
Day 0. [0381] Subjects whose baseline IOP measured at 2 baseline
visits (i.e., average of IOP values obtained at 2 baseline visits)
meets the following criteria in each eye after the screening
period: [0382] a. .gtoreq.22.0 mmHg [0383] b. .ltoreq.34.0 mmHg
[0384] For subjects on topical prostaglandin therapy at screening:
Is increased .gtoreq.5.0 mmHg from screening. [0385] Subjects whose
baseline IOP measurements in each eye are .ltoreq.3 mmHg apart
between 2 sequential baseline visits. [0386] Subjects who have
central corneal thickness in each eye .gtoreq.500 .mu.m and
.gtoreq.600 .mu.m. [0387] Subjects who have Snellen BCVA 20/100 or
better in each eye. [0388] Subjects who are women of child-bearing
potential must not be pregnant or lactating, must have a negative
pregnancy test at screening and must be practicing an adequate
method of birth control. Acceptable methods of birth control
include intrauterine device (IUD); oral, dermal ("patch"),
implanted or injected contraceptives; tubal ligation; and barrier
methods with spermicide. [0389] Subjects who sign an approved
informed consent form for the study. [0390] Subjects who are
willing to comply with the protocol.
Study Procedures and Assessments
[0391] IOP measurements were determined in each eye at the
screening visit. The duration of the screening period depended on
the time required for washout of topical ocular hypotensive
therapy. Washout was not required for treatment-naive subjects.
[0392] After the screening period, IOP measurements were determined
in each eye on 2 separate visits, 2 to 4 days apart. For
treatment-naive subjects the initial screening visit was considered
as the first visit for determination of baseline IOP.
[0393] The L-PPDS treatment period was 12 weeks. Study visits
occurred at Days 1, 3, 7, and 14, and Weeks 3, 4, 6, 8, 10 and 12.
(Subjects who were prostaglandin-naive at study entry had a visit
at Week 14 after the Xalatan run-out period is complete.) There was
a follow-up telephone call 3 days after the last visit. The
following tests and procedures were performed during study
follow-up. [0394] Goldmann IOP measurements (the average of 3
measurements) will be measured in each eye at every visit. The
baseline IOP will be taken on 2 separate days, at least 48 hours
apart. IOP measurements must be taken at 8:30 am (.+-.30 minutes)
at each visit. [0395] Visual acuity will be measured with best
correction or pinhole using a Snellen chart at every visit; the
method (best correction or pinhole) should be consistent for a
given subject throughout the study. [0396] Biomicroscopy
examinations, including an inspection of L-PPDS placement, will be
performed in each eye at every visit. [0397] Subjects will rate the
acceptability of the tearing and comfort level of the plugs, and
the frequency of tearing, on a visual analog scale at each visit
starting at Day 0. Subjects will also be asked at the end of the
study which they prefer: punctal plugs or eye drops. [0398]
Treatment-emergent ocular and systemic AEs and concomitant
medications will be monitored at every visit with standardized
questioning techniques. [0399] Investigators will rate the ease of
insertion of the plugs. [0400] Automated perimetry will be
performed to measure visual fields at screening and Week 12. [0401]
A funduscopy examination will be performed at screening and Week
12.
[0402] All ocular procedures were performed by an experienced and
appropriately qualified individual(s). Subjects who discontinue the
study treatment prematurely underwent the tests and procedures for
the last visit.
[0403] It is unexpected for the L-PPDS to malfunction and release
all or a major portion of its contents in a short period of time.
The expected exposure to latanoprost (190 .mu.g delivered over 3
months) is within the safety profile established in a series of
ocular toxicity studies conducted to support the FDA approval of
Xalatan. Specifically, no adverse effects were observed in rabbits
with twice-daily ocular instillation of latanoprost doses up to 50
.mu.g per eye for 52 weeks (100 .mu.g/eye/day). In a similar
52-week ocular study in cynomolgus monkeys, the only effects
observed at doses up to 50 .mu.g/eye given twice daily (100
.mu.g/eye/day) were a reversible change in the aspect of the
palpebral fissure and a non-reversible increase in iris
pigmentation, which were not judged to be deleterious (Xalatan
Product Monograph 2011). In a study of 28 healthy volunteers, in
which 1 drop of latanoprost 50 .mu.g/mL was administered once daily
in 1 eye and 4 times daily in the other eye for 2 weeks, transient
photophobia, cells, and mild flare were common during the 4-dose
regimen, but these effects resolved spontaneously without cessation
of treatment (Linden and Alm 2001).
