U.S. patent application number 10/843893 was filed with the patent office on 2004-10-21 for sustained release drug delivery devices.
Invention is credited to Brubaker, Michael J., Krishnamoorthy, Ramesh, Lesczynski, Michael A., Martin, E. Allen, Natalie, Thomas F., Papadopoulos, Pavlos, Renner, Steven B., Shropshire, Jason Paul, Viscasillas, Santos.
Application Number | 20040208909 10/843893 |
Document ID | / |
Family ID | 22983671 |
Filed Date | 2004-10-21 |
United States Patent
Application |
20040208909 |
Kind Code |
A1 |
Brubaker, Michael J. ; et
al. |
October 21, 2004 |
Sustained release drug delivery devices
Abstract
The present invention is directed to an improved sustained
release drug delivery device comprising a drug core, a unitary cup,
and a permeable plug.
Inventors: |
Brubaker, Michael J.; (Fort
Worth, TX) ; Krishnamoorthy, Ramesh; (Apex, NC)
; Lesczynski, Michael A.; (Honeoye Falls, NY) ;
Natalie, Thomas F.; (Rochester, NY) ; Papadopoulos,
Pavlos; (Antioch, IL) ; Renner, Steven B.;
(Rochester, NY) ; Viscasillas, Santos; (Tampa,
FL) ; Martin, E. Allen; (Charlotte, NC) ;
Shropshire, Jason Paul; (Huntersville, NC) |
Correspondence
Address: |
Bausch & Lomb Incorporated
One Bausch & Lomb Place
Rochester
NY
14604-2701
US
|
Family ID: |
22983671 |
Appl. No.: |
10/843893 |
Filed: |
May 12, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10843893 |
May 12, 2004 |
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10023391 |
Dec 17, 2001 |
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6756049 |
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60259135 |
Dec 29, 2000 |
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Current U.S.
Class: |
424/424 ;
604/891.1 |
Current CPC
Class: |
A61P 27/02 20180101;
A61K 9/4808 20130101; A61K 9/0051 20130101 |
Class at
Publication: |
424/424 ;
604/891.1 |
International
Class: |
A61F 002/00 |
Claims
1. A sustained release drug delivery device comprising: a) a drug
core comprising a therapeutically effective amount of least one
agent effective in obtaining a diagnostic effect or effective in
obtaining a desired local or systemic physiological or
pharmacological effect; b) a unitary cup essentially impermeable to
the passage of said agent that surrounds and defines an internal
compartment to accept said drug core, said unitary cup comprising
an open top end with at least one recessed groove around at least
some portion of said open top end of said unitary cup; and c) a
permeable plug which is permeable to the passage of said agent,
said permeable plug is positioned at said open top end of said
unitary cup wherein said groove interacts with said permeable plug
holding it in position and closing said open top end, said
permeable plug allowing passage of said agent out of said drug
core, through said permeable plug, and out said open top end of
said unitary cup.
2. The sustained release drug delivery device according to claim 1,
wherein said unitary cup is made of polymer or metal.
3. The sustained release drug delivery device according to claim 1,
wherein said unitary cup is made of silicone.
4. The sustained release drug delivery device according to claim 3,
wherein said permeable plug is made of PVA.
5. The sustained release drug delivery device according to claim 1,
wherein said unitary cup further comprises a plurality of recessed
grooves around at least some portion of said open top end of said
unitary cup.
6. The sustained release drug delivery device according to claim 1,
wherein said agent is a low solubility agent.
7. The sustained release drug delivery device according to claim 1,
wherein said agent is selected from a group consisting of immune
response modifiers, neuroprotectants, corticosteroids, angiostatic
steriods, anti-parasitic agents, anti-glaucoma agents,
anti-biotics, anti-sense compounds, anti-angiogenic compounds,
differentiation modulators, anti-viral agents, anti-cancer agents,
and nonsteroidal anti-inflammatory agents.
8. The sustained release drug delivery device according to claim 1,
wherein said drug core comprises a plurality of agents.
9. The sustained release drug delivery device according to claim 1,
further comprising an impermeable plug with at least one passageway
positioned between said drug core and said permeable plug.
10. A sustained release drug delivery device comprising: a) a drug
core comprising at least one agent effective in obtaining a
diagnostic effect or effective in obtaining a desired local or
systemic physiological or pharmacological effect; b) a unitary cup
essentially impermeable to the passage of said agent that surrounds
and defines an internal compartment to accept said drug core, said
unitary cup comprising an open top end and at least one lip around
at least a portion of said open top end of said unitary cup; and c)
a permeable plug permeable to the passage of said agent positioned
at said open top end of said unitary cup wherein said lip interacts
with said permeable plug holding it in position and closing said
open top end, said permeable plug allowing passage of said agent
out of said drug core, through said permeable plug, and out said
open top end of said unitary cup.
11. The sustained release drug delivery device according to claim
10, wherein said lip extends around the entirety of said open top
end of said unitary cup.
12. The sustained release drug delivery device according to claim
10, wherein said unitary cup comprises a plurality of lips at said
open top end of said unitary cup.
13. The sustained release drug delivery device according to claim
10, wherein said drug core comprises an effective amount of a low
solubility agent.
14. The sustained release drug delivery device according to claim
10, wherein said agent is selected from a group consisting of
immune response modifiers, neuroprotectants, corticosteroids,
angiostatic steriods, anti-parasitic agents, anti-glaucoma agents,
anti-biotics, anti-sense compounds, anti-angiogenic compounds,
differentiation modulators, anti-viral agents, anti-cancer agents,
and nonsteroidal anti-inflammatory agents.
15. The sustained release drug delivery device according to claim
10, wherein said unitary cup is made of polymer or metal.
16. The sustained release drug delivery device according to claim
10, wherein said unitary cup is made of silicone.
17. The sustained release drug delivery device according to claim
16, wherein said permeable plug is made of PVA.
18. The sustained release drug delivery device according to claim
10, wherein said drug core comprises a plurality of agents.
19. The sustained release drug delivery device according to claim
10, further comprising an impermeable plug with at least one
passageway positioned between said drug core and said permeable
plug.
