Note: Descriptions are shown in the official language in which they were submitted.
CA 02592541 2007-06-20
PUNCTAL PLUGS FOR THE DELIVERY OF ACTIVE AGENTS
Field of the Invention
The present invention relates to devices suitable for delivering substances to
one or
more of the eye, nose and throat. In particular, the invention relates to
punctal plugs for
delivery of at least one active agent.
Related Applications
This application claims priority from provisional application United States
Serial
No. 60/805,383 filed on June 21, 2006.
Background of the Invention
Human tears are secreted by the lacrimal gland and flow across the surface of
the
eye to a shallow poo1, known as the lacrimal lake, located where the eyelids
come together
at their inner ends. From there, the tears drain through small openings in
each of the
eyelids, termed the superior lacrimal punctum and the inferior lacrimal
punctum. From the
superior and inferior puncta, the tears pass into the superior and inferior
lacrimal
canaliculus, respectively, which are duct-like pathways that lead to the
lacrimal sac. The
lacrimal sac is the superior, expanded portion of the nasolacrimal duct, which
drains tears
into the nasal system.
Active agents can thus be delivered to the nose and throat through the
lacrimal canaliculi,
which lead into the nasolacrimal duct.
Active agents frequently are administered to the eye for the treatment of
ocular
diseases and disorders. Conventional means for delivering active agents to the
eye involve
topical application to the surface of the eye. The eye is uniquely suited to
topical
administration because, when properly constituted, topically applied active
agents can
penetrate through the cornea and rise to therapeutic concentration levels
inside the eye.
Active agents for ocular diseases and disorders may be administered orally or
by injection,
but such administration routes are
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CA 02592541 2007-06-20
disadvantageous in that, in oral administration, the active agent may reach
the eye in too
low a concentration to have the desired pharmacological effect and their use
is complicated
by significant, systemic side effects, while injections pose the risk of
infection.
The majority of ocular active agents are currently delivered topically using
eye
drops which, though effective for some applications, are inefficient. When a
drop of liquid
is added to the eye, it overfills the conjunctival sac, 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
onto the cheek. In addition, a substantial portion of the drop that remains on
the ocular
surface is drained into the lacrimal puncta, diluting the concentration of the
drug.
Brief Description of the Drawings
Figure 1 A is a sectional view of a punctal plug having a body 10 with an
enlarged
segment 12 and a cap 6 that contains active agent 8.
Figure 1 B is a sectional view of a punctal plug having a body 10 with an
enlarged
segment 12 and a cap 6 that contains active agent 8.
Figure 1 C is a sectional view of a punctal plug having a body 10 with an
enlarged
segment 12, a first cap 6 that contains active agent 8, and a second cap 6'
that contains
active agent 8'.
Figure 2A is a sectional view of a punctal plug having a body 20 with an
enlarged
segment 22 and a cap 26 that includes a stem 27 and contains active agent 28.
The stem
portion of the cap 27 is positioned within the body of the punctal plug 20.
Figure 2B is a sectional view of a punctal plug having a body 20 with an
enlarged
segment 22 and a cap 26 that includes a stem 27 and contains active agent
28. The stem portion of the cap 27 is positioned within the body 20 of the
punctal plug.
Figure 2C is a sectional view of a punctal plug having a body 20 with an
enlarged
segment 22, a first cap 26 that includes a stem 27 and contains active agent
28, and a
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CA 02592541 2007-06-20
second cap 26' that contains active agent 28'. The stem portion of the first
cap 27 is
positioned within the body 20 of the punctal plug.
Figure 3A is a sectional view of a punctal plug having a body 30 with an
enlarged
segment 32 and a cap 36 that includes stem 37 and contains active agent 38.
The stem
portion 37 of the cap is screwed into the body 30 of the punctal plug.
Figure 3B is a sectional view of a punctal plug having a body 30 with an
enlarged
segment 32 and a cap 36 that includes stem 37 and contains active agent 38.
The stem
portion 37 of the cap is screwed into the body 30 of the punctal plug.
Figure 3C is a sectional view of a punctal plug having a body 30 with an
enlarged
segment 32 a first cap 36 that includes stem 37 and contains active agent 38,
and a second
cap 36' that includes active agent 38'. The stem portion 37 of the first cap
is screwed into
the body 30 of the punctal plug.