[0404] Results: Interim analysis (n=83) showed sustained mean IOP
decreases from baseline at Week 8 greater than 5 mmHg for the 190
.mu.g dose, with somewhat lower levels for the 141 .mu.g dose.
[0405] Final Study Results: A total of 57 subjects enrolled in the
study. Men and women were represented approximately evenly (51% and
49%, respectively). Subjects were Caucasian (37%), Hispanic (32%),
Black (26%), and Asian (5%), with an average age of 65 years. Most
eyes were assessed to have primary open angle glaucoma (74% right
eyes, 69% left eyes), while the other eyes had ocular hypertension
(26% right eyes, 31% left eyes). Mean IOP at screening was 18.79
mmHg for right eyes and 18.97 mmHg for left eyes; by baseline
(after the washout period) mean IOP had increased to 24.75 mmHg for
right eyes and 24.66 mmHg for left eyes.
[0406] At Week 4, 47 subjects (82%) had IOP measured; at Week 12,
35 subjects (61%) had IOP measured. A total of 44 subjects (77%)
completed the main study (Week 12). Twelve subjects (21%)
participated in the Xalatan run-out. Nineteen subjects (100%)
entered the addendum study, and 12 (62%) completed C2 (Week 8) and
had IOP measured at that visit. Six subjects (100%) began C3, and 5
subjects (83%) completed C3 (Week 4) had IOP measured at that
visit.
[0407] The ITT data set included 109 eyes, EVAL included 101 eyes,
and safety included all 57 subjects. Five subjects received 190
.mu.g latanoprost in both eyes (95 .mu.g L-PPDS in upper and lower
puncta of both eyes) because the 46 .mu.g L-PPDS was not available
when they started treatment. Consequently, although the ITT data
set included 57 subjects (114 eyes), the average IOP from the eyes
of the 5 subjects who received 190 .mu.g latanoprost in both eyes
was used for the analysis, so ITT results are based on 109 data
points (eyes).
[0408] Treatment with L-PPDS resulted in significant mean IOP
decreases from baseline across all time points (Table 7 and FIG.
23) in the main study.
TABLE-US-00007 TABLE 7 Summary of IOP (mmHg) Results ITT (N = 109
eyes) EVAL (N = 101 eyes) Visit (Main Study) Observed IOP
Excl.sup.b Observed IOP Excl.sup.b Day 14 n 99 83 91 76 Mean IOP
18.9 18.8 19.0 18.8 Mean IOP .dwnarw. -5.8 -6.0 -5.8 -5.9 CI
(-6.40, -5.26) (-6.58, -5.42) (-6.37, -5.23) (-6.51, -5.36) Week 4
n 89 73 81 67 Mean IOP 19.3 19.3 19.2 19.2 Mean IOP .dwnarw. -5.6
-5.6 -5.7 -5.7 CI (-6.12, -5.05) (-6.13, -5.09) (-6.27, -5.16)
(-6.21, -5.16) Week 8 n 70 54 62 48 Mean IOP 20.6 20.3 20.5 20.2
Mean IOP .dwnarw. -4.3 -4.7 -4.3 -4.7 CI (-4.96, -3.64) (-5.29,
-4.00) (-5.06, -3.59) (-5.37, -3.95) Week 12 n 67 48 61 44 Mean IOP
20.8 21.1 20.8 21.2 Mean IOP .dwnarw. -4.0 -3.9 -4.1 -3.8 CI
(-4.77, -3.28) (-4.77, -3.01) (-4.86, -3.28) (-4.75, -2.89)
[0409] Significant reduction in mean IOP was observed at Weeks 4
and 6 (-5.4 and -5.8 mmHg, respectively, in the ITT group. No
meaningful difference in IOP results was observed between eyes (ie,
190 .mu.g and 141 .mu.g latanoprost).
[0410] In the main study, retention rate of L-PPDS in the lower
puncta was .gtoreq.96% through Week 12. Retention of upper L-PPDS
was 69%, 53%, and 48% at Weeks 4, 8, and 12, respectively. In C2,
upper L-PPDS retention was notably higher than in the main study
(90% and 88% at Weeks 4 and 8, respectively).
