U.S. patent application number 09/888757 was filed with the patent office on 2001-10-25 for systems and methods for local delivery of an agent.
Invention is credited to Ahern, John E., Crittenden, James F..
Application Number | 20010033867 09/888757 |
Document ID | / |
Family ID | 25539727 |
Filed Date | 2001-10-25 |
United States Patent
Application |
20010033867 |
Kind Code |
A1 |
Ahern, John E. ; et
al. |
October 25, 2001 |
Systems and methods for local delivery of an agent
Abstract
A system and method for implanting pellets into myocardial
tissue for treatment of coronary artery restenosis, ischemic heart
disease, or cardiac conduction of disturbances. The mechanism of
delivery can be transcatheter via chambers of the heart, endoscopic
pericardial approach via minimally invasive transthoracic access,
or intraoperative pericardial approach during open-chest surgery.
Noncardiac tissues can also be treated.
Inventors: |
Ahern, John E.; (Melrose,
MA) ; Crittenden, James F.; (Hollis, NH) |
Correspondence
Address: |
John F. Perullo
Kirkpatrick & Lockhart LLP
75 State Street
Boston
MA
02109-1808
US
|
Family ID: |
25539727 |
Appl. No.: |
09/888757 |
Filed: |
June 25, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09888757 |
Jun 25, 2001 |
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08993586 |
Dec 18, 1997 |
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6251418 |
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Current U.S.
Class: |
424/489 ;
604/508 |
Current CPC
Class: |
A61K 31/165 20130101;
A61P 9/00 20180101; A61M 2025/0089 20130101; A61B 2017/00247
20130101; A61B 2018/00392 20130101; A61K 9/0024 20130101; A61M
2210/125 20130101; A61M 37/0069 20130101; A61M 25/0133 20130101;
A61M 2025/0091 20130101 |
Class at
Publication: |
424/489 ;
604/508 |
International
Class: |
A61K 009/14; A61M
031/00 |
Claims
We claim:
1. A method for providing local delivery of a therapeutic agent,
comprising the step of implanting said therapeutic agent into a
portion of myocardial tissue.
2. A method according to claim 1, including the steps of providing
a catheter having a distal end adapted for delivering said
therapeutic agent, guiding said catheter into the interior of a
patient's heart, and disposing said distal end against an
endocardial wall of the heart for implanting said therapeutic agent
into the myocardial tissue.
3. A method according to claim 1 including the further step of,
providing a steerable catheter having a drilling element for
penetrating an endocardial wall.
4. A method according to claim 1, including the step of delivering
a pellet containing said therapeutic agent into the myocardial
tissue.
5. A method according to claim 4, including the step of delivering
sequentially a plurality of pellets containing said therapeutic
agent into the myocardial tissue.
6. A method according to claim 1, including the step of providing a
pellet containing said therapeutic agent and a radio-opaque
material.
7. A method according to claim 2, including the step of steering
said catheter through the femoral artery and into the heart.
8. A method according to claim 2, including the step of positioning
a marker in a selected portion of a coronary artery, for providing
a marker to identify a location for receiving said therapeutic
agent.
9. A method according to claim 2, including the step of penetrating
said distal end of said catheter through said endocardial wall, for
delivering said therapeutic agent into said myocardial tissue.
10. A method according to claim 2, including the step of delivering
through said distal end of said catheter, a pellet having a pointed
or helical, conical end adapted to penetrate said endocardial
wall.
11. A method according to claim 2, including the step of delivering
pellets containing said therapeutic agent and having an outer
surface adapted to adhere said pellets to said endocardial
wall.
12. A method according to claim 1, including the step of
endoscopically delivering said therapeutic agent through the
epicardium.
13. A method according to claim 1, including the step of implanting
said therapeutic agent into the myocardial tissue during open-chest
surgery.
14. A method for delivering a pellet containing a therapeutic
agent, comprising the steps of providing a catheter having a distal
end adapted for delivering said pellet, guiding said catheter
through a body lumen and disposing said distal end proximate a
tissue wall, and delivering said pellet through said distal end
with sufficient force to implant said pellet within said tissue
wall.
15. A method for delivering a therapeutic agent to a septal artery,
comprising the steps of providing a catheter having a distal end
adapted for delivering said therapeutic agent, guiding said
catheter into the interior of a patient's heart, and disposing said
distal end against a septal wall of the heart for implanting said
therapeutic agent into the septal wall.
16. A method according to claim 15, wherein the step of disposing
said distal end of the catheter includes a step of, delivering a
pellet containing said therapeutic agent from said distal end with
sufficient force to implant said pellet within the septal wall.
17. A method according to claim 15, wherein the step of disposing
said distal end of the catheter includes a step of, delivering from
said distal end of the catheter a pellet containing said
therapeutic agent and having a surface adapted to adhere to a
tissue wall.
18. A method for treating vascular restenosis, comprising the steps
of identifying a portion of tissue proximate to a site of a
patient's vasculature to be treated for restenosis, and implanting
a therapeutic agent into the portion of tissue.
19. A pellet, comprising a therapeutic agent surrounding a
radio-opaque material, whereby delivery of the therapeutic agent is
facilitated by viewing the position of the radio-opaque material
relative to a position of a targeted site for implanting the
pellet.