20. A method for providing controlled and sustained administration
of an agent effective in obtaining a desired local or systemic
physiological or pharmacological effect comprising inserting in a
desired location in the body of a mammalian organism a sustained
release drug delivery device comprising; a) a drug core comprising
a therapeutically effective amount of at least one agent effective
in obtaining a diagnostic effect or effective in obtaining a
desired local or systemic physiological or pharmacological effect;
b) a unitary cup essentially impermeable to the passage of said
agent that surrounds and defines an internal compartment to accept
said drug core, said unitary cup comprising an open top end with at
least one recessed groove around at least some portion of said open
top end of said unitary cup; and c) a permeable plug which is
permeable to the passage of said agent positioned at said open top
end of said unitary cup wherein said groove interacts with said
permeable plug holding it in position and closing said open top
end, said permeable plug allowing passage of said agent out of said
drug core, through said permeable plug, and out said open top end
of said unitary cup.
21. The method according to claim 20, wherein said inserting step
comprises inserting said sustained release drug device in a
location selected from a group consisting of the vitreous of the
eye, under the retina, and onto the sclera.
22. The method according to claim 20, wherein said drug core
comprises a plurality of agents.
23. The method according to claim 20, wherein said inserting step
comprises injecting said sustained release drug delivery device at
the desired location.
24. A method for providing controlled and sustained administration
of an agent effective in obtaining a desired local or systemic
physiological or pharmacological effect comprising inserting at a
desired location in the body of a mammalian organism a sustained
release drug delivery device comprising; a) a drug core comprising
at least one agent effective in obtaining a diagnostic effect or
effective in obtaining a desired local or systemic physiological or
pharmacological effect; b) a unitary cup essentially impermeable to
the passage of said agent that surrounds and defines an internal
compartment to accept said drug core, said unitary cup comprising
an open top end and at least one lip around at least a portion of
said open top end of said unitary cup; and c) a permeable plug
permeable to the passage of said agent positioned at said open top
end of said unitary cup wherein said lip interacts with said
permeable plug holding it in position and closing said open top
end, said permeable plug allowing passage of said agent out of said
drug core, through said permeable plug, and out said open top end
of said unitary cup.
25. The method according to claim 24, wherein said inserting step
comprises inserting said sustained release drug delivery device in
a location selected from a group consisting of the vitreous of the
eye, under the retina, and onto the sclera.
26. The method according to claim 24, wherein said drug core
contains a plurality of said agents.
27. The method according to claim 24, wherein said inserting step
comprises injecting said sustained release drug delivery device at
the desired location.
28. A method of manufacturing a sustained release drug delivery
device comprising: a) manufacturing a drug core comprising at least
one agent effective in obtaining a diagnostic effect or effective
in obtaining a desired local or systemic physiological or
pharmacological effect; b) providing a unitary cup essentially
impermeable to the passage of said agent that surrounds and defines
an internal compartment to accept said drug core, said unitary cup
comprising an open top end with at least one recessed groove around
at least some portion of said open top end of said unitary cup; c)
inserting said drug core into said unitary cup; and d) filling a
material which is permeable to the passage of said agent into said
open top end of said unitary cup, allowing said material to
solidify thereby forming a permeable plug positioned at said open
top end of said unitary cup wherein said groove interacts with said
permeable plug holding it in position and closing said open top
end, said permeable plug allowing passage of said agent out of said
drug core, through said permeable plug, and out said open top end
of said unitary cup.
29. The method of manufacturing a sustained release drug delivery
device according to claim 28, wherein said drug core is
manufactured as a solid dose form.
30. The method of manufacturing a sustained release drug delivery
device according to claim 28, wherein said drug core is
manufactured as a solid dispersion.
31. The method of manufacturing a sustained release drug delivery
device according to claim 28, comprising the further step of curing
the assembled sustained release drug delivery device.
32. A method of manufacturing a sustained release drug delivery
device comprising: a) manufacturing a drug core comprising at least
one agent effective in obtaining a diagnostic effect or effective
in obtaining a desired local or systemic physiological or
pharmacological effect; b) providing a unitary cup essentially
impermeable to the passage of said agent that surrounds and defines
an internal compartment to accept said drug core, said unitary cup
comprising an open top end with at least one lip extending around
at least a portion of the said open top end of said unitary cup; c)
inserting said drug core into said unitary cup; and d) filling a
material which is permeable to the passage of said agent into said
open top end of said unitary cup, allowing said material to
solidify thereby forming a permeable plug positioned at said open
top end of said unitary cup wherein said lip interacts with said
permeable plug holding it in position and closing said open top
end, said permeable plug allowing passage of said agent out of said
drug core, through said permeable plug, and out said open top end
of said unitary cup.
33. The method of manufacturing a sustained release drug delivery
device according to claim 32, wherein said drug core is
manufactured as a solid dose form.
34. The method of manufacturing a sustained release drug delivery
device according to claim 32, wherein said drug core is
manufactured as a solid dispersion.
35. The method of manufacturing a sustained release drug delivery
device according to claim 32, comprising the further step of curing
the assembled sustained release drug delivery device.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to an improved device and
method for delivering drug directly to the interior portions of the
body of a mammalian organism, such as to the eye. The method
includes administration of an agent effective in obtaining a
desired diagnostic effect or local or systemic physiological or
pharmacological effect by inserting in a desired location in the
body of a mammalian organism a sustained release drug delivery
device.
BACKGROUND
[0002] Over the years, various drugs have been developed to assist
in the treatment of a wide variety of ailments and diseases.
However, in many instances such drugs are not capable of being
administered either orally or intravenously without the risk of
various detrimental side effects.
[0003] CMV retinitis is a disease that is characterized by
inflammation of the retina caused by infection with
cytomegalovirus. CMV retinitis is one of the most common causes of
sight-threatening infections among people with HIV. The symptoms
include loss of visual acuity, blind spots, and the loss of
peripheral vision. Left untreated, CMV retinitis can lead to
blindness.
[0004] Intravenous ganciclovir (GCV) is effective in the treatment
of CMV retinitis in AIDS patients, but bone marrow toxicity limits
its usefulness. Continuous maintenance GCV therapy is necessary to
prevent progression or recrudescence of the disease, but despite
maintenance therapy a significant number of patients experience a
relapse during treatment. Additionally, there are other risks and
problems associated with systemic GCV administration.