Figure 4A is a sectional view of a punctal plug having a body 40 with an
enlarged
segment 42 and a cap 46 that includes a stem 47 and contains active agent 48.
The stem
portion 47 of the cap is clipped into the body 40 of the punctal plug.
Figure 4B is a sectional view of a punctal plug having a body 40 with an
enlarged
segment 42 and a cap 46 that includes a stem 47 and contains active agent 48.
The stem
portion 47 of the cap is clipped into the body 40 of the punctal plug.
Figure 4C is a sectional view of a punctal plug having a body 40 with an
enlarged
segment 42 a first cap 46 that includes stem 47 and contains active agent 48,
and a second
cap 46' that includes active agent 48'. The stem portion 47 of the first cap
is clipped into
the body 40 of the punctal plug.
Figure 5A is a sectional view of a punctal plug having a body 50 with an
enlarged
segment 52, a collarette 54, and a cap 56 that contains active agent 58.
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CA 02592541 2007-06-20
Figure 5B is a sectional view of a punctal plug having a body 50 with an
enlarged
segment 52, a collarette 54, a first cap 56 that contains active agent 58, and
a second cap
56' that contains active agent 58'.
Figure 6A is a sectional view of a punctal plug having a body 60 with an
enlarged
segment 62, a collarette 64, and a cap 66 that includes a stem 67 and contains
active agent
68. The stem portion 67 of the cap is positioned within the body 60 of the
punctal plug.
Figure 6B is a sectional view of a punctal plug having a body 60 with an
enlarged
segment 62, a collarette 64, a first cap 66 that includes a stem 67 and
contains active agent
68, and a second cap 66' that includes active agent 68'. The stem portion 67
of the first
cap is positioned within the body 60 of the punctal plug.
Figure 7A is a sectional view of a punctal plug having a body 70 with an
enlarged
segment 72, a collarette 74, and a cap 76 that includes a stem 77 and contains
active agent
78. The stem portion 77 of the cap is screwed into the body 70 of the punctal
plug.
Figure 7B is a sectional view of a punctal plug having a body 70 with an
enlarged
segment 72, a collarette 74, a first cap 76 that includes a stem 77 and
contains active agent
78, and a second cap 76' that includes active agent 78'. The stem portion 77
of the first
cap is screwed into the body 70 of the punctal plug.
Figure 8A is a sectional view of a punctal plug having a body 80 with an
enlarged
segment 82, a collarette 84, and a cap 86 that includes a stem 87 and contains
a active
agent. The stem portion 87 of the cap is clipped into the body 80 of the
punctal plug.
Figure 8B is a sectional view of a punctal plug having a body 80 with an
enlarged
segment 82, a collarette 84, a first cap 86 that includes a stem 87 and
contains active agent
88, and a second cap 86' that includes active agent 88'. The stem portion 87
of the first
cap is clipped into the body 80 of the punctal plug.
Figure 9A is a sectional view of a punctal plug having a body 90 with an
enlarged
segment 92, a collarette 94, and a cap 96 that includes a stem 97 and contains
active agent
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CA 02592541 2007-06-20
98. The stem portion 97 of the cap is positioned within the body 90 of the
punctal plug,
and a portion 99 of the cap extends beyond the collarette 94.
Figure 9B is a sectional view of a punctal plug having a body 90 with an
enlarged
segment 92, a collarette 94, a first cap 96 that includes a stem 97 and
contains active agent
98, and a second cap 96' that includes active agent 98'. The stem portion 97
of the first
cap is positioned within the body 90 of the punctal plug, and a portion 99 of
the first cap
extends beyond the collarette 94.
Figure 10 is a three-dimensional view of the punctal plug depicted two-
dimensionally in figure 8. The punctal plug has a body 100 with an enlarged
segment 102,
a collarette 104, and a cap 106 that includes a stem 107 and contains
active agent 108. The stem portion 107 of the cap is clipped into the body 100
of the
punctal plug.