20. Apparatus for implanting a therapeutic agent within a tissue
wall, comprising an elongate flexible body having a proximal end
and a distal end, a delivery chamber coupled to the distal end of
the body and having a space for carrying the therapeutic agent, and
a port for releasing the therapeutic agent therefrom, and an
actuator coupled to the delivery chamber and capable of driving the
therapeutic agent through the port, whereby the therapeutic agent
is implanted within a tissue wall.
21. Apparatus according to claim 20, further including a control
mechanism coupled to the actuator and the proximal end of the body
for providing control of the actuator, whereby a user can operate
the control mechanism for controlling the delivery of the
therapeutic agent.
22. Apparatus according to claim 20, further including a steering
mechanism for turning the distal end of the body, to thereby allow
the delivery chamber to be selectively guided through a body
lumen.
23. Apparatus according to claim 20, wherein the delivery chamber
and the distal end of the flexible body are dimensionally adapted
to allow for transluminal delivery and for entry into the interior
of a patient's heart.
24. Apparatus according to claim 20, wherein the delivery chamber
includes a substantially cylindrical interior housing dimensionally
adapted to store in axial alignment a plurality of minispheres
containing a therapeutic agent.
25. Apparatus according to claim 20, further including a pointed
distal end adapted to penetrate a tissue wall for delivering the
therapeutic agent within the tissue wall.
26. Apparatus according to claim 20, wherein the actuator includes
a plunger for driving the therapeutic agent from the delivery
chamber.
27. Apparatus according to claim 20, further including a ratchet
assembly for allowing delivery of discreet volumes of the
therapeutic agent.
28. Apparatus according to claim 20, wherein the actuator includes
a threaded plunger for advancing into the delivery chamber
responsive to a rotating action.
29. Apparatus according to claim 20, wherein the delivery chamber
is adapted to receive at least one pellet containing the
therapeutic agent.
30. Apparatus according to claim 20, further including a
lever-action handle mounted at the proximal end of the flexible
body and coupled to the control mechanism.
31. Apparatus according to claim 20, further including means for
receiving at least one pellet containing the therapeutic agent and
having an arcuate shape for facilitating implanting within a body
of tissue.
Description
FIELD OF THE INVENTION
[0001] The invention relates to the local delivery of therapeutic
agents, and more particularly, to systems and methods that deliver
depots of therapeutic agents into a body of tissue to allow for the
treatment of a variety of conditions, including coronary conditions
and cardiovascular indications.
BACKGROUND OF THE INVENTION
[0002] Disease, injury and surgery can result in localized tissue
damage and morbidity. For example, the principal treatment for
occlusive vascular diseases is angioplasty, a procedure in which a
balloon is inserted into the vessel and then inflated to dilate the
area of narrowing. During inflation, the balloon can damage the
vessel wall. It appears that as a result of this damage, in 30 to
50% of cases, the initial increase in lumen dimensions is followed
by a localized re-narrowing (restenosis) of the vessel over a time
of three to six months. Thus, restenosis can result in the
dangerous and localized renarrowing of a patient's vessel at the
site of the recent angioplasty. Like many other localized diseases,
restenosis is complex and at present there is no clinically
effective treatment for this disease. Gibbons et al, Molecular
Therapies for Vascular Diseases, Science vol. 272, pages 617-780
(May 1996).
[0003] Restenosis, like many other localized injuries and diseases,
has responded poorly to pharmacological therapies and agents.
Numerous pharmacological agents have been clinically tested, and
none have demonstrated an unequivocal reduction in the incidence of
restenosis. However, the failure of these pharmacological therapies
may arise from the systemic intolerance of the doses required to
achieve local beneficial effects or in the difficulty of providing
controlled administration of proper dosages over time. Accordingly,
one possible reason for the failure of these therapies is that
submaximal doses of pharmacological agents are being administered
to avoid the serious side-effects that might result from systemic
administration of the proper dosage.
[0004] To address this problem, various researchers have proposed
methods for site-specific delivery of pharmacologic and molecular
therapies. These methods include the direct deposition of
therapeutic agents into the arterial wall through an intravascular
delivery system, systemic administration of therapeutic agents that
have a specific affinity for the injured or diseased tissue, and
systemic administration of inactive agents followed by local
activation.
[0005] At present, systems exist that attempt to achieve localized
delivery of therapeutic agents. These systems include dual balloon
delivery systems that have proximal and distal balloons that are
simultaneously inflated to isolate a treatment space within an
arterial lumen. A catheter extends between the two balloons and
includes a port that can admit within the treatment space between
the balloons an aqueous medium, typically one containing a
therapeutic agent. Pressure can be applied to the medium to create
conditions conducive to intramural infusion. Other balloon-based
localized delivery systems include porous balloon systems,
hydrogel-coated balloons and porous balloons that have an interior
metallic stent. Other systems include locally placed drug-loaded
coated metallic stents and drug-filled polymer stents. Wilensky et
al., Methods and Devices for Local Drug Delivery in Coronary and
Peripheral Arteries, Trend Cardiovasc Med, vol. 3 (1993).