[0411] Study Conclusions: Treatment with L-PPDS in both puncta
(total latanoprost dose of either 190 or 141 .mu.g/eye) resulted in
a clinically meaningful and statistically significant reduction in
IOP from baseline of approximately 6 mmHg after 4 weeks (primary
endpoint).
Example 6: GLAU 13: A Randomized Phase 2 Study of the Effect of
Plug Placement on Efficacy and Safety of the Latanoprost Punctal
Plug Delivery System (L-PPDS) in Subjects With Ocular Hypertension
(OH) or Open Angle Glaucoma (OAG)
[0412] Study PPL GLAU 11 (Example 1 and FIGS. 13-15) showed that
occlusion of both puncta with the L-PPDS at a total latanoprost
dose per eye of 141 .mu.g significantly reduced IOP for up to 4
weeks. This effect could have been due to the dose, double
occlusion of the puncta, placement of the L-PPDS in the upper
punctum, or a combination thereof. This study (GLAU 13), in which
the L-PPDS will be placed in either the upper or lower puncta, with
the other punctum either left open or blocked by a punctal plug
that does not contain latanoprost, will assess whether the effect
observed in Study PPL GLAU 11 was due to delivery of latanoprost
from the upper punctum, or was a result of having both puncta
blocked, thus increasing the residence time of latanoprost in the
tear film and making more drug available to the cornea. In
addition, this study will run for 12 weeks to determine the
duration of effect.
[0413] Each eye in this study had one 95 .mu.g L-PPDS. This dose
was chosen because it is the highest dose available when only one
lacrimal implant is utilized. The dose of 95 .mu.g (delivered over
3 months) is equivalent to the amount in approximately 63 drops of
Xalatan. The prescribed Xalatan dose over 3 months is 90 drops (1
drop/day), so 95 .mu.g latanoprost delivered over 3 months
represents a dose about one-third lower than that for Xalatan
drops.
[0414] Subjects diagnosed with bilateral OH or OAG who were
treatment naive or managed with up to 2 glaucoma medications were
eligible for study screening. During the washout period subjects
were discontinued from glaucoma therapy (if applicable).
Intraocular pressure (IOP) eligibility was established at baseline
prior to enrollment in the study. Successful plug insertion on Day
0 was required for study enrollment.
[0415] After eligibility was established, subjects received
treatment for 12 weeks. There were 3 different treatments studied,
as follows:
TABLE-US-00008 Upper Punctum Lower Punctum Treatment A 95 .mu.g
L-PPDS Punctal plug (no latanoprost) Treatment B 95 .mu.g L-PPDS No
plug Treatment C Punctal plug 95 .mu.g L-PPDS (no latanoprost)
[0416] The total dose of Latanoprost per eye was 95 .mu.g.
[0417] Subjects received different treatments in each eye. Because
there are 3 different treatments, subjects were randomly assigned
to 1 of 3 groups to determine what treatment combination they would
receive, as follows:
TABLE-US-00009 Eye Treatment Upper Punctum Lower Punctum Group 1
Right A 95 .mu.g L-PPDS Punctal plug Left B 95 .mu.g L-PPDS No plug
Group 2 Right A 95 .mu.g L-PPDS Punctal plug Left C Punctal plug 95
.mu.g L-PPDS Group 3 Right B 95 .mu.g L-PPDS No plug Left C Punctal
plug 95 .mu.g L-PPDS
[0418] Subjects were followed up for assessment of safety and IOP
effect. Safety was monitored with adverse events (AEs), IOP,
Snellen best-corrected visual acuity (BCVA), biomicroscopy, subject
tearing and comfort assessments, automated perimetry, and
funduscopy. Analysis of IOP effect was primarily based on change
from baseline in IOP measurements.
Discussion of Study Design
[0419] To address the study objective of evaluating the safety and
IOP lowering effects of the L-PPDS, IOP results were compared to
baseline IOP. The IOP entry criteria included precautions to ensure
that washout (if applicable) was complete and baseline IOP was
stable (e.g., minimum 5 mmHg change from the start of screening and
less than 3 mmHg difference in IOP between 2 baseline visits 2 days
apart).
