U.S. patent application number 10/865003 was filed with the patent office on 2004-12-30 for mechanical apparatus and method for dilating and delivering a therapeutic agent to a site of treatment.
Invention is credited to Scott, Neal, Segal, Jerome.
Application Number | 20040267355 10/865003 |
Document ID | / |
Family ID | 33538661 |
Filed Date | 2004-12-30 |
United States Patent
Application |
20040267355 |
Kind Code |
A1 |
Scott, Neal ; et
al. |
December 30, 2004 |
Mechanical apparatus and method for dilating and delivering a
therapeutic agent to a site of treatment
Abstract
A mechanical dilatation and medicament delivery device for
enlarging a flow passage of a vessel by dilating and delivering a
liposome or micelle-encapsulated therapeutic agent or medicament to
an obstruction in the vessel. The present invention comprises a
substantially cylindrically shaped expansion member and includes a
means engaged to the expansion member for altering the distance
between the proximal end and the distal end of the expansion member
thereby transforming the expansion member between a diametrically
contracted configuration to diametrically expanded configuration. A
liposome or micelle-encapsulated therapeutic agent or medicament is
coated on either the expansion member, or incorporated into a
substrate coated on the expansion member. The present method
comprises the steps of advancing the coated expansion member to the
obstruction in a vessel and applying opposed forces on said
expansion member in an axial direction to move the expansion member
to an expanded configuration wherein the expansion member dilates
the obstruction and the expansion member either passively or
actively delivers a liposome or micelle-encapsulated therapeutic
agent or medicament to the obstruction.
Inventors: |
Scott, Neal; (Houston,
TX) ; Segal, Jerome; (Chevy Chase, CA) |
Correspondence
Address: |
MICHAEL E. KLICPERA
PO BOX 573
LA JOLLA
CA
92038-0573
US
|
Family ID: |
33538661 |
Appl. No.: |
10/865003 |
Filed: |
June 10, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10865003 |
Jun 10, 2004 |
|
|
|
10135709 |
Apr 30, 2002 |
|
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Current U.S.
Class: |
623/1.42 |
Current CPC
Class: |
A61M 2025/0057 20130101;
A61M 29/02 20130101; A61M 2025/105 20130101 |
Class at
Publication: |
623/001.42 |
International
Class: |
A61F 002/06 |
Claims
We claim:
1. A method for dilating and delivering a medicament to an
obstruction in a body passageway which comprises the steps of:
advancing a mechanical dilatation catheter to a predetermined site
with a body passageway, said catheter having an substantially
cylindrical expansion member coated with a medicament, said
expansion member being moveable between a first contracted
configuration wherein said expansion member is defined by a first
dimension extending in a radial direction, and a second expanded
configuration wherein said member is defined by a second dimension
extending in said radial direction; applying a force on said coated
expansion member in an axial direction to move said expansion
member between said first contracted configuration to said second
expanded configuration wherein said expansion member dilates said
obstruction or body passageway and delivers a liposome encapsulated
medicament to an said obstruction or body passageway.
2. The method as recited in claim 1 which further comprises the
step of positioning a guidewire in the body passageway, and wherein
said advancing step is accomplished by threading said expansion
member over said guidewire.
3. The method as recited in claim 1 which further comprises the
step of allowing said expansion member to be in said second
expanded configuration for a predetermined period of time after the
dilatation step to further expose said obstruction to the
medicament.
4. The method as recited in claim 1, wherein said liposome
encapsulated medicament is an anticoagulant selected from the group
consisting of D-Phe-Pro-Arg chloromethyl ketone, an RGD
peptide-containing compound, heparin, an antithrombin compound, a
platelet receptor antagonist, an anti-thrombin antibody, an
anti-platelet receptor antibody, hirudin, hirulog,
phe-pro-arg-chloromethyketone (Ppack), Factor VIIa, Factor Xa,
aspirin, clopridogrel, ticlopidine, a prostaglandin inhibitor, a
platelet inhibitor and a tick anti-platelet peptide, and
combinations thereof.
5. The method as recited in claim 1, wherein said liposome
encapsulated medicament is a promoter of vascular cell growth
selected from the group consisting of a growth factor stimulator, a
growth factor receptor agonist, a transcriptional activator, and a
translational promoter, and combinations thereof.
6. The method as recited in claim 1, wherein said liposome
encapsulated medicament is an inhibitor of vascular cell growth
selected from the group consisting of a growth factor inhibitor, a
growth factor receptor antagonist, a transcriptional repressor, a
translational repressor, an antisense DNA, an antisense RNA,
synthetic DNA compounds, especially those with backbones that have
been modified to inhibit enzymatic degradation (e.g.
phosphorothioate compounds and morpholino diamidate compounds), a
replication inhibitor, an inhibitory antibody, an antibody directed
against growth factors, a bifunctional molecule consisting of a
growth factor and a cytotoxin, and a bifunctional molecule
consisting of an antibody and a cytotoxin, double stranded DNA,
single stranded DNA, single stranded RNA and a double stranded RNA
and combinations thereof.
7. The method as recited in claim 1, wherein said liposome
encapsulated medicament is selected from the group consisting of a
cholesterol-lowering agent, a vasodilating agent, and agents which
interfere with endogenous vasoactive mechanisms, estrogen,
testosterone, steroid hormones, cortisol, dexamethasone,
corticosteroids, thyroid hormones, thyroid hormones analogs, throid
hormones antagonist, adrenocorticotrophic hormone, thyroid
stimulating hormone, thyroid releasing factor, thyroid releasing
factor analogs, thyroid releasing factor antagonists and
combinations thereof.
8. The method as recited in claim 1, wherein said liposome
encapsulated medicament is a smooth muscle inhibitor selected from
the group consisting of an agent that modulates intracellular
calcium binding proteins, a receptor blocker for contractile
agonists, an inhibitor of the sodium/hydrogen antiporter, a
protease inhibitor, a nitrovasodilator, a phosphodiesterase
inhibitor, a phenothiazine, a growth factor receptor agonist, an
anti-mitotic agent, an immunosuppressive agent, and a protein
kinase inhibitor, and combinations thereof.
9. The method as recited in claim 1, wherein said liposome
encapsulated medicament is a compound that inhibits cellular
proliferation, Paclitaxel, Rapamycin, Actinomycin D, Methotrexate,
Doxorubicin, cyclophosphamide, and 5-fluorouracil,
6-mercapatopurine, 6-thioguanine, cytoxan, cytarabinoside,
cis-platin, chlorambucil, busulfan, and any other drug that can
inhibit cell proliferation, and combinations thereof.
10. The method as recited in claim 1 further comprising a plurality
of said liposome encapsulated medicaments coated on at least a
portion of said expansion member.
11. A method for dilating and delivering a medicament to an
obstruction in a body passageway which comprises the steps of:
advancing a mechanical dilatation catheter to a predetermined site
with a body passageway, said catheter having an substantially
cylindrical expansion member coated with a medicament, said
expansion member being moveable between a first contracted
configuration wherein said expansion member is defined by a first
dimension extending in a radial direction, and a second expanded
configuration wherein said member is defined by a second dimension
extending in said radial direction; applying a force on said coated
expansion member in an axial direction to move said expansion
member between said first contracted configuration to said second
expanded configuration wherein said expansion member dilates said
obstruction or body passageway and delivers a micelle encapsulated
medicament to an said obstruction or body passageway.