[0005] Intravitreal GCV injections administered once or twice
weekly have resulted in temporary remission of CMV retinitis in
AIDS patients. Intravitreal GCV injections may provide a higher
intraocular drug concentration than systemic therapy and reduce the
incidence of neutropenia. However, current treatment of CMV
retinitis in AIDS patients is clearly suboptimal. Ganciclovir is
virustatic and thus disease inhibition requires maintenance drug
administration.
[0006] A more detailed explanation of the use of intravenous of GCV
and intravitreal injections of GCV can be found in U.S. Pat. No.
5,902,598, herein incorporated in its entirety by reference. A
discussion of the difficulties associated with the systemic therapy
of cyclosporine A in the treatment of uveitis can be found in U.S.
Pat. Nos. 5,773,019 and 6,001,386, herein incorporated in their
entirety by reference.
[0007] Accordingly, there exists a strong need for the elimination
of the undesirable physiological problems associated with GCV
treatment of CMV retinitis, while maintaining the advantageous
properties of this treatment. Although delivering the drug locally
with injections may minimize the systemic toxicity of GCV, repeated
injection is not a practical mode of administration.
[0008] Due to the risks that certain drugs impose, researchers have
developed systems for administering such drugs to aid in the
treatment of these ailments and diseases. A general discussion of
drug delivery control systems is provided in Controlled Drug
Delivery (Part I), Xue Shen Wu, Ph.D. pp32, 33, 44-46, 63, 66, and
67 (Technomic Publishing Co. Inc., 1996), the entire contents of
which are incorporated herein by reference. The systems have been
designed largely to reduce and to control the release rate of
incorporated drugs. However, these systems fail to achieve the
advantages claimed by the present invention.
[0009] For example, U.S. Pat. No. 4,014,335 to Arnold, relates to
various ocular inserts that act as a deposit or drug reservoir for
slowly releasing a drug into the tear film for prolonged periods of
time. These inserts are fabricated as a three-layer laminate of
flexible polymeric materials that are biologically inert,
non-allergenic, and insoluble in tear fluid. To initiate the
therapeutic programs of these devices, the ocular inserts are
placed in the cul-de-sac between the sclera of the eyeball and the
eyelid for administering the drug to the eye. Multiple layer
laminate systems can present a challenge to reproducibly
manufacture and are more difficult to produce by large-scale
manufacturing procedures.
[0010] The device of U.S. Pat. No. 3,416,530 is manufactured with a
plurality of capillary openings that communicate between the
exterior of the device and the interior chamber generally defined
from a polymeric membrane. While the capillary openings in this
construction are effective for releasing certain drugs to the eye,
they add considerable complexity to the manufacture of the device
because it is difficult to control the size of these openings in
large-scale manufacturing using various polymers.
[0011] U.S. Pat. No. 3,618,604 describes a device that does not
involve such capillary openings, but instead provides for the
release of the drug by diffusion through a polymeric membrane. The
device, as disclosed in a preferred embodiment, comprises a sealed
container with the drug contained in an interior chamber.
Nonetheless, as described in U.S. Pat. No. 4,014,335, certain
problems have been identified with such devices such as the
difficult task of sealing the margins of the membrane to form the
container. In addition, stresses and strains introduced into the
membrane walls from deformation during manufacturing of those
devices may cause the reservoir to rupture and leak.
[0012] The above described systems and devices are intended to
provide sustained release of drugs effective in treating patients
at a desired local or systemic level for obtaining certain
physiological or pharmacological effects. However, there are many
disadvantages associated with their use, including the fact that it
is often difficult to obtain the desired release rate of the
drug.
[0013] The need for a better release system is especially
significant in the treatment of CMV retinitis. Thus, there remains
a long-felt need in the art for an improved device for providing
sustained release of a drug to a patient to obtain a desired local
or systemic physiological or pharmacological effect.
[0014] Prior to the development of the present invention, there was
developed a drug delivery device that ameliorated many of the
problems associated with sustained release drug delivery. The
device, which is disclosed in U.S. Pat. No. 5,378,475 (incorporated
herein by reference in its entirety), included a first coating
essentially impermeable to the passage of the effective agent and a
second coating permeable to the passage of the effective agent. In
the device, the first coating covered at least a portion of the
inner core; however, at least a small portion of the inner core is
not coated with the first coating layer. The second coating layer
essentially completely covers the first coating layer and the
uncoated portion of the inner core. The portion of the inner core
which is not coated with the first coating layer allows passage of
the agent into the second coating layer thus allowing controlled
release.
[0015] While the devices described in U.S. Pat. No. 5,378,475 solve
many of the aforementioned problems pertaining to drug delivery,
the devices and the method of making the devices are not without
some problems. In particular, polymers suitable for coating the
inner core are frequently relatively soft and technical
difficulties can arise in production of uniform films. This is
especially true when attempting to coat non-spherical bodies with
edges (such as a cylindrical shape). In such cases, relatively
thick films must be applied to achieve uninterrupted and uniform
coatings, which adds significant bulk to the device. Thus, the
devices tend to be larger than necessary as a result of the
thickness needed to seal the ends of the inner core. In addition to
adding bulk, multiple layer devices are more difficult to
manufacture reproducibly and are more difficult to produce by
large-scale manufacturing procedures. Often devices such as these
require manual assembly that is time consuming, limits available
supply, and adds variability.
[0016] U.S. Pat. No. 5,902,598 also presents solutions to some of
the problems associated with manufacturing small devices. The
device in U.S. Pat. No. 5,902,598 includes a third permeable
coating layer that essentially completely covers the device. While
the third coating layer improves the structural integrity of the
device and helps to prevent potential leakage, some manufacturing
difficulties can limit scaled up manufacturing. For example,
consistent application of the outermost coating layer and
reproducibility in manufacturing can be problems with designs which
require manual assembly, a significant number of steps in the
assembly process, or outer dip coatings.
[0017] In addition, depending on the materials selected for the
outermost coating layer of the devices in U.S. Pat. Nos. 5,902,598
and 5,378,475, there may exist a need to cure the entire device
including the agent. Depending on the amount of curing required and
the agents used, in some applications this could result in
undesirable degradation of the active.
[0018] The problem of device size is extremely important in the
design of devices for implantation into the limited anatomical
spaces such as small organs like the eye. Larger devices require
more complex surgery to both implant and remove. The increased
complexity can result in complication, longer healing or recovery
periods, and potential side effects (e.g. increased chance of
astigmatism). Further, the extra polymer required to achieve a
uniform coating reduces the potential internal volume of the
implant and hence limits the amount of drug that can be delivered,
potentially limiting both efficacy and duration.