[0420] Providing different treatments to each of a subject's eyes
necessitates that the eyes be independent of each other for the
results to be valid. Studies have shown that the contralateral
effect of prostaglandins is minimal, due to their rapid systemic
metabolism, and using different treatments on each of a subject's
eyes will produce valid and independent results (Ziai et al., The
effects on aqueous dynamics of PhXA41, a new prostaglandin F2
.alpha. analogue, after topical application in normal and ocular
hypertensive human eyes. Arch Ophthalmol. 111:1351-1358 (1993);
Realini et al., The uniocular drug trial and second-eye response to
glaucoma medications. Ophthalmol. 111:421-426 (2004)).
Contralateral treatment is also a more efficient study design as it
requires fewer subjects to be treated. The decision to use
contralateral treatment for this study was made in consultation
with glaucoma experts.
Study Population
[0421] Approximately 80 subjects were enrolled in the study to have
35 eyes available for the evaluable analysis for each treatment.
With a sample size of 35 evaluable eyes for each treatment, a
2-sided 95.0% confidence interval (CI) for the mean IOP change from
baseline will extend 1.0 mmHg from the observed mean, assuming that
the standard deviation is known to be 3.0 mmHg and the CI is based
on the large sample z statistic. The standard deviation of 3.0 mmHg
used in the above sample size calculation was based on results of
the L-PPDS clinical studies conducted to date.
Main Inclusion Criteria:
[0422] Diagnosed with bilateral OH or OAG and either
treatment-naive or currently managed with up to 2 medications.
Combination products such as Cosopt.RTM. will be considered 2
medications. [0423] For subjects on a topical prostaglandin
treatment either as monotherapy or in combination: Screening IOP is
.gtoreq.21.0 mmHg. [0424] Can be fitted with punctal plugs and
L-PPDS on Day 0. [0425] Baseline IOP measured at 2 baseline visits
meets the following criteria in each eye after the screening
period: [0426] c. .gtoreq.22.0 mmHg [0427] d. .ltoreq.34.0 mmHg
[0428] e. For subjects on topical prostaglandin therapy at
screening: Is increased .gtoreq.5.0 mmHg from screening [0429]
Baseline IOP measurements are .ltoreq.3 mmHg apart between 2
sequential baseline visits in each eye. [0430] Central corneal
thickness .gtoreq.500 .mu.m and .ltoreq.600 .mu.m in each eye.
Study Treatments
L-PPDS Treatment
[0431] At the Day 0 visit, investigational L-PPDS with 95 .mu.g of
Latanoprost was inserted into either the upper or lower puncta of
each eye (depending on the treatment group). The other punctum of
each eye had either a solid punctal plug (containing no
latanoprost), or did not have a plug inserted, depending on the
treatment group. The total latanoprost dose for each eye was 95
.mu.g. The plugs were removed at the Week 12 visit.
Study Variables
[0432] IOP, IOP change from baseline, and percentage IOP change
from baseline; BCVA and change from baseline BCVA; Biomicroscopy
examination variables; Subject tearing and comfort scores;
Funduscopy variables; Automated perimetry variables; Adverse events
(AEs); Concomitant medications; Proportion of subjects who lose an
L-PPDS/punctal plug; Proportion of eyes that lose an L-PPDS/punctal
plug; and Investigator assessment of L-PPDS insertion
Study Procedures and Assessments
[0433] IOP measurements were determined in each eye at the
screening visit. The duration of the washout period depended on the
time required for washout of topical ocular hypotensive therapy.
Washout was not required for treatment-naive subjects. After the
washout period, IOP measurements were determined in each eye on 2
separate visits, 2 to 4 days apart. For treatment-naive subjects
the initial screening visit was considered as the first visit for
determination of baseline IOP.
[0434] The L-PPDS treatment period was 12 weeks. Study visits
occurred at Days 1, 3, 7, and 14, and Weeks 3, 4, 6, 8, 10 and 12.
(Subjects who were prostaglandin-naive at study entry will also
have a visit at Week 14 after the Xalatan run-out period is
complete.) There was a follow-up telephone call 3 days after the
last visit. The following tests and procedures were performed
during study follow-up.
[0435] Goldmann IOP measurements (the average of 3 measurements)
were measured in each eye at every visit. The baseline IOP was
taken on 2 separate days, at least 48 hours apart. IOP measurements
must be taken at 8:30 am (.+-.30 minutes) at each visit.
[0436] Visual acuity was measured with best correction or pinhole
using a Snellen chart at every visit; the method (best correction
or pinhole) were consistent for a given subject throughout the
study.
[0437] Biomicroscopy examinations, including an inspection of
L-PPDS placement was performed in each eye at every visit.