Detailed Description of the Invention and Illustrative Embodiments
The present invention provides punctal plugs that can be used to deliver
active
agents to one or both of the nasolacrimal duct and to the tear fluid of the
eye. The punctal
plugs comprise, consist essentially of, and consist of: (a) a body having a
first end, a
second end, and a lateral surface extending between the two ends; and
(b) a cap adjacent to the first end of the body, a cap adjacent to the second
end of the body,
or caps adjacent to both the first and second ends of the body, wherein the
caps are
comprised of an active agent-containing material that contains at least one
active agent.
In Figures lA-C and 2A-C are depicted embodiments of the punctal plugs of the
present invention with bodies 10 and 20. The active agent, shown as 8, 8', 28,
and 28' in
the figures, is released from the caps 6 and 26, respectively, for example,
when the caps
dissolve or degrade, or the active agent simply diffuses from the caps,
depending upon the
an active agent-containing material material from which the caps are made. The
caps can
adhere to an end of the bodies. Alternatively, as depicted in Figures 2A-C,
the caps 26
may have a stem portion 27 that extends into the body 20 of the plug. In
another
embodiment and as shown in Figures 3A-C, the stem portion may be screwed
therein. As
yet another alternative and as shown in Figures 4A-C, the stem may be clipped
be into the
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CA 02592541 2007-06-20
body. As still another alternative and as shown in Figures 5A and B, the
punctal plugs
may have a collarette at the first end of the body. When such punctal plugs
are inserted
into the lacrimal canaliculus, the collarette preferably rests on the exterior
of the lacrimal
punctum and at least a portion of the cap is adjacent to the collarette. As
shown in Figures
9A and B, particular punctal plugs having collarettes 94 may have caps 99 that
are made
of a flexible material, and at least a portion of the cap of such punctal
plugs is elongated
and extends beyond the collarette, thereby increasing the amount of active
agent 98 that the
cap can contain.
For delivery of active agent into the tear fluid of the eye, when a punctal
plug is
inserted into the lacrimal canaliculus, preferably a cap is located adjacent
to the end of the
punctal plug that faces the eye, and the active agent is released into the
tear fluid of the
eye. For delivery of active agent into the nasolacrimal duct, when a punctal
plug is
inserted into the lacrimal canaliculus, preferably a cap is located adjacent
to the end of the
punctal plug that faces the nasolacrimal duct, and the active agent is
released into the
nasolacrimal duct. In particular embodiments of the invention, and as
illustrated in Figures
lA-C for example, the body contains an enlarged segment 12 that secures the
punctal plug
in the lacrimal canaliculus. In further aspects of the invention and as
depicted in Figures
2C and 5B for example, when a punctal plug is inserted into the lacrimal
canaliculus, a cap
is located adjacent to the end of the punctal plug that faces the eye, a
second cap is located
adjacent to the end of the punctal plug that faces the nasolacrimal duct, and
the active agent
may be released into both the tear fluid of the eye and the nasolacrimal duct.
As used herein, the term "punctal plug" refers to a device of a size and shape
suitable for insertion into the inferior or superior lacrimal canaliculus of
the eye through
the inferior or superior lacrimal punctum.
As used herein, the term "active agent" refers to an agent capable of
treating,
inhibiting, or preventing a disorder or a disease. Exemplary active agents
include, without
limitation, pharmaceuticals and nutraceuticals. Preferred active agents are
capable of
treating, inhibiting, or preventing a disorder or a disease of one or more of
the eye, nose
and throat.
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CA 02592541 2007-06-20
As used herein, the term "polymeric material" refers to a material made of one
or
more types of polymers that is capable of containing at least one active agent
and releasing
the active agent, for example, when the polymers dissolve or degrade, when the
active
agent diffuses from the polymers, or when a pro-drug is used in which the
active agent is
attached to the polymers and then released by being cleaved from the material.
As used herein, the phrase a "material that is at least partially water-
soluble" refers
to a material that exhibits a level of solubility in water sufficient to
result in dissolution of
the material upon exposure to an aqueous environment.
As used herein, the phrase a "material that is biodegradable" refers to a
material
that degrades to a detectable degree upon exposure to biologically active
substances
typically present in mammals.
As used herein, the phrase a "material that is insoluble in water" refers to a
material
that does not dissolve to a substantial degree upon exposure to water.
As used herein, the phrase a "material that is non-biodegradable" refers to a
material that does not degrade to a substantial degree upon exposure to
biologically active
substances typically present in mammals.