12. The method as recited in claim 11 which further comprises the
step of positioning a guidewire in the body passageway, and wherein
said advancing step is accomplished by threading said expansion
member over said guidewire.
13. The method as recited in claim 11 which further comprises the
step of allowing said expansion member to be in said second
expanded configuration for a predetermined period of time after the
dilatation step to further expose said obstruction to the
medicament.
14. The method as recited in claim 11, wherein said micelle
encapsulated medicament is an anticoagulant selected from the group
consisting of D-Phe-Pro-Arg chloromethyl ketone, an RGD
peptide-containing compound, heparin, an antithrombin compound, a
platelet receptor antagonist, an anti-thrombin antibody, an
anti-platelet receptor antibody, hirudin, hirulog,
phe-pro-arg-chloromethyketone (Ppack), Factor VIIa, Factor Xa,
aspirin, clopridogrel, ticlopidine, a prostaglandin inhibitor, a
platelet inhibitor and a tick anti-platelet peptide, and
combinations thereof.
15. The method as recited in claim 11, wherein said micelle
encapsulated medicament is a promoter of vascular cell growth
selected from the group consisting of a growth factor stimulator, a
growth factor receptor agonist, a transcriptional activator, and a
translational promoter, and combinations thereof.
16. The method as recited in claim 11, wherein said micelle
encapsulated medicament is an inhibitor of vascular cell growth
selected from the group consisting of a growth factor inhibitor, a
growth factor receptor antagonist, a transcriptional repressor, a
translational repressor, an antisense DNA, an antisense RNA,
synthetic DNA compounds, especially those with backbones that have
been modified to inhibit enzymatic degradation (e.g.
phosphorothioate compounds and morpholino diamidate compounds), a
replication inhibitor, an inhibitory antibody, an antibody directed
against growth factors, a bifunctional molecule consisting of a
growth factor and a cytotoxin, and a bifunctional molecule
consisting of an antibody and a cytotoxin, double stranded DNA,
single stranded DNA, single stranded RNA and a double stranded RNA
and combinations thereof.
17. The method as recited in claim 11, wherein said micelle
encapsulated medicament is selected from the group consisting of a
cholesterol-lowering agent, a vasodilating agent, and agents which
interfere with endogenous vasoactive mechanisms, estrogen,
testosterone, steroid hormones, cortisol, dexamethasone,
corticosteroids, thyroid hormones, thyroid hormones analogs, throid
hormones antagonist, adrenocorticotrophic hormone, thyroid
stimulating hormone, thyroid releasing factor, thyroid releasing
factor analogs, thyroid releasing factor antagonists and
combinations thereof.
18. The method as recited in claim 11, wherein said micelle
encapsulated medicament is a smooth muscle inhibitor selected from
the group consisting of an agent that modulates intracellular
calcium binding proteins, a receptor blocker for contractile
agonists, an inhibitor of the sodium/hydrogen antiporter, a
protease inhibitor, a nitrovasodilator, a phosphodiesterase
inhibitor, a phenothiazine, a growth factor receptor agonist, an
anti-mitotic agent, an immunosuppressive agent, and a protein
kinase inhibitor, and combinations thereof.
19. The method as recited in claim 11, wherein said micelle
encapsulated medicament is a compound that inhibits cellular
proliferation, Paclitaxel, Rapamycin, Actinomycin D, Methotrexate,
Doxorubicin, cyclophosphamide, and 5-fluorouracil,
6-mercapatopurine, 6-thioguanine, cytoxan, cytarabinoside,
cis-platin, chlorambucil, busulfan, and any other drug that can
inhibit cell proliferation, and combinations thereof.
20. The method as recited in claim 11 further comprising a
plurality of said micelle encapsulated medicaments coated on at
least a portion of said expansion member.
Description
PRIOR APPLICATIONS
[0001] This application is a divisional of application Ser. No.
10/135,709 filed on Apr. 30, 2002.
BACKGROUND OF THE INVENTION
[0002] Cardiovascular disease is commonly accepted as being one of
the most serious health risks facing our society today. Diseased
and obstructed coronary arteries can restrict the flow of blood and
cause tissue ischemia and necrosis. While the exact etiology of
sclerotic cardiovascular disease is still in question, the
treatment of narrowed coronary arteries is more defined. Surgical
construction of coronary artery bypass grafts (CABG) is often the
method of choice when there are several diseased segments in one or
multiple arteries. Open heart surgery is, of course, very traumatic
for patients. In many cases, less traumatic, alternative methods
are available for treating cardiovascular disease percutaneously.
These alternate treatment methods generally employ various types of
percutaneous transluminal angioplasty (PTCA) balloons or excising
devices (atherectomy) to remodel or debulk diseased vessel
segments. A further alternative treatment method involves
percutaneous, intraluminal installation of expandable, tubular
stents or prostheses in sclerotic lesions.
[0003] A recurrent problem with the previous devices and PTCA
procedures is their failure to maintain patency due to the growth
of injured vascular tissue. This is known as "restenosis" and may
be a result of the original injury to the vessel wall occurring
during the angioplasty procedure. Pathologically restenosis
represents a neointimal proliferative response characterized by
smooth muscle cell hyperplasia that results in reblockage of the
vessel lumen necessitating repeat PTCA procedures up to 35-50% of
all cases. It has been generally accepted that a certain
therapeutic agents or medicaments may be capable of selectively
inhibiting the growth of these hyperproliferating smooth muscle
cells and thereby reduce the rate of restenosis after the primary
interventional procedure.
[0004] Heretofore, various devices have been disclosed which may be
used to deliver a therapeutic agent or medicament to a blood vessel
while undergoing angioplasty. Balloon angioplasty catheters have
been used to place and deliver a various therapeutic agents or
medicaments within human vessels. For example, in U.S. Pat. Nos.
5,112,305, 5,746,716, 5,681,281, 5,873,852, 5,713,863 and 6,102,904
disclose and claim a balloon catheter system with various injector
plates mounted on the balloon for delivering a drug into an
arterial segment.
[0005] Alternatively a standard angioplasty balloon may be coated
with a polymeric material which is then used to bond certain
medicaments or theraputic agents. These agents are then delivered
to the desired therapeutic site by inflation of the balloon and
diffusion of the medicatment or therpeutic agent into the vessel
wall. Only limited quantities of therapeutic agents can be
delivered because of "wash-out" of the drug into the circulation
during balloon placement and due to the limited time the inflated
balloon can be left in place due to ischemia caused by the
balloon.
[0006] In addition, previously disclosed methods of delivering drug
to a site of treatment are described which utilize iontophoretic or
electrophoretic means as disclosed in U.S. Pat. No. 5,499,971.