[0438] Subjects will rate the acceptability of the tearing and
comfort level of the plugs, and the frequency of tearing, on a
visual analog scale at each visit starting at Day 0. Subjects were
also asked at the end of the study which they prefer: punctal plugs
or eye drops.
[0439] Treatment-emergent ocular and systemic AEs and concomitant
medications were monitored at every visit with standardized
questioning techniques.
[0440] Investigators rated the ease of insertion of the plugs.
[0441] Automated perimetry was performed to measure visual fields
at screening and Week 12.
[0442] A funduscopy examination was performed at screening and Week
12.
[0443] All ocular procedures are performed by an experienced and
appropriately qualified individual(s). Subjects who discontinued
the study treatment prematurely underwent the tests and procedures
for the last visit.
[0444] It is unexpected for the L-PPDS to malfunction and release
all or a major portion of its contents in a short period of time.
The expected exposure to latanoprost (95 .mu.g delivered over 3
months) was within the safety profile established in a series of
ocular toxicity studies conducted to support the FDA approval of
Xalatan. Specifically, no adverse effects were observed in rabbits
with twice-daily ocular instillation of latanoprost doses up to 50
.mu.g per eye for 52 weeks (100 .mu.g/eye/day). In a similar
52-week ocular study in cynomolgus monkeys, the only effects
observed at doses up to 50 .mu.g/eye given twice daily (100
.mu.g/eye/day) were a reversible change in the aspect of the
palpebral fissure and a non-reversible increase in iris
pigmentation, which were not judged to be deleterious (Xalatan
Product Monograph 2011). In a study of 28 healthy volunteers, in
which 1 drop of latanoprost 50 .mu.g/mL was administered once daily
in 1 eye and 4 times daily in the other eye for 2 weeks, transient
photophobia, cells, and mild flare were common during the 4-dose
regimen, but these effects resolved spontaneously without cessation
of treatment (Linden and Alm, the effect on intraocular pressure of
latanoprost once or four times daily. Br. J. Ophthalmol.
85:1163-1166 (2001)).
IOP Variables and Analyses
[0445] The primary efficacy variable was IOP change from baseline
and the primary analysis time point will be at Week 4. The
secondary efficacy variables were IOP and percentage IOP change
from baseline.
[0446] Baseline IOP was defined as the average of 6 measurements: 3
measurements taken on Day -2 (end of screening period) and 3
measurements taken on Day 0 (before L-PPDS insertion).
[0447] The analyses of IOP variables were performed based on the
values from each eye. For analyses using the ITT data set, all data
from all eyes with at least 1 follow-up IOP measurement was
included. For analyses using the evaluable (EVAL) data set, data
from subjects, eyes or visits with significant protocol deviations
were excluded.
[0448] The primary and secondary IOP variables were summarized for
each treatment at each study visit using means with 95% CIs,
standard deviations, minimums, medians and maximums. The primary
and secondary IOP variables were summarized similarly based on the
difference between treatments within a subject. The calculations of
mean and 95% CI of the IOP change from baseline for each treatment
at Week 4 is considered the primary analysis. All the other
analyses are secondary analyses.
[0449] Interim results at week 8 (where n is the number of eyes),
with the 3 different plug placement configurations, showed IOP
decreases from baseline of -4.95 mmHg in Treatment group A (n=14),
-4.31 mm Hg in treatment group B (n=14) and -6.07 mmHg in treatment
group C (n=12). With the 95 .mu.g dose comparing 3 different plug
placement configurations (n=40), IOP decreases from baseline at
Week 8 ranged from -4.31 mmHg to -6.07 mmHg.
[0450] Final Study Results: A total of 77 subjects enrolled in the
study. Men and women were represented approximately evenly (47% and
53%, respectively). Most subjects were Caucasian (70%) or Black
(25%), with an average age of 66 years. Most eyes were assessed to
have open angle glaucoma (74%; of those, most were primary [98%]),
while the other eyes had ocular hypertension (26%). Mean IOP at
screening was 18.02 mmHg overall (18.3, 17.9, and 17.9 mmHg for
eyes who received Treatment A, B, and C, respectively); by baseline
(after the washout period) mean IOP had increased to 25.39 mmHg
overall (25.56, 25.00, and 25.61 mmHg for eyes who received
Treatment A, B, and C, respectively).