As used herein, the phrases "cap is removable," "removable cap," and
variations
thereof, refer to caps of certain punctal plugs of the invention that can be
removed from the
punctal plugs before insertion, after insertion, or both of the punctal plugs
into the lacrimal
canaliculus, wherein removal of the cap does not affect the integrity of the
remaining
portion of the punctal plugs.
As used herein, "flexible material" refers to a material that is not rigid and
that
conforms to the surface of whatever object the material contacts.
The present invention encompasses numerous punctal plugs for the delivery of
active agent to the tear fluid of the eye or to the nasolacrimal duct. The
punctal plugs
preferably are inserted into the inferior lacrimal canaliculus, the superior
lacrimal
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CA 02592541 2007-06-20
canaliculus, or both the inferior and superior lacrimal canaliculi. If the
punctal plugs are
being used to deliver active agent to the tear fluid of the eye, the punctal
plugs preferably
have a collarette at one end of the body. The collarette is a portion of the
punctal plug that
extends radially outwardly from one end of the body to a degree sufficient so
that at least a
portion of the collarette will extend beyond and be exterior to the lacrimal
punctum after
insertion of the punctal plug into the lacrimal canaliculus. In Figure 5A is
depicted an
example of a collarette 54. The portion of the punctal plugs without the
collarette is
inserted into one of the inferior lacrimal punctum or the superior lacrimal
punctum, which
are the openings of the lacrimal canaliculus on the margin of each eyelid.
Referring to
Figure 5A, enlarged segment 52 and body 50 are inserted into one of the
punctum, and the
collarette rests against the exterior of the lacrimal punctum and keeps the
punctal plug
from slipping down into the lacrimal canaliculus, so that contact between the
punctal plug
and the tear fluid of the eye is maintained. The collarette can be of any size
and shape
sufficient to at least partially secure the punctal plug in the lacrimal
punctum.
If the punctal plugs are being used to deliver active agent to the
nasolacrimal duct,
the punctal plugs preferably do not have a collarette so that they may be
inserted at a
sufficient depth within one or both of the lacrimal canaliculi such that the
active agent is
released into the lacrimal sac. In Figures 1B, 2B, and 3B are depicted
examples of
punctual plugs useful for delivery of an active agent to the nasal lacrimal
duct.
The numerous punctal plugs of the invention each have various features and
advantages. For example, certain punctal plugs have a body with a first end, a
second end,
and a lateral surface extending between the two ends. The lateral surface
preferably has an
outer diameter that is substantially circular in shape. A portion of the
lateral surface of
certain punctal plugs has an outer diameter that is greater than the outer
diameter of the
remainder of the lateral surface. With reference to Figure lA, the enlarged
portion 12 of
the lateral surface anchors or secures the punctal plugs in the lacrimal
canaliculus. The
enlarged portion can be any size or shape, and can be present on any part of
the lateral
surface, so long as the enlarged portion at least partially anchors the
punctal plug in the
lacrimal canaliculus. Conveniently, the enlarged portion may take the shape of
an inverted
triangle having a flattened apex.
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CA 02592541 2007-06-20
The body of the punctal plugs may be made of any suitable biocompatible
including, without limitation, silicone, silicone blends, silicone co-
polymers, such as, for
example, hydrophilic monomers of pHEMA (polyhydroxyethlymethacrylate),
polyethylene
glycol, polyvinylpyrrolidone, and glycerol, and silicone hydrogel polymers
such as, for
example, those described in U.S. Patent Nos. 5,962,548, 6,020,445, 6,099,852,
6,367,929,
and 6,822,016, incorporated herein in their
entireties by reference. Other suitable biocompatible materials include, for
example:
poly(ethylene glycol); poly(ethylene oxide); poly(propylene gycol); poly(vinyl
alcohol);
poly(hydroxyethyl methacrylate); poly(vinylpyrrolidone); polyacrylic acid;
poly(ethyloxazoline); poly(dimethyl acrylamide); phospholipids, such as, for
example,
phosphoryl choline derivatives; polysulfobetains; polysaccharides and
carbohydrates, such
as, for example, hyaluronic acid, dextran, hydroxyethyl cellulose, hydroxyl
propyl
cellulose, gellan gum, guar gum, heparan sulfate, chondritin sulfate, heparin,
and alginate;
proteins such as, for example, gelatin, collagen, albumin, and ovalbumin;
polyamino acids;
fluorinated polymers, such as, for example, polytetrafluoroethylene ("PTFE"),
polyvinylidene fluoride ("PVDF"), and teflon; polypropylene; polyethylene;
nylon; and
ethylene vinyl alcohol ("EVA").