Using these iontophoretic or electroporetic means passive diffusion
of the drug or medicament is enhanced by placing the medicament or
theraputic agent in close proximity to the site of treatment and
then using electrically to augment delivery of the drug into the
tissues or cells. These methods generally place the drug inside a
balloon mounted distally on a catheter whereby the balloon is
composed of a semi-porous material through which the drug can
diffuse.
[0007] Alternatively the electrodes themselves may be used as a
method for iontophoretic or electroporetic drug delivery. One such
method is disclosed in U.S. Pat. No. 6,219,577 which describes
coating the surface of band-like electrodes with a polymer which
bonds the drug and delivers it to the site of treatment. This
method has the disadvantage of not have the capability to dilate
the obstruction prior or concurrent to the delivery of a drug.
Additionally the surface area of contact of the electrode bands
with the vessel wall are limited to only the central portion of the
arc shaped bands. This limits the contact surface area of the drug
coated electrodes. This method also has the inherent disadvantage
that since the site of therapy is intravascular, most of the drug
will be washed off or dissolved off the electrodes into the
circulating blood stream before it is advanced through the vascular
system from its percutaneous entry and to the distal site of
treatment. This again limits the amount of the drug delivered to
the site and also potentially subjects the patient to harmful or
toxic systemic exposure.
[0008] Additional devices have been disclosed which attempt to
improve the depth of penetration into tissue by pressure driving a
solution of the drug into the vessel wall through small orifices in
the balloon material. There is, however, some evidence that high
pressure "jetting" of a drug solution out of small pores close to
the vessel lumen can in fact cause vessel wall injury. The
development of double skinned, microporous (or weeping) balloons
obviated this "jetting" effect to some extent, but diffusion of the
drug into the vessel wall is still slow, and much of the drug can
be lost through subsequent "washout effects". This method leads to
limited amounts of drugs or therapeutics agents delivered to the
tissues or cells. Furthermore, in all of these methods the balloon
must be expanded and thereby restricts blood flow to the distal
arterial segments while the balloon is in the expanded
configuration thus limiting the time the drug delivering balloon
can be clinically utilized.
[0009] There are also several disadvantages using either a stent or
balloon catheter to delivery a therapeutic agent or medicament to a
vascular segment. Regarding the therapeutic agent eluting stents,
once the stent is deployed, there is no means outside of invasive
surgical excision, to remove the eluting stent from the vascular
segment. Therefore, stents or implanted prostheses with therapeutic
agent eluting properties must be precisely calibrated to deliver an
exact quantity of the therapeutic agent or medicament to the
vascular segment upon stent deployment. Balloon catheters employed
to delivery a therapeutic agent or medicament to a vascular segment
have limitations including potential balloon rupture and ischemia
due to balloon inflation limiting distal blood flow to the artery.
This leads to tissue ischemia and potential necrosis. Even
"perfusion" type angioplasty balloons used to delivery a
therapeutic agent or medicament to the affected artery provide far
less than physiological blood flow during balloon inflation and
dwell times are limited by ischemia and tissue necrosis.
[0010] Recent studies have demonstrated the effectiveness of a
number of agents (e.g., paclitaxel, rapamycin, Actinomycin D) on
the prevention of unwanted cellular proliferation. These agents
have proven efficacy in the treatment of cancer and transplant
rejection. A major advantage of these agents is the high lipid
solubility that causes tissue levels to be high for an extended
period of time since they cannot be rapidly cleared. However, this
advantage is also a disadvantage because the delivery of these
medicaments must generally pass hydrophilic boundaries.
[0011] Thus, it can be seen that there is a need for a new and
improved device to selectively delivery a therapeutic agent or
medicament to an arterial segment and which overcomes these
disadvantages.
[0012] In general, it is an object of this present invention to
provide a mechanical dilatation device and method which is capable
of dilating an obstruction within a vascular segment while
delivering, either passively or by an electrically active means, a
therapeutic agent or medicament to the vessel segment.
[0013] Another object of the invention is to provide a method to
deliver high concentrations of agents that are poorly soluble or
insoluble in aqueous media to selected sites in the body including
arteries, veins or other tubular structures, prosthetic devices
such as grafts, and tissues such as, but not limited to, brain,
myocardium, colon, liver, breast and lung.
[0014] Another object of the invention is to provide a percutaneous
device and method of the above character which can be used for
prolonged periods in exposing or delivering a therapeutic agent or
medicament to a vascular segment while allowing continuous
perfusion of blood into the vessel distal to the treatment
area.
[0015] Another object of the invention is to provide a device that
can control the release or diffusion of a medicament or therapeutic
agent to minimize potential systemic affects and maximize the
diffusion or delivery of the medicament or therapeutic agent to the
site of treatment.
[0016] Another object of the invention is to provide a device that
is not susceptible to structural damage (balloon rupture) and
subsequent release of therapeutic agents or drug materials into the
vasculature.
SUMMARY OF THE INVENTION
[0017] It is known that therapeutic agent therapy can reduce the
proliferation of rapidly growing cells. The present invention
employs various means of delivery with a mechanical dilatation
device for enlarging a flow passage of a vessel by dilating and
delivering a liposome or micelle or micelle-encapsulated
therapeutic agent or medicament to an obstruction in a vessel.
Since the therapeutic agent or medicament is capable of selectively
inhibiting the growth of proliferating cells, the present invention
not only achieves acute patency of a vessel but employs medical
therapy to maintain chronic patency through the prevention of
restenosis.
[0018] The present invention comprises a substantially
cylindrically shaped expansion member and includes a means engaged
to the expansion member for altering the distance between the
proximal end and the distal end of the expansion member thereby
transforming the expansion member between a diametrically
contracted configuration and a diametrically expanded
configuration. A liposome or micelle-encapsulated therapeutic agent
or medicament can be coated directly on the expansion member or
alternatively, the therapeutic agent or medicament can be
incorporated into a polymer or other substrate coated on the
expansion mesh. If desired, the same or another therapeutic agent
or medicament can be coated on the marker bands mounted on the
catheter located within the expansion mesh or injected through a
delivery lumen which has a distal port located inside the expansion
member. Due to its unique design, the present invention has
significant perfusion capability which allows the catheter and its
distal expansion member or mesh to be in a expanded configuration
and engaged to the vessel wall for proloned periods. This allows
sufficient time for passive or electrically active migration of the
therapeutic agent or medicament to the vessel or organ without
causing ischemic related events. The catheter also comprises either
an over-the-wire or rapid exchange designs.
[0019] The present invention also can include a conduction means
that provides electrical communication from a connector on the
proximal end of the catheter to the distal conductive flexible
elongate elements thereby providing the distal expandable mesh with
a means to control or facilitate the release or delivery of a
medicament or therapeutic agent to a treatment site. In this
embodiment, the invention relates to catheter-based devices which
provide an electrical driving force that can increase the rate of
migration of liposome or micelle-encapsulated medicaments and other
therapeutic agents from the expansion member and into body tissues
and cells using iontophoresis only, electroporation only, or
combined iontophoresis and electroporation. In addition, a charge
can be applied to the expansion member that is opposite the
liposome or micelle-encapsulated therapeutic agent or medicament,
or to the substrate that incorporates the therapeutic agent or
medicament in order to create a significant bond between the
therapeutic agent and the expandable mesh.