[0451] At Week 4, 66 subjects (86%) had IOP measured; at Week 12,
49 subjects (64%) had IOP measured. A total of 53 subjects (69%)
completed the study (Week 12),
[0452] The ITT data set included 154 eyes (53, 51, and 50 for
Treatments A, B, and C, respectively), EVAL included 148 eyes (49,
51, and 48 for Treatments A, B, and C, respectively), and safety
included all 77 subjects. Six eyes were completely excluded from
the EVAL analysis (both eyes of 3 subjects, 3 eyes from Treatment A
and 3 from Treatment C), and 2 additional eyes were excluded from
Week 8 only (both eyes of 1 subject, Treatments A and B); all eyes
were excluded because of concomitant medication.
[0453] Treatment with L-PPDS resulted in significant mean IOP
decreases from baseline with all treatments across all time points
(Table 8 and FIG. 23)
TABLE-US-00010 TABLE 8 Summary of IOP (mmHg) Results (ITT Observed)
Treatment A Treatment B Treatment Total Visit (N = 53) (N = 51) C
(N = 50) (N = 154) Day 14 n 51 48 45 144 Mean IOP 20.16 19.98 20.04
20.06 Mean IOP .dwnarw. -5.29 -4.86 -5.35 -5.17 CI (-6.29, -4.28)
(-5.67, -4.05) (-6.17, -4.53) (-5.67, -4.66) Week 4 n 45 46 41 132
Mean IOP 20.44 20.51 19.96 20.32 Mean IOP .dwnarw. -4.84 -4.38
-5.07 -4.75 CI (-6.01, -3.66) (-5.33, -3.43) (-6.11, -4.04) (-5.35,
-4.15) Week 8 n 63 41 35 112 Mean IOP 20.53 20.63 20.14 20.45 Mean
IOP .dwnarw. -4.65 -4.22 -4.88 -4.56 CI (-5.72, -3.58) (-5.18,
-3.25) (-5.77, -3.99) -5.11, -4.01) Week 12 n 31 37 30 98 Mean IOP
20.42 20.45 19.83 20.25 Mean IOP .dwnarw. -4.34 -4.21 -5.06 -4.51
CI (-5.32, -3.37) (-5.33, -3.09) (-6.20, -3.93) (-5.12, -3.90)
[0454] Across time points after Day 1, Treatment C (95 .mu.g L-PPDS
lower punctum, blank plug upper punctum) resulted in the best mean
IOP reduction compared with the other treatment groups. Results for
ITT observed data including IOP after plug loss or removal (Table
8) were similar both to the results for ITT observed data excluding
IOP after plug loss or removal and to EVAL data.
[0455] Retention rate of plugs in the lower puncta was .gtoreq.96%
through Week 10 and 92% at Week 12. Retention of upper plugs was
76%, 65%, and 58% at Weeks 4, 8, and 12, respectively.
[0456] Study Conclusions: Treatment with L-PPDS (latanoprost dose
of 95 .mu.g/eye) resulted in a clinically meaningful and
statistically significant reduction in IOP from baseline of
approximately 5 mmHg after 4 weeks (primary endpoint). The
configuration of a 95 .mu.g L-PPDS in the lower punctum and a blank
plug in the upper punctum (Treatment C) showef the best IOP
reduction of the three configurations investigated.
Example 7: Discussion and Final Analysis of GLAU 12 and GLAU 13
Studies
[0457] The primary endpoint in the Phase II studies was the mean
change in IOP from baseline (measured as mmHg) at 4 weeks.
Secondary endpoints were the IOP change from baseline at other time
points as well as the IOP and percentage IOP change from baseline
at all time points in the 12-week study period.
[0458] A total of 57 ITT (Intent to Treat) subjects were included
in the L-PPDS treatments in PPL GLAU 12, and a total of 77 ITT
subjects were included in L-PPDS treatments in PPL GLAU 13. See,
FIG. 21. Two ITT datasets were analyzed, one including all IOP
values regardless of plug loss, and the other, or second group,
with IOP excluded after first plug loss/removal. FIG. 23 summarizes
IOP changes from baseline at 4, 8 and 12 weeks for the two studies
for both ITT datasets. For both studies, mean IOP changes from
baseline were statistically significant at all time points. Across
the 5 treatment arms of both studies, 3 arms showed clinically
significant IOP lowering of 5 mmHg or greater at 4 weeks for both
datasets, and 2 arms showed clinically significant lowering of 5
mmHg or greater at 4 and 6 weeks for one ITT dataset (IOP excluded
after plug loss). One arm (the 95 .mu.g lower/blank plug upper
configuration (Treatment C)) showed a clinically significant IOP
lowering of approximately 5.0 mmHg at 4, 8 and 12 weeks for both
ITT datasets.