[0019] It would, therefore, be desirable to have a structurally
stable device that can be reproducibly manufactured and
manufactured by commercial techniques. As a result of all of the
above, there remains a long felt need in the art for an improved
device for providing sustained release of a drug to a mammalian
organism to obtain a desired local or systemic physiological or
pharmacological effect, especially for ocular use.
SUMMARY OF THE INVENTION
[0020] The sustained release drug delivery device according to the
first embodiment of the present invention comprises:
[0021] a) a drug core comprising a therapeutically effective amount
of at least one agent effective in obtaining a diagnostic effect or
effective in obtaining a desired local or systemic physiological or
pharmacological effect;
[0022] b) a unitary cup essentially impermeable to the passage of
said agent that surrounds and defines an internal compartment to
accept said drug core, said unitary cup comprising an open top end
with at least one recessed groove around at least some portion of
said open top end of said unitary cup; and
[0023] c) a permeable plug which is permeable to the passage of
said agent, said permeable plug is positioned at said open top end
of said unitary cup wherein said groove interacts with said
permeable plug holding it in position and closing said open top
end, said permeable plug allowing passage of said agent out of said
drug core, through said permeable plug, and out said open top end
of said unitary cup.
[0024] In accordance with another embodiment of the present
invention is a sustained release drug delivery device
comprising:
[0025] a) a drug core comprising at least one agent effective in
obtaining a diagnostic effect or effective in obtaining a desired
local or systemic physiological or pharmacological effect;
[0026] b) a unitary cup essentially impermeable to the passage of
said agent that surrounds and defines an internal compartment to
accept said drug core, said unitary cup comprising an open top end
and at least one lip around at least a portion of said open top end
of said unitary cup; and
[0027] c) a permeable plug permeable to the passage of said agent
positioned at said open top end of said unitary cup wherein said
lip interacts with said permeable plug holding it in position and
closing said open top end, said permeable plug allowing passage of
said agent out of said drug core, through said permeable plug, and
out said open top end of said unitary cup.
[0028] This invention is also directed to a method for providing
controlled and sustained administration of an agent effective in
obtaining a desired local or systemic physiological or
pharmacological effect comprising inserting in a desired location
in the body of a mammalian organism sustained release drug delivery
devices of the first and second embodiments of the present
invention.
[0029] A method of manufacture of a sustained release drug delivery
device according to the present invention comprises:
[0030] a) manufacturing a drug core comprising at least one agent
effective in obtaining a diagnostic effect or effective in
obtaining a desired local or systemic physiological or
pharmacological effect;
[0031] b) providing a unitary cup essentially impermeable to the
passage of said agent that surrounds and defines an internal
compartment to accept said drug core, said unitary cup comprising
an open top end with at least one recessed groove around at least
some portion of said open top end of said unitary cup;
[0032] c) inserting said drug core into said unitary cup; and
[0033] d) filling a material which is permeable to the passage of
said agent into said open top end of said unitary cup, allowing
said material to solidify thereby forming a permeable plug wherein
said groove interacts with said permeable plug holding it in
position and closing said open top end, said permeable plug
allowing passage of said agent out of said drug core, through said
permeable plug, and out said open top end of said unitary cup.
[0034] The present invention is further directed to a method of
manufacturing a sustained release drug delivery device
comprising:
[0035] a) manufacturing a drug core comprising at least one agent
effective in obtaining a diagnostic effect or effective in
obtaining a desired local or systemic physiological or
pharmacological effect;
[0036] b) providing a unitary cup essentially impermeable to the
passage of said agent that surrounds and defines an internal
compartment to accept said drug core, said unitary cup comprising
an open top end with at least one lip extending around at least a
portion of the said open top end of said unitary cup;
[0037] c) inserting said drug core into said unitary cup; and
[0038] d) filling a material which is permeable to the passage of
said agent into said open top end of said unitary cup, allowing
said material to solidify thereby forming a permeable plug wherein
said lip interacts with said permeable plug holding it in position
and closing said open top end, said permeable plug allowing passage
of said agent out of said drug core, through said permeable plug,
and out said open top end of said unitary cup.
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] The drawings, which are not drawn to scale, are set forth to
illustrate various embodiments of the invention. The drawings are
as follows:
[0040] FIG. 1 of the present invention is an enlarged
cross-sectional view down the center of one embodiment of the
sustained release drug delivery device showing a unitary cup with a
lip extending inward around some portion of the open top end of the
cup, a permeable plug, the cup and plug acting as a reservoir for
the drug core.
[0041] FIG. 2 of the present invention is an enlarged
cross-sectional view down the center of another embodiment of the
sustained release drug delivery device showing a unitary cup with a
recessed groove around some portion of the inside of the open top
end of the cup, a permeable plug, the cup and plug acting as a
reservoir for the drug core.
[0042] FIG. 3 of the present invention is an enlarged top view of
another embodiment of the sustained release drug delivery device
showing a unitary cup with a plurality of lips extending inward
around at least a portion of the open top end of the cup, a
permeable plug, the cup and plug acting as a reservoir for the drug
core.
[0043] FIG. 4 of the present invention is an enlarged
cross-sectional view down the center of another embodiment of the
sustained release drug delivery device showing a unitary cup with a
plurality of lips and an integral suture tab, a permeable plug, the
cup and plug acting as a reservoir for the drug core.
[0044] FIG. 5 is an enlarged top view of the embodiment of a
sustained release drug delivery device according to the present
invention showing an lip extending outward around only a portion of
the open top end of the cup.
[0045] FIG. 6 of the present invention is an enlarged
cross-sectional view down the center of another embodiment of the
sustained release drug delivery device showing a unitary cup with a
plurality of grooves and an integral suture tab, an impermeable
plug with a passageway, a permeable plug, the cup and plugs acting
as a reservoir for the drug core.
DETAILED DESCRIPTION OF THE INVENTION
[0046] The inventors have unexpectedly discovered a sustained
release drug delivery device that because of its unitary cup and
permeable plug design is structurally stabile and can be more
easily and reproducibly manufactured than current designs that are
known in the art.