[0006] Although these systems can provide working devices for local
drug delivery, the efficacy of these devices turns on, and is
limited by, a number of factors including the rate of fluid flux
through the vascular wall, the residence time of the deposited
agent and the local conditions and vasculature of the deposition
site. Essentially, the success of these systems is limited by the
amount of time that a delivered drug will stay resident locally
before being carried downstream by circulating blood. Further, to
the extent that these systems allow the therapeutic agent to be
carried away, these systems run the risk of applying a therapeutic
agent to areas of the patient's vasculature where such agents may
not be beneficial. Additionally, these existing systems are limited
by the amount of drug that can be delivered to the diseased site.
Moreover, drug filled polymer stents have structural problems that
argue against their use.
[0007] It would be advantageous to develop other methods of
treatment for patients having localized cardiovascular conditions
and in particular to develop methods of treatment that reduce
adverse side effects and have heightened efficacy.
SUMMARY OF THE INVENTION
[0008] It is therefore, an object of the invention to provide
methods of treatment of a coronary artery or cardiac indication
that provide a longer duration of drug pendency at the site of a
localized disease.
[0009] It is a further object of the invention to provide systems
and methods that reduce or eliminate the downstream flow of a
locally delivered agent.
[0010] Other objects of the invention will, in part, be obvious,
and, in part, be shown from the following description of the
systems and methods shown herein.
[0011] To these ends, the invention provides systems and methods
for implanting a depot into a tissue wall to thereby deliver a
therapeutic agent selected for the condition being treated. In one
embodiment, the invention provides systems and methods for
delivering a therapeutic agent into the myocardial tissue wall for
treating various vascular conditions including restenosis, ischemic
tissue, and myocardial infarction. Other applications of the
systems and methods described herein include the delivery of
angiogenesis compounds that can be implanted into ischemic tissue;
and/or antiarrhythmic drugs that can be implanted at the sites of
conduction abnormalities. Accordingly, the agent being locally
delivered can depend on the application at hand, and the term
agent, or therapeutic agent, as employed herein will be understood
to encompass any agent capable of being locally delivered
including, but not limited to, pharmaceutical compositions or
formulations, viral or non-viral vectors (e.g., adenovirus vectors,
retroviral vectors and the like), implantable (genetically
engineered) cells, plasmid-liposome complexes or other DNA delivery
complexes, oligonucleotides or any other suitable composition
compatible with the subject being treated.
[0012] In one embodiment the invention is understood as apparatus
for delivering therapeutic agents, comprising an elongate flexible
body having a proximal end and a distal end, a delivery chamber
coupled to the distal end of the body and having a space for
carrying the therapeutic agent, and a port for releasing the
therapeutic agent therefrom. The apparatus further includes an
actuator coupled to the distal delivery chamber and being capable
of driving therapeutic agent through the port.
[0013] The terms proximal and distal as used herein will be
understood to describe opposite ends of a device or element, and
generally will be employed so that proximal is understood as "away
from the heart" and distal is understood as "towards the heart" or
to mean "toward the physician" and "away from the physician"
respectively.
[0014] In one embodiment, the apparatus further includes a control
mechanism that couples to the actuator and to the proximal end of
the body for providing control of the actuator. In this way a user
can operate the control mechanism for selectable delivery of the
agent. Optionally, the apparatus can also include a "steering"
mechanism for bending the distal end of the body to thereby allow
the delivery chamber to be selectively aimed or directed within the
chambers of the heart. The distal end of the flexible body can be
dimensionally adapted to allow for transluminal delivery and for
entry into the interior of a patient's heart. This allows the
distal end of the apparatus, which carries the delivery chamber, to
travel through the patient's vasculature, enter the patient's
heart, and butt against or penetrate through the endocardial tissue
and penetrate into the myocardium. To this end, the distal end of
the delivery chamber can be further provided with a pointed distal
end which is adapted to penetrate a tissue wall for delivering the
therapeutic agent into the tissue wall.
[0015] In a further embodiment, the apparatus can further include a
plunger for driving a therapeutic agent from the delivery chamber.
The plunger can include a ratchet assembly for allowing the
delivery of discrete volumes of therapeutic agent, or a discreet
number of pellets containing a therapeutic agent. Alternatively,
the plunger can be provided with a threaded assembly and worm gear
assembly for rotatably advancing the plunger into the delivery
chamber responsive to a rotating action. Accordingly, an actuator
such as a plunger disposed within the delivery chamber can act on
pellets of therapeutic agents stored within the delivery chamber to
force the pellets from the delivery chamber and implant them within
a tissue wall. Optionally a delivery chamber can be dimensioned to
receive one or a plurality of pellets containing a therapeutic
agent. The activation of the plunger or actuator can be by
manipulation of a lever action handle mounted at the proximal end
of the flexible body and coupled to the control mechanism.
Alternatively, a rotary mechanism, optionally motorized, can be
provided for rotating a threaded plunger to advance the plunger
within the delivery chamber thereby forcing pellets of therapeutic
agent from the chamber.
[0016] In a further embodiment of the invention, a mechanism is
provided for receiving at least one pellet containing the
therapeutic agent and having a pointed shape for facilitating
implanting the pellet within a body of tissue. As discussed above,
a plunger can be provided for forcing the pointed pellet from the
delivery chamber and implanting the pellet within a tissue wall of
the patient, such as within the myocardium.