[0459] In GLAU 12, at the end of 4 weeks, the percentage of eyes
with an IOP reduction vs baseline of 5 mmHg or greater was 70% for
the 190 .mu.g dose and 58% for the 141 .mu.g dose. At 12 weeks
these values were 45% of eyes at the 190 .mu.g dose and 27% of eyes
at the 146 .mu.g dose (ITT observed data with IOP excluded after
first plug loss/removal). See FIG. 30.
[0460] In GLAU 13, at the end of 4 weeks, the percentage of eyes
with an IOP reduction vs. baseline of 5 mmHg or greater was 58% for
the blank plug lower/95 .mu.g L-PPDS upper configuration (Treatment
A), 50% for the open lower punctum/95 .mu.g L-PPDS upper
configuration (Treatment B), and 57% for the 95 .mu.g L-PPDS
lower/blank plug upper configuration (Treatment C); at 12 weeks
these values were 52%, 59% and 66% for the three configurations,
respectively (ITT observed data with IOP excluded after first plug
loss/removal). See, FIG. 32.
[0461] During the 8-week second treatment course in GLAU 12 (n=38
eyes), the L-PPDS (190 .mu.g) produced a statistically and
clinically significant reduction in mean IOP at 4 and 6 weeks of
5.4 and 5.8 mmHg, respectively for the all-observed IOP ITT dataset
and 5.7 and 5.8 mm Hg, respectively for the IOP excluded after plug
loss ITT dataset. See FIG. 26. Upper plug retention was notably
higher compared to the main study, achieving values of 90 and 88%
at 4 and 8 weeks, respectively, for this shorter re-treatment
course. See, FIG. 36
[0462] The 95 .mu.g lower/blank upper configuration (Treatment C)
demonstrated the most sustained IOP reduction (12 weeks) across all
plug configurations and doses, suggesting IOP lowering with the
L-PPDS as currently designed may be affected by the plug position
(and tearing effects) of these designs. See, FIGS. 27 and 28.
Results of these studies also suggest that double-plugging
(simultaneous placement of both an upper and lower plug) may be
necessary to achieve a minimum IOP lowering effect using the
current design configurations.
[0463] Data from the high dose study (PPL GLAU 12) demonstrated
that higher dose levels of the current designs produced the largest
mean IOP change from baseline at 4 weeks of all configurations
across these two studies. However, higher doses alone did not
result in a sustained effect beyond 4 weeks, suggesting potentially
different dose delivery mechanics with the higher dose plugs. In
addition, the high dose effects observed in the repeat treatment
phase of GLAU 12 (8 weeks at 190 ug for 19 subjects) show differing
effects between the first course (12 weeks) and second course (8
weeks). With the second treatment course of L-PPDS at the 190 .mu.g
dose over 8 weeks, the IOP lowering effect was sustained longer,
until 6 weeks (both ITT datasets)
[0464] In PPL GLAU 12, 2 subjects discontinued from the study due
to AEs, 17 discontinued due to plug loss, and 2 withdrew.
[0465] In PPL GLAU 13, 5 subjects discontinued from the study due
to AEs, 14 discontinued due to plug loss, 8 discontinued due to
inadequate IOP control and 1 withdrew.
Example 8: Retention Study (GLAU 11, 12 and 13 Studies)
[0466] A clinical study (Glau 11) was conducted to evaluate
exemplary embodiments of the present invention in comparison with a
modified commercial implant. The commercial implant 1000 is
illustrated in FIGS. 10A and 10B, where a side view and a top view
are depicted respectively along with corresponding major
dimensions. The commercial implant 1000 has no cavity. For the
purpose of comparison study, the commercial implant 1000 is
modified by constructing a cavity 1002 in the implant 1000, as
shown in FIGS. 10C and 10D. The cavity 1002 is configured such that
it has essentially the same shape and the same size as of the
cavity 458 in the exemplary embodiments of the present invention
selected for the comparison study.