[0047] In one preferred embodiment, the device includes an
impermeable unitary cup made of silicone with an integral suture
tab, the unitary cup acts as a reservoir for a drug core containing
an agent such as fluocinolone acetonide. A hole through the
proximal end of the suture tab enables a suture to be used for
securing the device. The open end of the unitary cup has lips
extending inwardly around a portion of the top open end of said
cup. A permeable polymer solution of 10% polyvinyl alcohol (PVA) is
filled in the recess above the drug core. The PVA solution is
allowed to dry. The device is cured for 60 minutes at
135-140.degree. C. The PVA is sufficiently rigid to maintain its
shape and the integrity of the device and thereby forming a
permeable plug such that the lips interact with the plug holding it
in position and closing the open top end. Together the cup with
lips and the permeable plug act as a reservoir surrounding the drug
core and keeping it in place.
[0048] The expression "agent" as used herein broadly includes any
compound, composition of matter, or mixture thereof that can be
delivered from the device to produce a beneficial and useful
result.
[0049] The term "impermeable" refers to a material that is
sufficiently impermeable to environmental fluids as well as
ingredients contained within the delivery device, such that the
migration of such fluids and ingredients into or out of the device
through the impermeable material is so low as to have substantially
no adverse impact on the function of the device.
[0050] The term "permeable" refers to a material that is capable of
being passed through or permeated. Permeating includes passing
through openings, holes, pores, or intersections.
[0051] The term "drug core" refers to any drug supply, drug depot,
drug in suspension, reservoir or drug matrix. It includes one or
more agents necessary to obtain the desired diagnostic effect or
local or systemic physiological or pharmacological effect. It
includes any excipients, suspending agents, or binders. Reference
may be made to any standard pharmaceutical textbook such as
Remington's Pharmaceutical Sciences. The drug core can be in liquid
form, solid form, in dispersion, or any other form known in the
art. Solid dose includes all conventional solid dose forms known in
the art including tablets and pellets. Dispersions include all
conventional forms known in the art, such as liquid in liquid
dispersions and solid in liquid dispersions.
[0052] The expression "passageway" as used herein includes an
aperture, orifice, or bore sufficient to allow the agent to pass
through. The passageway can be formed by mechanical procedures such
as erosion, laser, or molding; and chemical procedures.
[0053] Referring to the drawing figures, like reference numerals
designate identical or corresponding elements throughout the
several figures.
[0054] Turning now to the drawings in detail, which examples are
not to be construed as limiting, one embodiment of a device is
indicated in FIG. 1. While the device shown in FIG. 1 is generally
U like in shape, the cup can be any open container or bowl of any
shape. FIG. 1 is a cross sectional view of a drug delivery device
in accordance with the present invention. FIG. 1 includes an
impermeable unitary cup 3 containing a drug core 1 comprising an
agent, the cup 3 has lips 4 extending inward around the open top
end 5 of the cup 3; and a permeable plug 2 formed of a material
permeable to the passage of agent contained in the drug core 1. The
permeable plug 2 is positioned in the recess between the top of the
drug core 1 and below the lips 4 such that the lips 4 interact with
the permeable plug 2 holding it in position and closing the open
top end 5 of the cup 3.
[0055] The lips 4 are the same impermeable material as the unitary
cup 3 and protrude inwardly from the top open end 5 of the cup 3.
The cup 3 and lips 4 are formed in a single unitary design to
provide structural integrity to the device and facilitate
manufacturing and handling. The lips 4 are designed to hold the
plug 2 in place during use. They can vary in size or shape. The
lips 4 of the present invention include nubs, tabs, ridges, and any
other raised or protruding member.
[0056] The permeable plug 2 can be formed in the unitary cup by
filling the permeable material in the device in one step, such as
injecting a solution of PVA. The permeable plug 2 can be formed to
various dimensional specifications which can be used to control
diffusion properties to achieve a desired release rate. For
example, changing the amount of the permeable material filled into
the cup can vary the thickness of the permeable plug. The same
unitary cup and lips design can be used for implants with a variety
of release rates, making it possible to use a single manufacturing
line or type of equipment. Thus, the present invention allows for
ease of construction by more standard manufacturing techniques into
devices with different release rates.
[0057] Together the cup 3 with lips 4 and the permeable plug 2 act
as a reservoir surrounding the drug core 1 and keeping it in place.
The agent diffuses out of the drug core 1, through the permeable
plug 2, and out the open top end 5. The permeable plug 2 has
substantially the same radial extent as the cup 3, so that the only
diffusion pathway is out of the plug 2 and not around the sides 6.
Glue or other adhesion means can be employed to further bond the
plug to the cup.
[0058] The invention further relates to a method for treating a
mammalian organism to obtain a desired local or systemic
physiological or pharmacological effect. The method includes
administering the sustained release drug delivery device to the
mammalian organism and allowing the agent effective in obtaining
the desired local or systemic physiological or pharmacological
effect to pass through the plug 2. The term "administering", as
used herein, means positioning, inserting, injecting, implanting,
or any other means for exposing the device to a mammalian organism.
The route of administration depends on a variety of factors
including type of response or treatment, type of agent, and the
preferred site of administration. However, the preferred method is
to insert the device into the target organ. In ocular applications,
more preferably through a surgical procedure followed by suturing
the device in place.
[0059] FIG. 2 illustrates an enlarged cross sectional view down the
center of a sustained release drug delivery device in accordance
with the present invention. FIG. 2 includes an impermeable unitary
cup 10 containing a drug core 1 comprising an agent, the cup 10 has
a recessed groove 11 around the inside of the open top end 12 of
the cup 10; and a permeable plug 2 formed of a material permeable
to the passage of agent contained in the drug core 1. The permeable
plug 2 is positioned such that the groove 11 interacts with the
permeable plug 2 holding it in position and closing the open top
end 12 of the cup 10.
[0060] Together the cup 10 with the groove 11 and the permeable
plug 2 act as a reservoir surrounding the drug core 1 and keeping
it in place. The agent diffuses out of the drug core 1, through the
permeable plug 2, and out the open top end 12. The permeable plug 2
has substantially the same radial extent as the groove 11, so that
the only diffusion pathway is out of the plug 2 and not around the
sides 6. Glue or other adhesion means can be employed to further
bond the plug to the cup.