[0017] In a further aspect, the invention can be understood as
pellets adapted for carrying a therapeutic agent into the tissue
wall of a patient. In one embodiment, the pellets include a
radio-opaque marker typically located at the core of the pellet
which facilitates the fluoroscopic viewing of the delivery of the
pellets.
[0018] In yet a further aspect, the invention can be understood as
methods for providing local delivery of a therapeutic agent which
include the step of implanting the therapeutic agent into a portion
of myocardial tissue. In one practice, the methods include the step
of providing a catheter having a distal end adapted for delivering
the therapeutic agent, guiding the catheter into the interior of a
patient's heart and disposing the distal end of the catheter
against an endocardial wall of the heart for implanting the
therapeutic agent into the myocardial tissue. The step of providing
a catheter can include the step of providing a steerable catheter
which, optionally, can include a drilling element for penetrating a
tissue wall such as the endocardium. In one practice, a plurality
of pellets containing a therapeutic agent, or a plurality of
therapeutic agents, are delivered sequentially into the myocardial
tissue. Optionally, each pellet can contain a therapeutic agent and
a radio-opaque marker.
[0019] In one practice of the invention, the local delivery of the
therapeutic agent is accomplished by transluminal delivery in which
the catheter is steered through access at the femoral artery or
vein and directed into the heart. Optionally, a marker can be
positioned in a selected portion of a coronary artery to identify a
location for receiving the therapeutic agent. In this practice, the
marker can be observed fluoroscopically during the procedure, and a
treating physician can use the positioned marker for targeting the
location of the myocardium into which the therapeutic agent is to
be implanted.
[0020] In a further practice, the procedure includes a step of
endoscopically delivering the therapeutic agent through the
epicardium. In yet another practice, the therapeutic agent is
implanted into the myocardial tissue during open chest surgery.
[0021] In a further aspect, the invention provides methods for
delivering a therapeutic agent to a septal artery. In one practice,
the method comprises the steps of providing a catheter having a
distal end that is adapted for delivering the therapeutic agent,
guiding the catheter into the interior of a patient's heart and
disposing the distal end of the catheter against a septal wall of
the heart for implanting the therapeutic agent into the septal
tissue.
BRIEF DESCRIPTION OF THE FIGURES
[0022] The foregoing and other objects and advantages of the
invention will be appreciated more fully from the following further
description thereof with reference to the accompanying drawings
wherein;
[0023] FIG. 1 depicts one embodiment of a catheter having a
delivery chamber carried at the distal end;
[0024] FIGS. 2A and 2B depict in more detail the delivery chamber
of the catheter depicted in FIG. 1;
[0025] FIGS. 3A and 3B depict an alternative delivery chamber for
use with the catheter of FIG. 1;
[0026] FIGS. 4A and 4B depict two embodiments of pellets suitable
for implantation by the catheter of FIG. 1;
[0027] FIG. 5 depicts one method for delivering a therapeutic agent
to the myocardium;
[0028] FIG. 6 provides a cross-cut perspective of a coronary artery
extending through the myocardium and having pellets of therapeutic
agent disposed around the artery; and
[0029] FIG. 7 depicts a local drug delivery device having a pistol
grip and being suitable for use during an endoscopic procedure.
DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS
[0030] To provide an overall understanding of the invention, the
methods and devices illustrated herein are described with reference
to the application of treating cardiac indications by implanting
drug delivery pellets into myocardial tissue for the treatment of
coronary artery restenosis, ischemic heart disease, cardiac
conduction disturbances and other similar conditions. However, it
will be understood that the systems and methods described herein
are applicable to any condition that can benefit from the
implanting of a depot of a therapeutic agent, and the invention is
not to be limited to the applications illustrated herein. For
example, the techniques herein are directly applicable for
implanting therapeutic agents to stimulate angiogenesis.
[0031] The depot implanting systems illustrated herein include
catheter systems for delivery via the chambers of the heart,
endoscopic systems for pericardial approach via minimally invasive
transthoracic access, and systems for use during intraoperative
pericardial approach during open-chest surgery. In one practice,
the devices deliver a plurality of pellets that surround, or
partially surround, an artery being treated. This is understood to
achieve the effect of implanting a drug-filled ring around the
artery. The pellets remain in the myocardial tissue, and can give
off drug(s) for a selected time period and then be absorbed by the
body. The systems described herein can implant pellets that contain
radio-opaque markers to facilitate viewing the pellets by
fluoroscopy during catheter delivery.
[0032] FIG. 1 depicts one embodiment of a system for providing
local delivery of a therapeutic agent. The delivery device 10
includes a catheter 12, a delivery chamber 14, steering switches
16a and 16b, a handle 18, and a delivery control switch 20.
[0033] The depicted system 10 is a catheter system that can be
guided through vascular access at the femoral artery or vein of a
patient until the delivery chamber 14 enters into the interior
chambers of the patient's heart to implant a depot of drug within
the myocardium. To that end, the catheter 12 which extends between
the delivery chamber 14 and the handle 18 can be approximately 175
cm to 200 cm in length and can include an elongated rotationally
rigid, longitudinally flexible body optionally made of woven
polyester fibers, stainless steel wires, thermoset or thermoplastic
polymers or any other material suitable for use as a catheter
shaft. The catheter can have a substantially uniform diameter of
approximately 0.025 to 0.100 inches (0.62 to 2.5 mm).