The punctal plugs of the invention have a cap, or a material or substance that
covers
a portion of the body. The caps can be of various shapes and sizes, but
conveniently are of
a size and shape suitable for being carried on or attached to one end of the
punctual plug or
a collarette. The caps are preferably adjacent to the first end of the body,
the second end of
the body, or both the first and second ends of the body. For those punctal
plugs that have
collarettes, a portion of the cap is preferably adjacent to the collarette.
The caps can adhere to the surface of a portion of the body, the collarette,
or both
the body and the collarette. The cap preferably adheres to the surface of an
end of the
either or both the body and the surface of the collarette. The cap can adhere
to the surface
of the body or collarette if the material that comprises the cap is itself
adhesive. Such
materials include, without limitation, cyanoacrylates and urethanes.
Alternatively, a
biocompatible adhesive can be used to adhere the cap to a portion of the
surface of the
body or collarette. Suitable biocompatible adhesives include, without
limitation, silicones,
polyurethanes, cyanoacrylates, polyacrylic acid, fibrin, and cross-linked
proteins such as
9
CA 02592541 2007-06-20
albumin and collagen-gelatin. Suitable agents that can be used for cross-
linking include,
without limitation, polyfunctional, homobifunctional or heterobifunctional
cross-linkers
such as bis N-succinimidyl-(pentaethylene glycol) esters. The adhesive can act
via
chemical reaction, or
physical or mechanical interlock, and can be initiated via light, thermal or
laser activation.
At least one active agent is disposed on, dispersed throughout, or otherwise
contained within the cap of the punctal plugs, such that the cap serves as a
carrier for the
active agent. Depending upon the active agent-containing material from which
the cap is
made, the active agent can be released from the cap almost immediately, or the
active agent
can be released in a sustained manner over a desired period of time. The
material may be
any material that is compatible with the active agent or agents to be
delivered by the plug
and is capable of releasing the active agent in the desired manner, for
example by
dissolving or degrading of the material or diffusion of the active agent from
the material.
Any number of material may be used as the active agent-containing material
including,
without limitation, polymeric materials, both naturally occurring and
synthetic, non-
polymeric materials including, without limitation, glasses and clays, organic
materials,
inorganic materials including, without limitation, porous ceramics, lipids,
waxes and the
like and combinations thereof.
For example, the cap can be comprised of a polymeric material that is at least
partially soluble in water. When such a cap is exposed to the aqueous
environment of the
lacrimal canaliculus or the tear fluid, it preferably will dissolve and
release the active agent
as it dissolves. The solubility in water of the material from which the cap is
made typically
will be directly proportional to its rate of dissolution. Suitable polymeric
materials that are
at least partially soluble in water include, for example: poly(ethylene
glycol);
poly(ethylene oxide); poly(propylene gycol); poly(vinyl alcohol);
poly(hydroxyethyl
methacrylate); poly(vinylpyrrolidone); polyacrylic acid; poly(ethyloxazoline);
poly(dimethyl acrylamide); phosolipids, such as, for example, phosphoryl
choline
derivatives; polysulfobetains; polysaccharides and carbohydrates, such as, for
example,
hyaluronic acid, dextran, hydroxyethyl cellulose, hydroxyl propyl cellulose,
gellan gum,
guar gum, heparan sulfate, chondritin sulfate, heparin, and alginate; proteins
such as, for
example, gelatin, collagen, albumin, and ovalbumin; and polyamino acids. The
polymeric
CA 02592541 2007-06-20
materials in this list typically can be copolymerized or blended with
hydrophobic
polymers, monomers, or both.