[0061] FIG. 3 is an enlarged top view of another exemplary
embodiment of a sustained release drug delivery device of the
present invention. The view in FIG. 3 is the top of a unitary cup
comprising a plurality of lips 15 extending inwardly around the
open top end of the cup. The permeable plug 2 is held in place by
the lips 15 extending inwardly around the top open end of the
cup.
[0062] FIG. 4 is a enlarged cross sectional view of a drug delivery
device in accordance with the present invention. FIG. 4 includes an
impermeable unitary cup 23 containing a drug core 1 comprising an
agent, the cup 23 has lips 24, 25 extending inward around the open
top end 20 of the cup 23; and a permeable plug 2 formed of a
material permeable to the passage of agent contained in the drug
core 1. The permeable plug 2 is positioned in the recess between
the top of the drug core 1 and the second lip 24 such that the lips
24, 25 interact with the permeable plug 2 holding it in position
and closing the open top end 20 of the cup 23.
[0063] The cup 23 further comprises an integral suture tab 21 with
a hole 22 through the proximal end through which a suture can be
placed to anchor the device to a structure of the organism
requiring treatment. The proximal end of the suture tab is at the
point of attachment, i.e. the point where the suture is attached.
The preferred point of attachment is at the end of the suture tab
opposite the cup.
[0064] The location of the suture and the structure the device is
sutured to can be any that meet with current surgical techniques
known in the art, such as the sclera of the eye. Depending upon the
location of administration, the devices of the current invention
may not require suturing in position.
[0065] Making the cup and suture tab in a single unitary design
provides structural integrity to the device, and facilitates
manufacturing and handling as one integral structure. In addition,
by eliminating the assembly step of attaching the suture tab onto
the cup, the single unitary design decreases variability in the
size and shape of the device.
[0066] Providing a suture hole 22 at the proximal end of the suture
tab of the device enables the surgeon to attach the device without
additional steps. Providing the suture hole reduces the possibility
of tearing the tab while passing the needle through during surgery.
Some materials, such as cured polyvinyl alcohol, are also very
difficult to create a suture hole in once the device is assembled
without causing cracks or breaks in the suture tab.
[0067] The devices of the present invention may comprise a
plurality of lips. These lips can be on the same vertical plane, as
illustrated in FIG. 3, or on a different vertical plane, as
illustrated in FIG. 4. The device may also be formed with any
combination of lips in different vertical planes suitable to hold
the permeable plug in place. For example, a single lip may be
placed in the top vertical plane (position 24 in FIG. 4) and a
plurality of lips, as in FIG. 3, at a lower vertical plane
(position 25 in FIG. 4) positioned above the drug core to
facilitate holding the permeable plug in place. The function of the
lips is to hold the permeable plug in place and prevent failure of
the structural integrity of the device.
[0068] The devices of the present invention that employ recessed
grooves to secure the permeable plug in place may also have a
plurality of grooves in the same or different vertical planes as
described above.
[0069] FIG. 5 is an enlarged top view of another exemplary
embodiment of a sustained release drug delivery device of the
present invention. The view in FIG. 5 is the top of a unitary cup
comprising a single lip 30. The permeable plug 2 is held in place
by the lip 30 extending inwardly around the top open end of the
cup. The single lip can extend around the entire diameter of the
top open end of the cup or extend around some portion, as
illustrated in FIG. 5.
[0070] FIG. 6 illustrates an enlarged cross sectional view down the
center of a sustained release drug delivery device in accordance
with the present invention. FIG. 6 includes an impermeable unitary
cup 35 containing a drug core 1 comprising an agent, the cup 35 has
a plurality of grooves 38,39 around the inside of the open top end
40 of the cup 35; an impermeable plug 36 with a passageway 37, and
a permeable plug 2 formed of a material permeable to the passage of
agent contained in the drug core 1. The impermeable plug 36 is
positioned such that the groove 39 interacts with the impermeable
plug 36 holding it in position. The permeable plug 2 is positioned
such that the groove 38 interacts with the permeable plug 2 holding
it in position and closing the open top end 40 of the cup 35. Glue
or other adhesion means can be employed to further bond the plugs
to each other or the cup.
[0071] The impermeable plug of the embodiment in FIG. 6, can
interact with a groove, as illustrated, or be the same radial
extent as the cup. An expanded recess groove could retain the
impermeable plug and still provide an anchor groove for the
permeable plug. The impermeable plug can also be utilized in this
manner in the unitary cup design that comprises a lip or lips. Due
to elastic nature of some polymers, such as silicone, the same
result could be achieved by essentially molding the impermeable
plug as part of the unitary cup and stretching the passageway wide
enough to insert the tablet or filling in a liquid or powder drug
core through the passageway.
[0072] In combination with the examples above, a variety of methods
may also be utilized to provide adhesion of the permeable plug to
the unitary cup portion of the device. These methods include the
use of adhesives, polymers such as PVA, or any other procedure
known in the art to provide adhesion at the points of contact
between the permeable plug and the unitary cup. The sealant can be
permeable or impermeable to the agent or agents in the device
depending upon the method and location of application. If the
adhesive is permeable to the beneficial agent, such as in the case
of a permeable polymer, it could be applied on top of the drug core
or directly to the permeable plug. The methods to improve adhesion
will vary depending on the materials that the components are
manufactured from.
[0073] The above-described methods of adhesion may also be utilized
to provide adhesion of the impermeable plug to the unitary cup or
permeable plug. For example, impermeable adhesives could be applied
to only the edges of the impermeable plug and because the adhesive
is present only on the edges, it improves the bond between the
impermeable plug and the device without interfering with diffusion
through the passageway(s) and the permeable plug. If the adhesive
is permeable to the beneficial agent, such as in the case of a
permeable polymer, it could be applied on top of the drug core, on
top of the impermeable plug, or directly to the impermeable plug
before the impermeable plug is put into place.