[0034] In the embodiment depicted in FIG. 1, the catheter 12 is a
steerable catheter that allows or facilitates the guiding of the
catheter through the patient's vasculature and into the chamber of
the patient's heart. Further, the steerable catheter 12 allows the
physician to bend the catheter once the catheter has entered into
the interior of the heart, to thereby position the delivery chamber
14 adjacent the area of the endocardial wall through which the
delivery chamber is to penetrate. The steering capability of the
catheter 12 is illustrated by the bend located at the distal end of
the catheter 12. Steering catheters suitable for use with the
present invention are known in the art, and include steering
catheters employed in Electrophysiology procedures.
Electrophysiology catheters typically provide steering through a
combination of rotation and tip bending.
[0035] One suitable steerable catheter is described in U.S. Pat.
No. 5,656,029, which is incorporated herein by reference. This
catheter provides an elongate flexible body that carries a bending
mechanism at its distal end. The bending mechanism consists of a
shape-memory element typically formed of Nitinol which is provided
with a memory which makes it assume a straight condition when it is
heated, such as by application of an electrical current. The shape
memory element extends through the distal portion of the catheter
and is adapted to remain straight along its full length in response
to a current passing through the element. To control the location
of the bending, an electrical bypass is slidably mounted about the
bending element. The bypass element can be an elongate cylindrical
sleeve formed of a conductive material and through which the
bending element can extend. The bypass element can act as a short
circuit that bypasses current away from the bending element.
Accordingly, the bypass element prevents current from heating the
bending element at the location of the bypass. Consequently, the
bending element will bend at the location of the bypass. By
allowing the bypass to be slid along the length of the bending
element, the physician can select the location of the bypass,
thereby selecting the location of bending. As the delivery chamber
14 is carried at the distal extremity of the catheter 12, this
allows the physician to selectively position the delivery chamber
14 within the interior of the patient's heart.
[0036] The bending elements and bypass elements described above are
carried within the catheter 12 and are not shown in FIG. 1, but
however are described in detail in the above identified reference.
Additionally, it is noted that although the catheter 12 has been
described with reference to one type of steerable catheter it will
be apparent to one of ordinary skill in the art that other suitable
steering mechanisms can be employed with the present invention
including steering mechanisms that include actuating poles or wires
that extend longitudinally through the catheter body. Moreover, it
will be further understood that although the depicted catheter 12
is optionally a steerable catheter, the devices of the invention
are not to be limited to steerable devices, and will be understood
to encompass conventional catheter systems as well.
[0037] Control of the depicted catheter 12 and the delivery chamber
14 is provided by the integrated hand-held control mechanism and
handle 18 mounted on the proximal end of the catheter 12. The
control mechanism/handle 18 can be of various types, and the
depicted handle 18 is adapted for operating a steerable catheter
wherein the bend of the catheter can be selectively controlled by
the physician. To these ends, the hand-held control/handle 18 is
dimensionally adapted to provide the treating physician with a
device that is facile to manipulate and comfortable to hold.
Additionally, the hand-held mechanism/handle 18 includes a set of
control switches, 16a, 16b and 20 that allow the physician to
control the steering of the catheter 12 and the implanting of the
depot. Switches 16a and 16b can provide steering control for the
catheter 12. The switch 16a can be a slidable switch that allows
the physician to control the longitudinal position of the bend
within the distal tip of the catheter. The switch 16a can activate
the bending mechanism to cause the catheter tip to bend as needed.
The control switch 20 can activate the delivery chamber 14 to cause
a pellet containing a therapeutic agent to be delivered into a
tissue wall.
[0038] It will be apparent to one of ordinary skill in the art that
other control mechanisms/handles can be employed with the systems
of the invention without departing from the scope thereof
Specifically, other systems can include joystick controls for
operating the steerable catheters and can include controls for
rotating the angle at which the distal end of the catheter bends.
Still other control mechanisms/handles can include pistol grips for
providing manual activation of the delivery chamber 14. Other
modifications and additions can be made to the control
mechanism/handle without departing from the scope of the
invention.
[0039] FIG. 2A depicts in greater detail one delivery chamber 14
which is suitable for being carried at the distal end of the
catheter 12 depicted in FIG. 1. The delivery chamber 14 is sized to
hold the plurality of minispheres 22, each of which contains a
therapeutic agent. The minispheres 22 are carried within an
interior chamber 24 which is bound at the proximal end by a plunger
33 and bound at the distal end by a wall formed of a plurality of
flexible finger elements 36 that define a port 30. In the
embodiment depicted in FIG. 2A, an optional detent 34 is connected
to a sidewall of the chamber 24 to provide a mechanical stop that
prevents the minispheres 22 from freely exiting through the port
30. Upon application of mechanical force by the plunger 33, the
minispheres 22 can be pushed over the detent 34, for allowing one
minisphere 22 to be ejected through port 30.