[0020] The invention also takes advantage of the prior body of
knowledge that has demonstrated the enhanced solubility and
delivery of agents after they have been incorporated into liposome
and micelles. Since liposome or micelles and micelles possess both
lipophilic and hydrophilic regions, they can be used to solubilize
compounds that are insoluble in water. If charged liposome or
micelles are used, these charged molecules can move in an
electrical field.
[0021] This disclosure demonstrates the delivery of uncharged,
lipophilic medicaments or agents by incorporating them into charged
liposome or micelles and then delivering them to the target site by
electrophoresis.
[0022] The present method also comprises the steps of advancing the
catheter and expansion member to the obstruction in a vessel and
applying opposed forces on said expansion member in an axial
direction to move the expansion member to an expanded configuration
wherein the expansion member dilates the obstruction and the
catheter/expansion member assembly actively (or passively) delivers
the liposome or micelle-encapsulated therapeutic agent or
medicament to the obstruction.
[0023] One preferable approach may be to 1) energize the catheter
to create a bond between the therapeutic agent and expansion mesh
and then advance the system to the treatment segment, 2) expand the
expansion member to dilate the segment, 3) allow perfusion to
passively transfer the therapeutic agent into the tissues.
[0024] Another preferable approach may be to 1) energize the
catheter to create a bond between the liposome or micelle enclosed
therapeutic agent and expansion mesh and then advance the system to
the treatment segment, 2) expand the expansion member to dilate the
segment while allowing perfusion, 3) apply electrical energy to
cause iontophoresis of the therapeutic agent into the tissues
and/or 4) apply electrical energy for electroporation to be applied
to permeabilize the cells. Preferably, the catheter is able to
perform steps 2, 3 and 4 sequentially without repositioning of the
catheter. Even more preferably, the catheter is designed to
maintain a high concentration of drug in the tissue extracellular
spaces (e.g. by iontophoresis) such that the subsequent creation of
transient pores in cell surface membranes by electroporation pulses
results in greatly improved intracellular delivery of the
medicament or therapeutic agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is a side-elevational view partially in section of a
mechanical dilatation and medicament delivery device incorporating
the present invention.
[0026] FIG. 2 is a cross-sectional view taken along the line 2-2 of
FIG. 1.
[0027] FIG. 3 is a cross-sectional view taken along the line 3-3 of
FIG. 1.
[0028] FIG. 4 is a cross-sectional view taken along the line 4-4 of
FIG. 1.
[0029] FIG. 5 is a cross-sectional view taken along the line 5-5 of
FIG. 1.
[0030] FIG. 6 is a cross-sectional view taken along the line 6-6 of
FIG. 1.
[0031] FIG. 7 is a greatly enlarged view of a portion of the
dilatation and medicament delivery device in a partially expanded
state.
[0032] FIGS. 8a-8f depict a variety of electric waveforms for use
in iontophoresis and electrophoresis with the catheter and distal
mesh of the present invention.
[0033] FIG. 9 is a partial side-elevational view of another
embodiment of a mechanical dilatation and medicament delivery
device incorporating the present invention that can be utilized in
conjunction with a rapid exchange technique.
[0034] FIG. 9a is an enlarged side-elevational view of the rapid
exchanged embodiment of the mechanical dilatation and medicament
delivery device demonstrating the guidewire entry ports in the
inner and outer elongated tubular members.
[0035] FIG. 10 is a side-elevational view of the distal extremity
of the device shown in FIGS. 1-9 showing the distal extremity with
the expansion member in an expanded condition.
[0036] FIG. 11 is a cross sectional view of the flexible elongated
elements demonstrating the passive or electrically active
dispensing of the liposome or micelle-encapsulated therapeutic
agent or medicament into the vessel wall.
[0037] FIG. 12 is a cross sectional view demonstrating the
dispensing of a liposome or micelle-encapsulated therapeutic agent
or medicament from bands affixed to the inner tubular member
located within the expandable mesh.
[0038] FIG. 13 is a cross sectional view of the one flexible
elongate elements of the expandable mesh demonstrating the passive
or electrically active dispensing of a liposome or
micelle-encapsulated therapeutic agent or medicament from the
elongate element.
[0039] FIG. 14 is a cross sectional view of one of the flexible
elongate elements of the expandable mesh demonstrating the
dispensing of the liposome or micelle-encapsulated therapeutic
agent or medicament incorporated within a substrate coating over
the elongate element.
[0040] FIG. 15 is a cross sectional view of one of the flexible
elongate elements of the expandable mesh demonstrating the
dispensing of a liposome or micelle-encapsulated therapeutic agent
or medicament with the aid of electrical current.
[0041] FIG. 16 is a cross sectional side view of the flexible
elongated elements demonstrating the passive or electrically active
dispensing of the liposome or micelle-encapsulated therapeutic
agent or medicament into the vessel wall.
[0042] FIG. 17 is a cross section side view of a typical liposome
or micelle encapsulating a generic medicament.
DETAILED DESCRIPTION OF THE DRAWINGS
[0043] In general, the present invention relates generally to
devices that are used to dilate and dispense a medicament or
therapeutic agent to an obstruction within a stenotic segment of a
vessel. The device is comprised of an cylindrical expansion member
to be disposed in an obstruction in a vessel carrying flowing
blood. The cylindrical expansion member has first and second ends
and an intermediate portion between the first and second ends. The
cylindrical expansion member also has a flow passage extending
therethrough with a diameter and a longitudinal central axis. The
diameter of the flow passage is a variable with movement of the
first and second ends relative to each other along the longitudinal
central axis from a diametrically contracted position to a
diametrically expanded condition. The cylindrical expansion member
is comprised of a plurality of flexible elongate elements each of
which extends helically about the longitudinal extending central
axis. The flexible elongate elements are coated with one or more
liposome or micelle-encapsulated medicaments, therapeutic agents,
drugs, pharmaceuticals, plasmids, genes or other agents. For the
purposes of this application, the terms used, liposome or
micelle-encapsulated medicaments and therapeutic agents, will be
used to encompass all the particular agents described herein. It is
also contemplated that the liposome or micelle-encapsulated
medicament or therapeutic agent may be incorporated with a
non-medicament substrate that has been previously or simultaneously
coated on the flexible elongate elements. Furthermore, an
electrical means can be incorporated into the catheter system to
cause 1) electrical bonding of the therapeutic agent to the mesh
and/or 2) active migration/dispersion of the agent into the
vessel/tissues. In addition, the present invention can include
coating one or more of the bands secured to the central catheter
element within the expansion mesh with one or more therapeutic
agents.
[0044] The plurality of the flexible elongate elements of the
expansion mesh have a first common direction of rotation are
axially displaced relative to each other and cross a further
plurality of the flexible elongate elements also axially displaced
relative to each other but having a second common direction
opposite to that of the first direction of rotation to form a
braided cylindrical expansion member. The crossing of the flexible
elongate elements occurs in an area of contact between the flexible
elongate elements.