Alternatively, the cap can be comprised of a biodegradable material that
chemically
degrades upon exposure to, for example, biologically active substances
typically present in
mammals. The biodegradable materials are preferably
hydrolyzable under in vivo conditions. Biodegradation typically occurs more
slowly than
dissolution, and the cap can thus be made of biodegradable materials if
slower, more
sustained release of the active agent is desired. Suitable polymeric
biodegradable materials
include, without limitation, polymers and oligomers of glycolide, lactide,
epsilon-
caprolactone, and other hydroxy acids, and other biologically degradable
polymers that
yield materials that are non-toxic or present as normal metabolites in the
body. Preferred
poly(alpha-hydroxy acids) are poly(glycolic acid), poly(2-dioxanone); poly(DL-
lactic acid)
and poly(L-lactic acid). Other useful materials include poly(amino acids),
polycarbonates,
poly(anhydrides), poly(orthoesters), poly(phosphazines) and
poly(phosphoesters).
Polylactones such as poly(epsilon-caprolactone), poly(delta-caprolactone),
poly(delta-
valerolactone) and poly(gamma-butyrolactone), for example, are also useful, as
are
chitosan, alginates, collagen, and gelatin. In particular aspects of the
invention, the
polymeric material of which the caps are made can be a mixture of one or more
dissolvable
and bio-degradable polymers.
The cap can also be made of a material that is insoluble in water and non-
biodegradable, but from which the active agent can diffuse. Suitable polymeric
materials
of this type include, for example, cross-liked polymers, such as, without
limitation, cross-
linked poly(ethylene glycol), poly(ethylene oxide), poly(propylene gycol),
poly(vinyl
alcohol), poly(hydroxethyl methacrylate), poly(vinylpyrrolidone), polyacrylic
acid,
poly(ethyloxazoline), and poly(dimethyl acrylamide). These polymers can be
copolymerized or blended with one or both of hydrophobic polymers and
monomers.
Additional examples of suitable polymers that are insoluble in either or both
water and
non-biodegradable include, without limitation, silicones, polyurethanes,
cyanoacrylates,
polyacrylic acid, fibrin, and cross-linked proteins, such as, for example,
albumin and
collagen-gellatin.
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CA 02592541 2007-06-20
In certain embodiments of the punctal plugs of the invention, the cap has a
stem
portion that is positioned within the body of the punctal plug. Figure 10 is a
three-dimensional view of a punctal plug body 100 having cap 106 affixed to
collarette
104. Cap 106 has stem portion 107, which extends downwardly into body 100. The
stem
may be screwed or clipped, as shown in Figure 10, into the body of the punctal
plug, or is
simply inserted into some portion of the body. Punctal plugs having caps with
a stem
portion may or may not have a collarette. The stem can be symmetrical or
asymmetrical,
depending upon the shape of the portion of the body into which it is inserted.
The internal
walls of the body may be substantially smooth or may include features that aid
in
maintaining the stem within the body including, without limitation, surfaces
with grooves,
indentations, roughness or the like in the interior walls. In an alternative
embodiment, in
addition to the active agent being disposed or dispersed throughout the cap,
the active
agent may be disposed on, dispersed throughout or otherwise contained in both
the cap
and the stem portion or in one of the cap or stem portion.
For those punctal plugs that have a collarette at the first end of the body,
at least a
portion of the cap is preferably adjacent to the collarette, and the active
agent is preferably
released into the tear fluid of the eye when the plugs are inserted into the
lacrimal
canaliculus. Punctal plugs that have a cap adjacent to the collarette can also
have a cap at
the second end of the body that faces the nasolacrimal duct when the punctal
plugs are
inserted into the lacrimal canaliculus, and the active agent is released from
such punctal
plugs into both the tear fluid of the eye and the nasolacrimal duct.
For certain punctal plugs, such as those having a collarette that are used to
deliver
active agent to the tear fluid of the eye, if the cap is made of a material
that dissolves or
erodes after insertion into the lacrimal canaliculus, a new cap can be added
to the punctal
plug, for example, after the cap dissolves or erodes, that contains active
agent that is the
same as or different from the active agent in the previous cap. The new cap
may be made
of a material that is the same as or different from the material of which the
previous cap
was comprised. The caps of certain punctal plugs can be replaced while the
punctal plugs
remain in the lacrimal canaliculus, while other punctal plugs are removed from
the lacrimal
canaliculus to replace the caps and are then reinserted into the lacrimal
canaliculus. The
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CA 02592541 2007-06-20
caps of the punctal plugs can be replaced at any time after insertion into the
lacrimal
canaliculus, regardless of whether the caps have completely dissolved or
degraded.