[0040] More specifically, the plunger 33 depicted in FIG. 2A
includes a plate 38 and an actuating rod 40. The plate 38 is
dimensioned to fill substantially the diameter of interior chamber
24 to provide thereby a surface that is adapted for forcing the
minispheres 22 through the chamber 24 and out of port 30. The
actuating rod 40 is connected to the plate 38 and provides a
mechanical force to plate 38 to advance, or drive, the plate 38
distally into the chamber 24. In one embodiment, the actuating rod
40 extends through the catheter 12 and couples to the control
mechanism/handle 18 at the proximal end of device 10. In this
embodiment, the control mechanism/handle 18 includes a mechanism
that drives the actuating rod 40 distally causing minispheres 22 to
be delivered through port 30. Optionally, this embodiment can
include a control mechanism/handle 18 that incorporates a ratchet
assembly that drives the actuating rod 40 distally in discreet
steps wherein a predetermined number of steps corresponds
substantially to the diameter of one of the minispheres 22. For
example, the depicted control switch 20 can be a rotatable switch
that allows for manual actuation of a ratchet assembly contained
within the control mechanism/handle 18. The ratchet assembly allows
the physician to drive the plunger 33 distally into the chamber 24
thereby driving the minisphere 22 out of the port 30. In this way,
the device 10 can allow for the discreet and sequential delivery of
minispheres 22 from the delivery chamber 14.
[0041] In an alternative embodiment of the invention, the plunger
33 is threaded to mate with a threaded interior portion of chamber
24. Manual or motor-driven rotation of actuating rod 40 will
advance or retract the plunger with a finer degree of control than
that provided by strictly linear actuation. Such control over the
travel distance of the plunger 33 into and out of the interior
chamber 24, gives control over the number of minispheres 22
delivered through port 30.
[0042] FIG. 2B provides a head-on perspective of the delivery
chamber 14, showing the distal most portion of the delivery chamber
14 as viewed from a position along the longitudinal axis of the
delivery chamber 14. Together, FIGS. 2A and 2B show that the distal
end of the delivery chamber 14 includes a port 30 that is formed
from the convergence of a plurality of flexible arched fingers 36,
each of which is formed from a resilient material and each of which
is biased to hold the minispheres 22 within the interior chamber
24. Upon action of the plunger 33 to move the minispheres 22
distally, the fingers 36 will yield to the axial pressure and
release a minisphere 22. Additionally, in the embodiment depicted
in FIG. 2A the optional detent 34 provides further resistance that
prevents minispheres 22 from exiting chamber 24 through the port 30
and for providing a tactile sensation that indicates when a
minisphere 22 has been released, or has become available to be
released, through port 30.
[0043] The delivery chamber 14 is adapted to facilitate the
implantation of a depot of drug within a tissue wall. For example
the delivery chamber 14 can be sized and made of a material rigid
enough to facilitate the penetration of the delivery chamber within
a tissue wall. Accordingly, the depicted delivery chamber 14 can be
about 0.010 to 0.050 inches in diameter, and about 0.05 to 0.075
inches in length, to have a needle-like profile that is suitable
for penetrating tissue. Additionally, the depicted delivery chamber
14 can be formed of stainless steel or of plastic material that is
sufficiently rigid to allow the delivery chamber 14 to pass into a
tissue wall.
[0044] FIGS. 3A and 3B depict an alternative embodiment of a
delivery chamber suitable for use with the catheter system 10 shown
in FIG. 1. The depicted delivery chamber 50 includes a cylindrical
sidewall 58 that defines an interior space that houses a plunger
52. The plunger 52 includes a grooved plate 62 that can be
rotatably driven along the threads 64 that extend along a portion
of the sidewall 58. Accordingly, in this embodiment, the plunger 52
advances into the delivery chamber 50 as the plate 62 turns across,
and travels over the threads 64. The distal end of the plunger 52
butts against a stack of nested drug delivery pellets 60 and forces
the pellets 60 against the elongate flexible finger elements 54
that, as shown by FIG. 3B, define the port 56.
[0045] The delivery chamber 50 implants drug pellets having a
hollow, conical shape which facilitates the penetration of the
implants 60 into the tissue wall. As shown, the plunger 52 can
drive the pellets 60 through the port 56 and into the tissue wall.
As discussed above, the flexible fingers 54 are biased to hold the
pellets 60 within the chamber 50, however, the mechanical force
applied by the plunger 52 will be sufficient to overcome the bias
force of the fingers 54. Again as discussed above, a ratchet
assembly, a rotary actuator, and/or optionally a detent, can be
employed to help the physician control the number of pellets being
delivered into the tissue wall. Specifically, the ratchet assembly
or rotary actuator controls the distance the plunger 52 is driven
into the chamber 50 and the detent provides a tactile sensation
each time a pellet 60 is moved a predetermined distance.
[0046] The delivery chamber 50 provides an alternative embodiment
that allows for the implantation of larger pellets of drugs where
the size of the pellet may require a delivery chamber that is too
large to readily penetrate through a tissue wall. Accordingly,
delivery chambers can be selectively developed for the implantation
systems described herein based on the applications of interest and
the size of the pellet being delivered. For example, in systems
that implant microspheres of drugs having diameters of about 5-15
.mu.m, the delivery chamber can be adapted to hold the microspheres
in a fluid medium and a plunger assembly, or other suitable system,
can be employed to flush the microspheres from the delivery chamber
and into the tissue wall. In this case, the delivery chamber can be
simply a hypodermic needle, and a syringe connected to the proximal
end of the system can inject the fluid medium through a lumen in
the catheter 12. Other delivery chambers can be employed with the
systems described herein without departing from the scope
hereof.