[0045] First and second means is provided respectively engaging the
first and second ends of said cylindrical expansion member for
retaining said first and second ends in contracted positions. Means
is provided for causing relative axial movement of the first and
second ends towards each other to cause the intermediate
cylindrical portion of the expansion member to contract
longitudinally and to expand diametrically by causing the flexible
elongate elements in the intermediate portion of the cylindrical
member to move closer to each other expanding the diametric
dimensions of the cylindrical expansion member thereby allowing it
to contact the vessel wall and enable it to dilate an obstruction
within the vessel. Flexible elongate elements at the first and
second ends of the cylindrical expansion member remain contracted
around and within first and second means and are thereby prevented
from moving closer which maintains spacing between the flexible
elongate members so that blood in the vessel can continue to flow
through the first and second ends and through the flow passage in
the cylindrical expansion member while the cylindrical expansion
member is in engagement with vessel wall and dilating an
obstruction within the vessel.
[0046] More in particular as shown in FIGS. 1-7 of the drawings,
the mechanical dilatation and medicament delivery device 11 shown
therein consists of a first or outer flexible elongate tubular
member 12 having proximal and distal extremities 13 and 14 with the
flow passage 16 extending from the proximal extremity 13 to the
distal extremity 14. FIGS. 2, 3, 4, 5, and 6 are provided to
represent both the non-electrical conduction means and the
electrical conduction means embodiment that includes an electrical
conduction means extending from the proximal connector and engaged
to the distal expansion member 31. A second or inner flexible
tubular member 21 is coaxially and slidably disposed within the
flow passage 16 of the first or outer flexible elongate tubular
member 12 and is provided with proximal and distal extremities 22
and 23 with a flow passage 24 extending from the proximal extremity
22 to the distal extremity 23. If the flexible elongate elements of
the dilating member are made of a metallic material such as
stainless steel, elgiloy or other conductive material, an
electrical lead can be connected to the mesh to make it part of the
circuit. The electrical lead can either run along or within one of
the lumens of the catheter or can be in the form of a braid that is
made of a conductive material and have generally functions to
provide reinforcement to the catheter shaft. A second electrode
could be placed on the distal tip of the catheter via a small band
with its electrical lead running down one of the lumens to the
proximal end of the catheter. Alternatively, the electircal lead
could be engaged to the patient's skin or could be the guidewire
over which the catheter is routinely advanced.
[0047] The flexible elongate elements of the catheter could be
coated with a polymeric material or similar substrate onto which
the liposome or micelle-encapsulated medicament or theraputic agent
could adsorb. Synthetic polymers or natural polymers can be used,
such as amino acid polymers or polysaccharides. The polymer is
selected depending on the therapeutic agent required, the polymer's
compatibility with a patient and the ultimate pharmacologic effect
desired. These polymers could include hydrophilic polymers used for
their absorptive properties of aqueous solutions. The flexible
elongate elements, either coated or uncoated, could then be
submerged in a solution of a liposome or micelle-encapsulated
therapeutic agents or medicaments with a specific charge and an
electrical charge could be applied to render the flexible elongate
members opposite in charge to that of the liposome or
micelle-encapsulated therapeutic agent or medicament. This would
create a significant bonding of the liposome or
micelle-encapsulated agent or medicament to the flexible elongate
elements. Typically, the flexible elongate elements of the mesh
will be charged with the attached liposome or micelle-encapsulated
therapeutic agent or medicament just prior to advancing the
catheter through the patient's vasculature to the site of
dilatation and therapy without significant loss of the drug in the
bloodstream. Once the site of obstruction or treatment is reached,
the charge on the mesh could be reversed using the same electrodes
thus driving the liposome or micelle-encapsulated therapeutic agent
or medicament into the target tissue. In this case, the electrode
placed on the skin of the patient would be used to cause active
diffusion or iontophoresis of the therapeutic agent or medicament
into the target tissues. As shown in FIGS. 8a-8f, the present
invention can employ flow of electrical current in the from of
various waveforms to perform the iontophoresis and/or
electroporation procedures. Possible waveforms contemplated for the
present invention include square waves, rectangular waves,
saw-toothed waves, sinusoidal waves that do not reverse polarity,
rectified sinusoidal waves, and other waveform shapes which may
reverse polarity but provide a net flow of current in the desired
direction.
[0048] Electrical current could also be coordinated with the
patient's elctrocardiogram such that electrical current is provided
to the mesh only during certain phases of cardiac depolarization.
This "gating" of the electrical current would avoid the potential
danger of discharging electrical current to the heart during
vunerable phases of depolarization which may lead to cardiac
arrhythmias.
[0049] Iontophoretically enhanced delivery requires that the
therapeutic agent carry a net charge under physiological conditions
whereas electroporation alone would be used for delivering
treatment agents that are not sufficiently ionized to iontophorese
well into tissues. Electroporation may also be the preferred
strategy for enhancing localized cellular targeting of a
systemically administered therapeutic agent.
[0050] As used herein, the term "iontophoresis" means the migration
of ionizable molecules through a medium driven by an applied
low-level electrical potential. This electrically mediated movement
of molecules into tissues is superimposed upon concentration
gradient dependent diffusion processes. If the medium or tissue
through which the molecules travel also carries a charge, some
electro-osmotic flow occurs. However, generally, the rate of
migration of molecules with a net negative charge towards the
positive electrode and vice versa is determined by the net charge
on the moving molecules and the applied electrical potential. The
driving force may also be considered as electrostatic repulsion.
Iontophoresis usually requires relatively low constant DC current
in the range of from about 2-10 mA. In a well established
application of iontophoresis, that of enhancing drug delivery
through the skin (transdermal iontophoresis), one electrode is
positioned over the treatment area and the second electrode is
located at a remote site, usually somewhere else on the skin. With
the present invention the return electrode may be similarly
positioned on the skin. Alternatively the tip of the guide wire
emerging from the distal end of the support catheter may serve as
the return electrode.
[0051] As used herein, the term "electroporation" means the
temporary creation of holes or aqueous pores in the surface of a
cell membrane by an applied electrical potential and through which
therapeutic agents may pass into the cell. Electroporation is now
widely used in biology, particularly for transfection studies,
where plasmids, DNA fragments and other genetic material are
introduced into living cells. During electroporation pulsing,
molecules that are not normally membrane permeant are able to pass
from the extracellular environment into the cells during the period
of induced reversible membrane permeabilization. The permeabilized
state is caused by the generation of an electrical field in the
cell suspension or tissue of sufficient field strength to perturb
the cell surface membrane's proteolipid structure. This
perturbation (sometimes referred to as dielectric breakdown) is
believed to be due to both a constituent charge separation and the
effect of viscoelastic compression forces within the membrane and
it's sub-adjacent cytoskeletal structures. The result is a
localized membrane thinning. At a critical external field strength,
pores or small domains of increased permeability are formed in the
membrane proteolipid bi-layer.