[0074] The drug core or reservoir contains an agent effective in
obtaining a desired local or systemic physiological or
pharmacological effect. The following classes of agents could be
incorporated into the devices of the present invention: anesthetics
and pain killing agents such as lidocaine and related compounds and
benzodiazepam and related compounds; anti-cancer agents such as
5-fluorouracil, adriamycin and related compounds; anti-fungal
agents such as fluconazole and related compounds; anti-viral agents
such as trisodium phosphomonoformate, trifluorothymidine,
acyclovir, ganciclovir, DDI and AZT; cell transport/mobility
impending agents such as colchicine, vincristine, cytochalasin B
and related compounds; antiglaucoma drugs such as beta-blockers:
timolol, betaxolol, atenalol, etc; antihypertensives; decongestants
such as phenylephrine, naphazoline, and tetrahydrazoline;
immunological response modifiers such as muramyl dipeptide and
related compounds; peptides and proteins such as cyclosporin,
insulin, growth hormones, insulin related growth factor, heat shock
proteins and related compounds; steroidal compounds such as
dexamethasone, prednisolone and related compounds; low solubility
steroids such as fluocinolone acetonide and related compounds;
carbonic anhydrize inhibitors; diagnostic agents; antiapoptosis
agents; gene therapy agents; sequestering agents; reductants such
as glutathione; antipermeability agents; antisense compounds;
antiproliferative agents; antibody conjugates; antidepressants;
bloodflow enhancers; antiasthmatic drugs; antiparasiticagents;
non-steroidal anti inflammatory agents such as ibuprofen; nutrients
and vitamins; enzyme inhibitors; antioxidants; anticataract drugs;
aldose reductase inhibitors; cytoprotectants; cytokines, cytokine
inhibitors, and cytokin protectants; uv blockers; mast cell
stabilizers; and anti neovascular agents such as antiangiogenic
agents like matrix metalloprotease inhibitors.
[0075] Examples of such agents also include neuroprotectants such
as nimodipine and related compounds; antibiotics such as
tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin,
gramicidin, oxytetracycline, chloramphenicol, gentamycin, and
erythromycin; antiinfectives; antibacterials such as sulfonamides,
sulfacetamide, sulfamethizole,sulfisoxazole; nitrofurazone, and
sodium propionate; antiallergenics such as antazoline,
methapyriline, chlorpheniramine, pyrilamine and prophenpyridamine;
anti-inflammatories such as hydrocortisone, hydrocortisone acetate,
dexamethasone 21-phosphate, fluocinolone, medrysone,
methylprednisolone, prednisolone 21-phosphate, prednisolone
acetate, fluoromethalone, betamethasone and triminolone; miotics
and anti-cholinesterase such as pilocarpine, eserine salicylate,
carbachol, di-isopropyl fluorophosphate, phospholine iodine, and
demecarium bromide; mydriatics such as atropine sulfate,
cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine,
and hydroxyamphetamine; sympathomimetics such as epinephrine; and
prodrugs such as those described in Design of Prodrugs, edited by
Hans Bundgaard, Elsevier Scientific Publishing Co., Amsterdam,
1985. In addition to the above agents, other agents suitable for
treating, managing, or diagnosing conditions in a mammalian
organism may be placed in the inner core and administered using the
sustained release drug delivery devices of the current invention.
Once again, reference may be made to any standard pharmaceutical
textbook such as Remington's Pharmaceutical Sciences for the
identity of other agents.
[0076] Any pharmaceutically acceptable form of such a compound may
be employed in the practice of the present invention, i.e., the
free base or a pharmaceutically acceptable salt or ester thereof.
Pharmaceutically acceptable salts, for instance, include sulfate,
lactate, acetate, stearate, hydrochloride, tartrate, maleate and
the like.
[0077] A large number of polymers can be used to construct the
devices of the present invention. The only requirements are that
they are inert, non-immunogenic and of the desired permeability.
Materials that may be suitable for fabricating the device include
naturally occurring or synthetic materials that are biologically
compatible with body fluids and body tissues, and essentially
insoluble in the body fluids with which the material will come in
contact. The use of rapidly dissolving materials or materials
highly soluble in body fluids are to be avoided since dissolution
of the wall would affect the constancy of the drug release, as well
as the capability of the device to remain in place for a prolonged
period of time.
[0078] Naturally occurring or synthetic materials that are
biologically compatible with body fluids and eye tissues and
essentially insoluble in body fluids which the material will come
in contact include, but are not limited to, glass, metal, ceramics,
polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked
polyvinyl butyrate, ethylene ethylacrylate copolymer, polyethyl
hexylacrylate, polyvinyl chloride, polyvinyl acetals, plasiticized
ethylene vinylacetate copolymer, polyvinyl alcohol, polyvinyl
acetate, ethylene vinylchloride copolymer, polyvinyl esters,
polyvinylbutyrate, polyvinylformal, polyamides,
polymethylmethacrylate, polybutylmethacrylate, plasticized
polyvinyl chloride, plasticized nylon, plasticized soft nylon,
plasticized polyethylene terephthalate, natural rubber,
polyisoprene, polyisobutylene, polybutadiene, polyethylene,
polytetrafluoroethylene, polyvinylidene chloride,
polyacrylonitrile, cross-linked polyvinylpyrrolidone,
polytrifluorochloroethylene, chlorinated polyethylene,
poly(1,4'-isopropylidene diphenylene carbonate), vinylidene
chloride, acrylonitrile copolymer, vinyl chloride-diethyl fumerale
copolymer, butadiene/styrene copolymers, silicone rubbers,
especially the medical grade polydimethylsiloxanes,
ethylene-propylene rubber, silicone-carbonate copolymers,
vinylidene chloride-vinyl chloride copolymer, vinyl
chloride-acrylonitrile copolymer and vinylidene
chloride-acrylonitride copolymer.
[0079] The device can be formulated in any convenient shape. For
example, the device can be of any geometric shape dimensionally
suitable for insertion in the eye. Thus, the device can be
ellipsoid, rectangular, round, etc. The shape of the cup in the
present can be optimized to provide a minimum profile for
insertion.
[0080] The dimensions of the device can vary with the size of the
device, the size of the core or reservoir, and the membrane that
surrounds the core or reservoir. The targeted disease state, type
of mammalian organism, location of administration, and agents or
agent administered are among the factors which would effect the
desired size of the sustained release drug delivery device.
[0081] The device according to the present invention may be made in
a variety of ways. For example, if the unitary cup is going to be
made entirely of polymer, then the polymer can be injection molded
or die cast into a desired shape and size. The permeable plug can
also be formed by any conventional means depending on the materials
selected. For example, the permeable plug can be formed by
injecting, pouring, adding drop wise, or molding the permeable
material. Depending on the permeable material chosen, it may be
required to dry and/or be cured to form the plug. The agent can be
filled into the reservoir by any conventional means such as
drop-wise, syringe, or pipette. The agent can also be made as a
solid dose form such as a tablet or pellet and placed into the
unitary cup. For example, a standard size tablet could be used with
varying compositions.