[0047] The systems described above are capable of implanting
pellets that contain a therapeutic agent. The therapeutic agent can
be any compound that is biologically active and suitable for long
term administration to a tissue or organ. The pellets described
above can be formed as mini-spheres that are on the order of about
0.005 inches to about 0.040 inches in diameter. Particles of this
size are capable of providing a therapeutically effective dose of
agent and can remain where implanted, resisting fluid flux through
the tissue wall.
[0048] Techniques and materials for forming pellets capable of
acting as drug delivery implants are well known in the art. In one
practice, a solid pellet is formed from a biodegradable polymer
that has been doped or "seeded" with the desired therapeutic agent.
Typically, the polymer is a synthetic polymer, such as poly(lactic
acid) or polyorthoesters, and is formed by solvent evaporation,
spray drying, or phase separation. Such a pellet 70 is depicted in
FIG. 4A. The polymer is capable of breaking down over time,
allowing the drug to be released into the adjacent tissue. To aid
in visualizing the implant by fluoroscopy or x-ray, a sphere of a
precious metal, such as gold or platinum, can be covered with the
drug-filled polymer 72 in a thickness that provides the desired
volume, dosage and/or time release profile. Other acceptable drug
delivery implants include the "container" implant which is filled
with a liquid drug. A wall of the container is at least partially
made of a biodegradable polymer that permits passage of drug
molecules at a certain rate. This design is common for injectable
microspheres. One advantage is that it can work for drugs that are
not amenable to doping in polymers because of heat processes or
other incompatibilities. A radioopaque metal core could be
incorporated into this "container" type pellet to facilitate
viewing.
[0049] Additionally, pellets delivered into or against the tissue
wall can be coated with or include adhesive materials that adhere
to tissue. Further, coatings can be provided that facilitate the
absorption of the pellet into the tissue wall. Such coatings can
include fumaric acid, sebacic acid and other similar materials.
[0050] FIG. 4B depicts in more detail a pellet 76 suitable for
delivery by the delivery chamber 50 depicted in FIGS. 3A and 3B.
The pellet 76 is a hollow conical body that provides a pointed end
that facilitates delivery of the pellet 76 into a tissue wall.
Optionally, the pellet 76 can carry a radio opaque marker (not
shown) and, in one embodiment, the radio opaque marker comprises
grains of a noble metal which are incorporated into the material of
which the pellet 76 is formed.
[0051] It will be apparent to one of ordinary skill in the art that
other drug delivery implants can be employed with the systems
described herein, including disc shaped pills or cylindrical
implants that incorporate a solid, drug-filled polymer core with
the container-type biodegradable polymer wall. One such implant is
described in U.S. Pat. No. 5,629,008, which is incorporated herein
in its entirety by reference.
[0052] FIGS. 5 and 6 depict more explicitly one method according to
the invention for implanting a therapeutic agent into a tissue
wall. The depicted method is a cardiovascular treatment for
restenosis that can occur in a coronary artery. The method includes
the steps of employing an elongate flexible surgical instrument
(e.g., a catheter) having a distal end that carries a delivery
chamber 14. The distal end is inserted into a vascular system of a
patient, such as by insertion via a femoral artery or vein. The
delivery chamber 14 is guided through the patient's vascular system
until the delivery chamber 14 is disposed within the heart, such as
within the left ventricle. Once within the heart, the delivery
chamber is employed to implant a therapeutic agent into the tissue
of the heart.
[0053] In a first step the physician can determine the therapeutic
agent, or agents, to be implanted and the depot for the selected
agents. The depot may be selected by considering, inter alia, the
desired time of drug residence within the tissue and the desired
dosage to be eluted during the course of the residence. Optionally,
the pellets can carry a plurality of therapeutic agents, either by
solidifying a plurality of agents within the polymer coating of
each pellet, or by providing pellets carrying different therapeutic
agents. This latter practice allows the physician to load both
active therapeutic agents and agents capable of activating
therapeutic agents upon contact, or capable of degrading the
polymer wall of an implanted pellet. This can allow for greater
time delay before activation of an agent, and for greater selection
in the delivery vehicle and the agents and drugs being delivered.
Once the agents are selected, the physician can select the delivery
chamber to use and can pre-load the delivery chamber with a
plurality of pellets, each of which can be a minisphere, a helical,
conical pellet, a cylindrical container, or other device capable of
being implanted into the myocardium. The physician can preload the
delivery chamber 14 with the set of pellets that have been selected
to deliver the proper depot of therapeutic agent to the tissue
around an artery that is suffering from, or may suffer from,
restentosis. Alternatively, pellets containing a desired
therapeutic agent can be preloaded into the delivery system, which
is provided to the physician as a sterile, disposable item.
[0054] Before delivering the preloaded delivery chamber 14 into the
heart, the treating physician optionally performs a preliminary
step of positioning a radio-opaque marker at the site of
restenosis. This allows the treating physician to view the marker
during delivery of the pellets. The marker can be a stent, or any
viewable marker that will remain present at the site of the
localized disease during the implanting of the drug delivery
pellets.