[0052] A guide wire 26 of a conventional type is adapted to be
introduced through the flow passage 24 in the inner flexible
elongate tubular member for use in guiding the mechanical
dilatation and medicament delivery device 11 as a over-the-wire
design as hereinafter described. The guide wire 26 can be of a
suitable size as for example 0.010"-0.035" and can have a suitable
length ranging from 150 to 300 centimeters. For example, the first
or outer flexible elongate tubular member 12 can have an outside
diameter of 0.6-3 millimeters with a wall thickness of 0.12
millimeters to provide a flow passage of 0.75 millimeters in
diameter. Similarly, the second or inner flexible elongate tubular
member 21 can have a suitable outside diameter as for example 0.6
millimeters with a wall thickness of 0.12 millimeters and a flow
passage 24 of 0.45 millimeters in diameter. The flexible elongate
tubular members 12 and 21 can be formed of a suitable plastic as
for example a polyimide, polyethylene, Nylon or polybutylterphalate
(PBT).
[0053] In accordance with the present invention an essentially
cylindrically shaped expansion member 31 is provided which has a
first or proximal end 32 and a second or distal end 33 with a
central or inner flow passage 34 extending from the proximal end 32
to the distal end 33 along a longitudinally extending central axis
and has a diameter which is a variable as hereinafter described.
The cylindrically shaped expansion member 31 is comprised of a
plurality of flexible elongate elements or filaments 36 each of
which extends helically about the longitudinally extending central
axis. The flexible elongate elements 36 are formed of suitable
materials which can be utilized in the human blood as for example
stainless steel, Nitinol, Aermet.TM., Elgiloy.TM. or certain other
plastic fibers. The flexible elongate elements 36 can have a
suitable diameter as for example 0.001 to 0.010 inches or can be
configured as a round, elliptical, flat or triangular wire ribbon.
A plurality of the flexible elongate elements 36 have a first
common direction of rotation about the central axis as shown in
FIGS. 1 and 7 are axially displaced relative to each other and
cross a further plurality of the flexible elongate elements 36 also
axially displaced relative to each other but having a second common
direction of rotation opposite to that of the first direction of
rotation to form a double helix or braided or mesh-like cylindrical
expansion member with the crossing of flexible elongate elements 36
occurring in the area of contact between the flexible elongate
elements to form openings or interstices 37 therebetween. Thus the
flexible elongate elements 36 form an expansion member 31 which
provides a central or inner flow passage 34 which is variable in
diameter upon movement of the first and second ends of the
expansion member 31 relative to each other along the longitudinally
extending central axis.
[0054] Means is provided for constraining the first and second or
proximal and distal ends 32 and 33 of the expansion member 31 and
consists of a first or proximal collar 41 and a second or distal
collar 42. The first and second collars 41 and 42 are formed of a
suitable material such as a polyimide. The first or proximal collar
41 has a suitable length as for example 1.0 to 5.0 millimeters and
is sized so that it can fit over the first or proximal end 32 of
the expansion member 31 when it is in a contracted position and
over the distal extremity 14 of the first or outer flexible
elongate member 12. In order to ensure that elongate elements or
filaments 36 of the first or proximal extremity 32 are firmly
secured to the distal extremity 14 of the first or outer flexible
elongate member 12, an adhesive can be provided bonding the first
or proximal end 32 to the collar 41 and to the distal extremity 14
of the first or outer flexible elongate tubular member 12. The
second or distal collar 42 can be of a suitable size and typically
may be slightly smaller in diameter because it need merely secure
the elongate element or filaments 36 of the distal end 33 of the
expansion member 31 to the distal extremity 23 of the second or
inner flexible elongate tubular member 21. An adhesive (not shown)
is provided to firmly secure the second or distal end 33 of the
expansion member 31 between the second or distal collar 42 and the
distal extremity of the inner flexible elongate tubular member 21.
In this manner it can be seen that the cylindrical expansion member
31 has its proximal end curved conically inward toward and secured
to the distal extremity of the outer flexible elongate tubular
member 12 and the second or distal end 33 of the expansion member
31 also curves conically inward toward and is secured to the distal
extremity of the second or inner flexible elongate tubular member
21.
[0055] Typically the distance between the first and second collars
41 and 42 can range from between 5 to 150 millimeters. Typically
the distal end 23 of the second or inner flexible elongate tubular
member 21 extends approximately 5-170 millimeters beyond the distal
extremity 14 of the first or outer flexible elongate tubular member
12.
[0056] It can be seen that by moving the first or outer flexible
elongate tubular member 12 and the second inner flexible elongate
tubular member 21 axially with respect to each other, the first and
second ends of the expansion member 31 are moved towards each other
causing the elongate elements or filaments 36 of an intermediate
portion of the cylindrical expansion member between the first and
second ends to move closer to each other to cause these flexible
elongate elements to move into apposition with each other and to
expand in a first radial direction the intermediate portion of the
cylindrical expansion member 31 (FIG. 7) and to cause the diameter
of the central flow passage 34 to increase. The portions of the
expansion member 31 immediately adjacent the first and second
collars 41 and 42 remain restrained by the collars 41 and 42
causing the flexible elongate elements 36 immediately adjacent to
the collars 41 and 42 to curve conically toward and remain crossed
and unable to come into close apposition and thereby provide
openings or interstices 37 therebetween, which remain relatively
constant in shape and size so that blood can flow from the first
and second ends 32 and 33 through the central or inner flow passage
34 as hereinafter described.
[0057] The essentially cylindrical shape of the expansion member
when expanded in a radial directon provides an enlarged surface of
contact between the expansion member and the vessel wall or
obstruction. This enlarged surface of contact enables the
cylindrical expansion member to deliver an amount of medicament or
therapeutic agent which is present on the surface of the flexible
elongate elements that comprise the expansion member. This delivery
of medicament or therpeutic agent may be by the various well known
means previously described such as passive or electrically active
diffusion, pressure, iontophoresis or electroporesis.
[0058] One example of the means provided in the mechanical
dilatation and medicament delivery device 11 for causing relative
movement between the first or outer flexible elongate tubular
member 12 and the second or inner flexible elongate tubular member
21 and consists of a linear movement mechanism 46. The linear
movement mechanism 46 includes a Y-adapter 49 that is provided with
a central arm 51 having a lumen 52 through which the second or
inner flexible elongate tubular member 21 extends. The lumen or
flow passage 52 is in communication with the lumen 16 of outer
flexible elongate tubular member 12 and with a flow passage 53 in a
side arm 54 which is adapted to receive a syringe (not shown) so
that saline, radiocontrast liquid or a medicament/therapeutic agent
can be introduced through the side arm 54 and into the flow passage
52 in the Y-adapter 49 and thence into lumen 16 of outer member 12.
The distal end of screw mechanism 46 is provided with a fitting 56
with inner lumen 57 into which the proximal end 13 of flexible
elongate tubular member 12 is seated and held in place by an
adhesive 58 at the distal end of fitting 56. Lumen 57 is thereby in
communication with flow passage 52 of central arm 51 and with flow
passage 53 of side arm 54. An O-ring 59 that is adapted to form a
fluid-tight seal with respect to the second or inner flexible
tubular member 21 is disposed in the lumen 52 of the central arm
51. An interiorly threaded knurled knob 66 is threaded onto an
exteriorly threaded member 67 which is secured to and surrounds the
proximal extremity 22 of inner flexible elongate tubular member 21.