The active agent preferably passively diffuses from the caps of those punctal
plugs
that are made of p materials that are insoluble in water and non-
biodegradable. Certain of
such punctal plugs, such as those having a collarette that are used to deliver
active agent to
the tear fluid of the eye, have caps that can be removed from the punctal
plugs, for
example, after substantially all the active agent has diffused from the caps,
and removal of
the caps does not adversely affect the integrity of the remainder of the
punctal plugs. New
caps containing active agent that is the same as or different from the active
agent in the
previous caps can be added to the punctal plugs. The new cap can be comprised
of a
polymeric material that is the same as or different from the polymeric
material of which
the previous cap was comprised. The caps can be removed from some of such
punctal
plugs, and new caps can be added, after the punctal plugs have been inserted
in the
lacrimal canaliculus, and while the punctal plugs remain in the lacrimal
canaliculus. Other
punctal plugs are removed from the lacrimal canaliculus to replace the
existing caps with
new caps.
Certain of the punctal plugs that have collarettes can have a caps adjacent to
the
collarettes that are made of a flexible material. One or more portions of such
caps can
extend beyond the collarettes to increase the amount of active agent that the
caps can hold.
Suitable materials for such caps include, for example, low molecular weight
polymers or
elastomers such as, for example, polyolefins, polyesters, polyurethanes,
acrylics, and
copolymers thereof. In such punctal plugs, a portion of the cap rests against
the collarette,
and at least one portion of the cap preferably extends beyond the portion that
rests against
the collarette. In such punctal plugs, the caps can be transparent or flesh-
colored.
Punctal plugs of the invention can be manufactured using processes that
include
techniques such as, for example, solution casting, extrusion, chemical cross-
linking
through the formation of covalent bonds or ionic bonds, lathing, compression
molding,
injection molding, liquid injection molding, blow molding, and polymerization,
including
photo polymerization, thermal polymerization, and ionic- and redox-initiated
polymerization. The punctal plugs and caps are typically manufactured
separately. The
13
CA 02592541 2007-06-20
caps can be manufactured using processes that include techniques such as, for
example,
solution casting, extrusion, chemical cross-linking through the formation of
covalent bonds
or ionic bonds, lathing, compression molding, injection molding, liquid
injection molding,
blow molding, and polymerization, including photo polymerization, thermal
polymerization, and ionic- and redox-initiated polymerization. The active
agent can be
incorporated into the caps by adding it to the materials that compose the caps
during their
manufacture through, for example, injection molding or dissolving the active
agent into the
cap material or the active agent can be added to the caps of the punctal plugs
following
their manufacture by, example and without limitation, soaking a solution of at
least one
active agent into a pre-formed cap as, for example, use of a solvent
containing drug or
covalently attaching the active agent following surface modification of the
material.
The amount of active agent used in the plugs of the invention will depend upon
the
active agent or agents selected, the desired doses to be delivered via the
punctual plug, the
desired release rate, and the melting points of the active agent and material
used to form
the cap. Preferably, the amount used is a therapeutically effective amount
meaning an
amount effective to achieve the desired treatment, inhibitory, or prevention
effect.
Typically, amounts of about 0.05 to about 8,000 micrograms of active agents
may be used.
The punctal plugs described herein can be used to deliver various active
agents for
the one or more of the treatment, inhibition, and prevention of numerous
diseases and
disorders. Each punctal plug can be used to deliver at least one active agent
and can be
used to deliver different types of active agents. For example, the punctal
plugs can be used
to deliver azelastine HC1, emadastine difumerate, epinastine HCI, ketotifen
fumerate,
levocabastine HCI, olopatadine HC1, pheniramine maleate, and antazoline
phosphate for
one or more of the treatment, inhibition, and prevention of allergies. The
punctal plugs
can be used to deliver mast cell stabilizers, such as, for example, cromolyn
sodium,
lodoxamide tromethamine, nedocromil sodium, and permirolast potassium.