[0082] The preceding descriptions of how to make the device of the
present invention is merely illustrative and should not be
considered as limiting the scope of the invention in any way. In
particular, the methods of making the device depend on the identity
of the agent.
[0083] The devices may be surgically implanted at or near the site
of action. This is the case for devices of the present invention
used in treatment of ocular conditions, primary tumors, rheumatic
and arthritic conditions, and chronic pain. The devices may also be
implanted subcutaneously, intramusclarly, intraarterially, or
intraperitoneally. This is the case when devices are to give
sustained systematic levels and avoid premature metabolism. In
addition, such devices may be administered orally.
[0084] Once in place, the device functions as a drug reservoir
gradually releasing drug to the organ such as the eye and
surrounding tissue. This device is particularly useful for treating
ocular conditions such as glaucoma, proliferative
vitreoretimopathy, diabetic retinopathy, uveitis, and keratitis.
The device is also particularly useful as an ocular device in
treating mammalian organisms suffering from cytomegalovirus
retinitis wherein the device is surgically implanted within the
vitreous of the eye.
[0085] As would be readily understood by one skilled in the art,
the preferred amounts, materials, and dimensions depend on the
method of administration, the effective agent used, the polymers
used, the desired release rate and the like. Likewise, actual
release rates and release duration depend on a variety of factors
in addition to the above, such as the disease state being treated,
the age and condition of the patient, the route of administration,
as well as other factors which would be readily apparent to those
skilled in the art. All of the forgoing U.S. Patents and other
publications are expressly incorporated by reference herein in each
of their entities.
[0086] Thus, the devices of the present invention provide many
important advantages over previously known sustained release drug
delivery devices. The unitary cup and plug design of the present
invention provide an improved device that maintains its physical
and chemical integrity in both the environments of use and in the
presence of agent during the controlled and continuous dispensing
of agent over a prolonged period of time.
[0087] Forming the permeable plug in the unitary cup enables
superior interaction with the lips or grooves of the unitary cup
thereby locking the permeable plug in place. The resulting device
has superior structural stability under the conditions of use.
[0088] Because of the structural integrity of the present design,
the need for coatings and multiple layers can be eliminated. For
transport of agent out of the device and into the target area, it
is only necessary that the permeable layer cover the portions of
the device not covered with the impermeable layer.
[0089] The unitary cup design and the use of plugs of the present
invention result in a device that is more easily and reproducibly
manufactured then current designs known in the art. Manufacturing
with the single unitary cup and plugs minimizes the number of steps
and decreases potential variability in assembly. The present design
also allows for mechanized manufacture. Eliminating manual assembly
greatly decreases the potential variability in the finished
product.
[0090] Another advantage of the devices of the present invention is
the ease of construction by more standard manufacturing techniques
into devices with different release rates. The passageway in the
impermeable plug allows for release of the agent. A single standard
cup size can be used for multiple dosage configurations by varying
the size or number of passageways in the impermeable plug, or by
not using the impermeable plug at all. The permeable plug can also
be made to various dimensional specifications that can be used to
control diffusion properties to achieve a desired release rate.
Thus, the same unitary cup can be used for implants with different
release rates making it possible to use a single manufacturing line
or type of equipment.
[0091] In addition, the use of a single unitary cup and permeable
plug to form the container or drug reservoir of the present design
provides more consistent and improved sealing capacity over the
devices in the prior art. This permits the therapeutic program to
be precisely controlled and the release of drug to be constant and
predicted with accuracy.
[0092] The ease of making the devices in the present invention
minimizes stresses, strains, and deformations of the devices during
manufacture which may cause the reservoir to rupture and leak. The
leaking of agent can result in harm to the patient and is a
significant concern in the manufacture of implantable devices.
[0093] The following specific examples demonstrate sustained
release drug delivery device designs of the present invention.
However, it is to be understood that these examples are for
illustrative purposes only and do not purport to be wholly
definitive as to the conditions and scope.
EXAMPLE 1
[0094] A device according to the present invention is prepared. The
unitary cup is made of silicone and has eight inwardly extending
lips around the top open end of the cup. The unitary cup has an
integral suture tab with a hole at the end of the tab opposite the
cup. The drug core is formed as a pellet composed of a 2.5 mg core
of fluocinolone acetonide and inserted into the cup. A 10% PVA
solution is injected into the unitary cup filling the recess
between the drug core and the lips. The PVA is allowed to dry. The
device is cured at 135-140.degree. C. for 50 minutes. The lips act
to hold the permeable plug in place.
EXAMPLE 2
[0095] The device of example 1 above is placed in a vial with 2.0
mL of a release media of 0.1 Sodium Acetate, pH 4.2. The vial is
maintained in a 37.degree. C. bath for 24 hours. After 24 hours,
the vial is inverted to ensure homogeneity and the device is
removed to a new vial with fresh media. This process is repeated
for each day. The media is tested to determine the amount of the
drug and verifies that it is being released from the device. From
the data that is collected, the release rate of the device can be
determined.
EXAMPLE 3
[0096] A device according to the present invention is prepared. The
unitary cup is made of silicone and has two recessed grooves, one
above the other, around the inside of the top open end of the cup.
The first groove, which is the one further from the top open end of
the cup, is deeper then the second groove. The unitary cup has an
integral suture tab with a hole at the end of the tab opposite the
cup for suturing the device to a structure of a mammalian organism.
The drug core is formed as a tablet composed of a 0.5 mg core of
fluocinolone acetonide and inserted into the cup. An impermeable
plug made of silicone, with a passageway in the center, is placed
in the cup fitting into the first groove. A 10% PVA solution is
filled into the unitary cup filling in the recess above the
impermeable plug. The PVA is allowed to dry. The device is cured at
about 140.degree. C. for 50 minutes. The second groove interacts
with the permeable plug holding it in place. From the foregoing
description, one of ordinary skill in the art can easily ascertain
the essential characteristics of the instant invention, and without
departing from the spirit and scope thereof, can make various
changes and/or modifications of the inventions to adapt it to
various usages and conditions. As such, these changes and/or
modifications are properly, equitably, and intended to be, within
the full range of equivalence of the following claims.
* * * * *