[0467] The comparison study involves ninety six subjects, baseline
demographics of which are provided in FIG. 11. Each subject is
fitted with two modified commercial implants indicated and two
selected exemplary embodiments of the present invention. The
modified commercial implants are referred as upper implants and the
selected exemplary embodiments of the present application as lower
implants. Both upper and lower implants contain 141 .mu.g of total
latanoprotst drug stored in their respective cavities. The 141
.mu.g of total latanoprotst drug is consistent with three months of
Xalatan drops.
[0468] The study was conducted over four weeks. During the study,
the subjects were examined and the intraocular pressure was checked
weekly. The observed retention rate is plotted and illustrated in
FIG. 9. In the study as well as in the present invention, the
retention rate is defined as the percentage of eyes that retains
implants over a certain period of time. As indicated by the plot in
FIG. 9, the selected exemplary embodiments of the present invention
achieves higher retention rates than the modified commercial
implants. For example, while the retention rate of the modified
commercial implants declines to a rate below 60% in week three, the
retention rate of the selected exemplary embodiments of the present
invention maintains at a relatively higher rate, approximately 95%
or more, over the entire clinical trial. Having higher retention
rate over a longer period of time is one of various advantages of
embodiments of the present invention.
[0469] Retention rates of different plug designs (FIG. 33) were
also evaluated in the GLAU 12 and 13 studies.
[0470] Retention rate by eye of plugs in the lower puncta was
>95% through week 12 in PPL GLAU 12 (FIGS. 34 and 35) and
through week 10 in PPL GLAU 13 (week 12 retention was 92%) (FIGS.
37 and 38). Retention of upper plugs by eye was 69%, 53% and 48% at
weeks 4, 8 and 12, respectively, in PPL GLAU 12. In PPL GLAU 13,
retention of upper plugs was 76%, 65% and 58% at weeks 4, 8 and 12,
respectively. In addition, for eyes that retained the plugs past 4
weeks the rates the plugs were lost slowed, See FIG. 39.
[0471] Upper plug retention with the proprietary punctal plugs was
notably improved (approximately 19-33%) over the commercial plugs
used in Study PPL GLAU 11. At 4 weeks, the upper plug retention by
eye had increased from 48% in GLAU 11 to 67-81% in PPL GLAU 12 and
PPL GLAU 13.
[0472] Upper plug retention was notably improved (by approximately
26%) over the commercial plugs used in GLAU 11:
a. At 4 weeks: i. The upper plug retention increased from 45% in
GLAU 11 to 71% for the 141 .mu.g total dose in GLAU 12 ii. The
upper plug retention for the higher 190 .mu.g total dose was
similar to improvements for the 141 .mu.g dose, at 67% iii. The
upper plug retention for the lower dose plug combinations (95
.mu.g) ranged from 77%-81% across the 3 treatment arms
[0473] At 8 weeks, 48%-69% upper plug retention across both
studies
i. Upper plug retention for the 190 and 141 .mu.g combinations
ranged from 48%-58% respectively ii. Upper plug retention for the
lower dose (95 .mu.g) combinations ranged from 62%-69% across the 3
combinations
[0474] At 12 weeks, 42%-64% upper plug retention across both
studies:
i. Upper plug retention for the 190 and 141 .mu.g combinations
ranged from 42%-55% respectively ii. Upper plug retention for the
lower dose (95 .mu.g) combinations ranged from 52%-64% across the
three combinations
[0475] The above detailed description is intended to be
illustrative, and not restrictive. For example, the above-described
examples (or one or more features thereof) may be used in
combination with each other. As an example, one or more dimensions
from the various implant embodiments shown or described may be
grouped together to form an implant embodiment capable of providing
a desired drug concentration. Other embodiments may be used, such
as by one of ordinary skill in the art upon reviewing the above
description. Also, in the above Detailed Description, various
features may be grouped together to streamline the disclosure. This
should not be interpreted as intending that an unclaimed disclosed
feature is essential to any claim. Rather, inventive subject matter
may be in less than all features of a particular disclosed
embodiment. Thus, the following claims are hereby incorporated into
the Detailed Description, with each claim standing on its own as a
separate embodiment. The scope of the invention should be
determined with reference to the appended claims, along with the
full scope of equivalents to which such claims are entitled.
[0476] The Abstract is provided to comply with 37 C.F.R. .sctn.
1.72(b), to allow the reader to quickly ascertain the nature of the
technical disclosure. It is submitted with the understanding that
it will not be used to interpret or limit the scope or meaning of
the claims.
* * * * *
References