The punctal plugs can be used to deliver mydriatics and cycloplegics, such as,
for
example, henylephrine, atropine sulfate, homatropine, scopolamine HBr,
cyclopentolate
HCI, tropicamide, and phenylephrine HCI. The punctal plugs can be used to
deliver
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CA 02592541 2007-06-20
ophthalmic dyes such as, for example and without limitation, rose begal,
sissamine green,
indocyanine green, fluorexon, and fluorescein.
The punctal plugs can be used to deliver corticosteroids such as, for example,
dexamethasone sodium phosphate, dexamethasone, fluoromethalone,
fluoromethalone
acetate, loteprednol etabonate, prednisolone acetate, prednisolone sodium
phosphate,
medrysone, rimexolone, and fluocinolone acetonide. The punctal plugs can be
used to
deliver non-steroidal anti-inflammatory agents such as, for example and
without limitation,
flurbiprofen sodium, suprofen, diclofenac sodium, ketorolac tromethamine,
cyclosporine,
rapamycin methotrexate, azathioprine, and bromocriptine.
The punctal plugs can be used to deliver anti-infective agents such as, for
example
and without limitation, tobramycin, moxifloxacin, ofloxacin, gatifloxacin,
ciprofloxacin,
gentamicin, sulfisoxazolone diolamine, sodium sulfacetamide, vancomycin,
polymyxin B,
amikacin, norfloxacin, levofloxacin, sulfisoxazole diolamine, sodium
sulfacetamide
tetracycline, doxycycline, dicloxacillin, cephalexin, amoxicillin/clavulante,
ceftriaxone,
cefixime, erythromycin, ofloxacin, azithromycin, gentamycin, sulfadiazine, and
pyrimethamine.
The punctal plugs can be used to deliver agents for the one or more of the
treatment, inhibition, and prevention of glaucoma including, without
limitation,
epinephrines, including, for example: dipivefrin; alpha-2 adrenergic
receptors, including,
for example, aproclonidine and brimonidine; betablockers, including, for
example, betaxolol, carteolol, levobunolol, metipranolol, and timolol; direct
miotics,
including, for example, carbachol and pilocarpine; cholinesterase inhibitors,
including, for
example, physostigmine and echothiophate; carbonic anhydrase inhibitors,
including, for
example, acetazolamide, brinzolamide, dorzolamide, and methazolamide;
prostoglandins
and prostamides, including, for example, latanoprost, bimatoprost, uravoprost,
and
unoprostone cidofovir.
The punctal plugs can be used to deliver antiviral agents, including, without
limitation, fomivirsen sodium, foscamet sodium, ganciclovir sodium,
valganciclovir
CA 02592541 2007-06-20
HCI, trifluridine, acyclovir, and famciclovir. The punctal plugs can be used
to deliver local
anesthetics, including, without limitation, tetracaine HCI, proparacaine HCI,
proparacaine
HCl and fluorescein sodium, benoxinate and fluorescein sodium, and benoxinate
and
fluorexon disodium. The punctal plugs can be used to deliver antifungal
agents, including,
for example, fluconazole, flucytosine, amphotericin B, itraconazole, and
ketocaonazole.
The punctal plugs can be used to deliver analgesics including, without
limitation,,
acetaminophen and codeine, acetaminophen and hydrocodone, acetaminophen,
ketorolac,
ibuprofen, and tramadol. The punctal plugs can be used to deliver
vasoconstricors
including, without limitation, ephedrine hydrochloride, naphazoline
hydrochloride,
phenylephrine hydrochloride, tetrahydrozoline hydrochloride, and
oxymetazoline. Finally,
the punctal plugs can be used to deliver vitamins, antioxidants, and
nutraceuticals
including, without limitation,, vitamis A, D, and E, lutein, taurine,
glutathione, zeaxanthin,
fatty acids and the like.
The active agents delivered by the punctal plugs can be formulated to contain
excipients including, without limitation, synthetic and natural polymers,
including, for
example, polyvinylalcohol, polyethyleneglycol, polyacrylic acid, hydroxymethyl
cellulose,
glycerine, hypromelos, polyvinylpyrrolidone, carbopol, propyleneglycol,
hydroxypropyl
guar, glucam-20, hydroxypropyl cellulose, sorbitol, dextrose, polysorbate,
mannitol,
dextran, modified polysaccharides and gums, phosolipids, and sulphobetains.
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