[0055] In one practice, the marker can be the radio-opaque marker
of a balloon being employed during a PTCA procedure. Specifically,
as restenosis may arise from the site of the angioplasty, one
practice of the invention performs the drug delivery at the same
time as the angioplasty. In this procedure, the treating physician
leaves the PTCA catheter in place, while the delivery implant
system is guided to the target area. A radiopaque marker in the
balloon gives fluoroscopic guidance during the implant
procedure.
[0056] At this time, the physician can guide the implant system
along the appropriate delivery route until the catheter enters the
interior of the patient's heart. The delivery chamber can approach
target areas from within any chamber of the heart. Notably, the
practices described herein allow that even septal arteries can be
treated for cardiac conditions or to stimulate angiogenisis. In
FIG. 5, the delivery chamber is shown as approaching the target
area from the interior of the heart, and positioning the delivery
chamber against the endocardial tissue over the myocardium. Upon
positioning the delivery chamber adjacent the interior tissue wall
of the heart, the physician drives the delivery chamber into the
tissue and to the targeted area. The physician actuates the control
mechanism and ejects a pellet from the delivery chamber, implanting
the pellet within the targeted area of the myocardium.
[0057] It is a realization of the present invention that the
practices described herein are often suitable for arteries normally
considered epicardial, with little surrounding myocardial tissue or
subepicardial fat in which to implant the drug delivery pellets.
Specifically, researchers have noted that tunneled epicardial
coronary arteries may represent a normal variant being recognized
in up to 86% of vessels. Waller, Anatomy, Histology, and Pathology
of the Major Epicardial Coronary Arteries Relevant to
Echocardiographic Imaging Techniques, Journal of American Society
of Echocardiographic Imaging, vol. 2 (1989).
[0058] FIG. 6 illustrates a further realization of the present
invention. FIG. 6 shows that it is desirable to implant the pellets
as close as possible to the artery being treated, and that
providing an array of implanted pellets about the periphery of the
artery may provide sufficient localized elution of therapeutic
agent to prevent restenosis. In one practice, the pellets are
implanted through a single point of entry through the myocardium.
The physician manipulates the distal tip of the catheter to dispose
the port of the delivery chamber at the depicted locations. At each
location, a pellet is ejected from the delivery chamber and
implanted into the myocardium.
[0059] FIG. 7 depicts a further alternative embodiment of the
invention. The depicted system 80 includes a short catheter 82 that
carries a delivery chamber 84 at its distal end and that connects
at its proximal end to a pistol grip control mechanism 88.
[0060] The system 80 is adapted for use during an endoscopic
procedure and to that end the depicted catheter 84 is a short
catheter adapted to slide within a endoscopic port that has been
placed through the chest and positioned abutting the pericardium.
The delivery chamber 84 can be a delivery chamber as discussed
above and can be dimensionally adapted to penetrate and extend
through the pericardial sac. The delivery chamber can penetrate
into the myocardium and thereby allow the physician to implant
pellets into the myocardium. Optionally, the catheter 82 can be a
steerable catheter which allows the physician to bend the distal
tip of the catheter 82 to place the delivery chamber 84 where
needed. Alternatively, the catheter can include a deflectable tip,
as is known in the art, which the physician can direct to the
targeted area. Other modifications to the system 80, including
providing the catheter with a fiber optic viewing device to allow
the physician to view the interior of the pericardial sac, can be
made without departing from the scope of the invention.
[0061] The depicted pistol grip 88 provides the physician with a
manual actuator that allows the physician to control the implanting
of pellets within the myocardium. The pistol grip 88 can be a
molded plastic assembly of the type well known in the art for
actuating a mechanical assembly, such as the plunger assembly of
the delivery chamber 14 described above.
[0062] In a further practice, the techniques of the invention can
be employed during an open chest procedure. Specifically, the
surgeon performing the open chest operation can employ a delivery
device that includes a delivery chamber as described above to
implant pellets into the myocardium. Additionally, in this
practice, the physician can employ a hypodermic needle to inject a
solution containing microspheres of a therapeutic agent. Other
practices of the invention can be practiced without departing from
the scope thereof.
[0063] Moreover, the systems and methods for implanting depots of
therapeutic agents can be applied to conditions other than those
relating to cardiac failure. For example, the systems described
herein can be applied to the treatment of muscle tissue afflicted
by insufficient circulation. In one practice, the systems described
herein are employed to deliver a human angiogenic growth factor,
such as VGEF, which is understood to stimulate the growth of blood
vessels. Thus, the systems described herein can promote the
survival of muscle tissue that is moribund as a result of poor
circulation due to failing or occluding blood vessels.
[0064] Those skilled in the art will know or be able to ascertain
using no more than routine experimentation, many equivalents to the
embodiments and practices described herein. For example, the
devices described herein can be used in cooperation with drilling
elements or laser devices capable of forming an opening in a tissue
wall, such as the myocardium. The delivery chamber can be inserted
into the preformed openings for delivering a therapeutic agent
therein. Further, pellets according to the invention can include
threaded exterior surfaces that facilitate implanting the pellet
within a tissue wall. Accordingly, it will be understood that the
invention is not to be limited to the embodiments disclosed herein,
but is to be understood from the following claims, which are to be
interpreted as broadly as allowed under the law.
* * * * *