The knob 66 is provided with an inwardly extending flange 68 which
seats in an annular recess 69 in the central arm 51. Thus, rotation
of the knob 66 causes advancement or retraction of threaded member
67 and the second or inner flexible elongate tubular member 21 with
respect to the fitting 56. Indicia 68 in the form of longitudinally
spaced-apart rings 70 are provided on the member 67 and serve to
indicate the distance that the second or inner flexible elongate
tubular member 21 has been advanced and retracted with respect to
the first or outer flexible elongate member 12.
[0059] A Luer-type fitting 71 is mounted on the proximal extremity
22 of the inner elongate flexible tubular member 21 and is adapted
to be engaged by a finger of the hand. The guide wire 26 extends
through the fitting 71 and into the lumen 24 of inner elongate
flexible tubular member 21.
[0060] It should be appreciated that even though one particular
linear movement mechanism 46 has been provided for advancing and
retracting the flexible elongate members 12 and 21 with respect to
each other, other mechanisms also can be utilized if desired to
provide such relative movement. Other possible designs that could
be employed are scissors-jack, rachet-type or straight slide
mechanisms.
[0061] Another embodiment of a dilatation and medicament delivery
device incorporating the present invention is shown in FIGS. 9 and
9a. As shown therein, the rapid exchange designed mechanical
dilatation and medicament delivery device 101 is constructed in a
manner similar to the mechanical dilatation and medicament delivery
device 11 with the exception that it is provided with rapid
exchange capabilities. This is accomplished by providing an outer
flexible elongate tubular member 102 having a lumen 103 therein and
an inner flexible elongate tubular member 106 having a lumen 107
which have the expansion member 31 secured thereto by the proximal
and distal collars 41 and 42. The outer flexible elongate tubular
member 102 is provided with a port or opening 111 into the
corresponding lumen 103 and which is 13-60 centimeters from the
distal extremity 32 of the expansion member 31. A corresponding
port or opening 112 into corresponding lumen 107 is provided within
the inner flexible elongate tubular member 106. These ports 111 and
112 are positioned so that when the expansion member 31 is in its
expanded position with the distal extremities of the members 102
and 106 being in closest proximity to each other, the openings 111
and 112 are in registration with each other. In this position, the
mechanical dilatation and medicament delivery device 101 can be
loaded onto the guide wire 16 by advancing the most proximal
extremity of guide wire 26 first into lumen 107 of the distal
extremity of the inner flexible elongate member 106 and then back
through port or opening 112 and port 111 which are in registration
and out of the flexible elongate tubular member 102. The expansion
member 31 is next contracted from its diametrically expanded
condition to a contracted condition by moving the distal
extremities of outer and inner flexible elongate tubular members
102 and 106 further apart by operation of screw mechanism 46. This
procedure is performed while maintaining a stable position of the
external position of guide wire 26 in a constant position in
relation to port 111. As the distal extremity of flexible tubular
member 106 is moved further from the distal extremity of flexible
elongate tubular member 102, port 112 will move out of registration
with port 111 while maintaining guide wire 26 within lumen 107 and
advancing the distal extremity of the flexible elongate tubular
member 106 along the guide wire 26. In this diametrically
contracted state of the expansion member 31, the mechanical
dilatation and medicament delivery device 101 may be advanced along
guide wire 26 through the region of stenosis in the blood vessel
and enlargement of expansion member 31 may occur using screw
mechanism 46 in the manner previously described. Once dilatation
and medicament delivery has been completed, expansion member 31 can
be diametrically contracted and the mechanical dilatation and
medicament delivery device 101 may be removed from the blood vessel
and the guiding catheter by maintaining a stable position of guide
wire 26 in relation to the blood vessel and retracting device 101
along guide wire 26 until the distal extremity of inner flexible
member 106 exits the patient's body. The mechanical dilatation and
medicament delivery device 101 may now be rapidly exchanged with
another mechanical device 101 as for example, one having an
expansion member 31 which can be increased to a larger diameter
over a standard 175 to 185 centimeter length guide wire 26.
[0062] The expansion member 31 is comprised of 16-64 individual
elements formed of 0.001 to 0.005 inch diameter wire of a suitable
metal such as stainless steel helically wound around a longitudinal
central axis. The helices are wound in opposite directions.
Stretching or elongation of the cylindrical expansion member 31
results in a reduction in diameter of the expansion member 31.
Mechanical fixation of the proximal and distal extremities 22 and
23 of the expansion member 31 holds these extremities in reduced
diameter configurations. The positions of the elements 21 in these
extremities cannot change in relation to each other. Therefore, the
crossing angles of the elements 36 remain constant. Shortening of
the cylindrical expansion member 31 with the ends fixed results in
the formation of a cylindrical center section of great rigidity
with the elements 36 in close apposition to each other. The tapered
proximal and distal extremities of the expansion member 31 causes
the stresses on the individual elements 36 to be balanced. Since
the proximal and distal extremities 22 and 23 are held in constant
tapered positions, the interstices between the elements are
maintained allowing blood to flow into and out of the cylindrical
center section when the expansion member 31 is shortened as shown
in FIG. 10. Shortening of the expansion member 31 results in a
significant increase in the metal density per unit length in the
center portion of the expansion member 31 while the metal density
at the ends is relatively constant. This increase in metal density
in the center section results in significant radial force
generation as the elements 36 are compressed in a longitudinal
direction.
[0063] As seen in FIG. 11 the flexible elongated elements 36 are
coated with a therapeutic agent or medicament 40 resulting in a
coated flexible elongated element 35 that is designed to either
passively or electrically cause the therapeutic agent or medicament
40 to dispense or migrate into the vessel wall 17. FIG. 13
demonstrates in a cross sectional view a more detailed view of one
of the coated flexible elongate elements 35 of the expandable mesh
31 designed to either passively or electrically dispense the
therapeutic agent or medicament 40 from the elongate element 35.
FIG. 12 shows a cross sectional view demonstrating the dispensing
of a therapeutic agent or medicament from bands 62 affixed to the
inner tubular member located within the expandable mesh 31.
[0064] FIG. 14 is another cross sectional view of one of the coated
flexible elongate elements 35 of the expandable mesh 31
demonstrating the dispensing of the therapeutic agent or medicament
40 that is incorporated within a substrate 43 over the elongate
element. The substrate 43 can function to better adhere the
medicament 40 to the surface of the flexible elongate element 36,
time the release of the medicament into the vessel wall 17, be an
agent for transferring the medicament 40 across the cell membrane
boundaries either by passive or pressure mediated transfer or
actively by iontophoresis or electroporation, or any combination of
the services. FIG. 15 is another cross sectional view of one of the
coated flexible elongate elements 35 of the expandable mesh 31
demonstrating the dispensing of a therapeutic agent or medicament
40 with the aid of electrical current applied to the flexible
elongate elements.
[0065] FIG. 16 is a cross sectional side view of the flexible
elongated elements 36 demonstrating the passive or electrically
active dispensing of the therapeutic agent or medicament 40 into
the vessel wall 17.
[0066] To perform as a liposome or micelle-encapsulated therapeutic
agent or medicament source 40 for the present invention, the coated
flexible elongate elements 35 themselves can be coated as described
in more detail below.
[0067] A liposome or micelle-encapsulated therapeutic agent or
medicament 40 can be coated on (or incorporated into a polymer or
other substrate 43 and coated on the expansion mesh 31 and/or
specific bands 62 mounted on the catheter located within the
expansion mesh. One particular therapeutic agent or medicament 40a
can be coated upon any one of the components described above, for
example the expansion mesh and another therapeutic agent or
medicament 40b can be coated upon another component, for example,
the marker bands. Alternately, a therapeutic agent delivery lumen
that has a distal port located inside the expansion member can be
used to selectively release and deliver a particular therapeutic
agent or medicament.
[0068] The liposome or micelle-encapsulated therapeutic agent 40
can be an anticoagulant, such as D-Phe-Pro-Arg chloromethyl ketone,
an RGD peptide-containing compound, heparin, an antithrombin
compound, a platelet receptor antagonist, an anti-thrombin
antibody, an anti-platelet receptor antibody, aspirin, a
prostaglandin inhibitor, a platelet inhibitor or a tick
anti-platelet peptide.
[0069] The liposome or micelle-encapsulated therapeutic agent 40
can be a promoter of vascular cell growth, such as a growth factor
stimulator, a growth factor receptor agonist, a transcriptional
activator, and a translational promoter. Alternatively, the
therapeutic agent 40 can be an inhibitor of vascular cell growth,
such as a growth factor inhibitor, a growth factor receptor
antagonist, a transcriptional repressor, a translational repressor,
an antisense DNA, an antisense RNA, a replication inhibitor, an
inhibitory antibody, an antibody directed against growth factors, a
bifunctional molecule consisting of a growth factor and a
cytotoxin, or a bifunctional molecule consisting of an antibody and
a cytotoxin.
[0070] The liposome or micelle-encapsulated therapeutic agent 40
can be a cholesterol-lowering agent, a vasodilating agent, or other
agents that interfere with endogenous vasoactive mechanisms.
Additionally, the therapeutic agent 40 can be a smooth muscle
inhibitor, such as: an agent that modulates intracellular calcium
binding proteins; a receptor blocker for contractile agonists; an
inhibitor of the sodium/hydrogen antiporter; a protease inhibitor;
a nitrovasodilator; a phosphodiesterase inhibitor; a phenothiazine;
a growth factor receptor agonist; an anti-mitotic agent; an
immunosuppressive agent; or a protein kinase inhibitor.
[0071] Alternatively, the liposome or micelle-encapsulated
therapeutic agent 40 may be disposed on or within a substrate or
polymer 43, which can be biodegradable and adapted for slow release
of the liposome or micelle-encapsulated therapeutic agent 40. A
substrate or polymer 43 laden with one or more therapeutic agents
40 can be positioned on the bands, or coated on the flexible
elongate elements 36.
[0072] A biodegradable substrate or polymer 43 such as polylactide,
polyanhydride, polyorthoester or polyglycolide, for example can be
used. In addition to synthetic polymers, natural polymers can be
used, such as amino acid polymers or polysaccharides. The polymer
50 is selected depending on the therapeutic agent required, the
polymer's 43 compatibility with a patient and the ultimate
pharmacologic effect desired. For example, if the effect need only
last a short period, a thin polymer 43 can be used with a limited
amount of therapeutic agent capable of diffusing from the polymer
50 into the arterial wall or lumen of the vesicle. Alternatively,
only the layer closest to the body fluid would contain the liposome
or micelle-encapsulated therapeutic agent 40. Another alternative
would be to use a polymer 43 which is biodegradable over a long
period of time. Naturally, the opposite characteristics would be
selected for a desired prolonged release.
[0073] Generally, the substrate or polymer 43 has a liposome or
micelle-encapsulated therapeutic agent 40 release rate of between
about 0.001 .mu.g/cm.sup.2-min and about 100 .mu.g/cm.sup.2-min,
especially between about 0.01 .mu.g/cm.sup.2-min and 10
.mu.g/cm.sup.2-min. In addition, the substrate or polymer 43
generally has a thickness of between about 0.01 mm and 10 mm,
especially between about 0.1 mm and 1.0 mm. As can be appreciated,
the device 10 can be comprised of two or more different therapeutic
agents 40 or two or more different polymers 43 to obtain a desired
effect and release rate. In addition, the polymers 43 can have
different solubilities or diffusion characteristics to accomplish
non-uniform therapeutic agent 40 release.
[0074] The methodology for coating of a polymer and/or a
therapeutic agent or medicament onto the bands or flexible elongate
elements of the expansion member is well known to those skilled art
or can be determined by reference to standard references. In
addition, the characteristics of the particular substrate or
polymer 43 for these purposes is well known to the skilled artisan
or can be determined by reference to standard references, e.g.,
Biodegradable Polymers as Therapeutic agent Delivery Systems, R.
Langer and M. Chasin, Eds., Marcel Dekker Inc., New York, N.Y., USA
(1990); Engleberg and Kohn, "Physico-mechanical properties of
degradable polymers used in medical applications: a comparative
study," Bionuzterials 12:292-304 (1991); Controlled Release
Delivery Systems, T. J. Roseman and S. D. Mansdorf, Eds., Marcel
Dekker Inc., New York, N.Y., USA (1983); and "Controlled Release
Technology, Pharmaceutical Applications, ACS Symposium Series, Vol.
348, P. I. Lee and W. R. Good, Eds., American Chemical Society,
Washington, D.C., USA (1987).
[0075] Operation and use of the mechanical dilatation and
medicament delivery device 11 may now be briefly described as
follows. Let it be assumed that the patient which the medical
procedure is to be performed utilizing the mechanical dilatation
and medicament delivery device 11 has one or more stenoses which at
least partially occlude one or more arterial vessels supplying
blood to the heart and that it is desired to enlarge the flow
passages through these stenoses. Typically the mechanical
dilatation and medicament delivery device 11 would be supplied by
the manufacturer with the cylindrical expansion member 31 in its
most contracted position to provide the lowest possible
configuration in terms of diameter and so that the diameter
approximates the diameter of the outer flexible elongate tubular
member 12 and previously coated with a therapeutic agent or
medicament 40. Alternatively, the mechanical dilatation and
medicament delivery device will be supplied either uncoated or
coated only with the bonding polymer present on the dilatation
member and without any liposome or micelle-encapsulated therapeutic
agent or medicament 40 on the expansion mesh. In this example, a
container having a solution of the liposome or micelle-encapsulated
therapeutic agent 40 can be separately supplied whereby sometime
prior to inserting the mechanical dilatation and medicament
delivery device into the patient, the expansion mesh 31 is immersed
or dipped into the container in order to coat the flexible elongate
members 36. Appropriate time and/or temperatures will be allowed
for the medicament solution to adsorb, dry and adhere to the
polymer coated expansion mesh, or alternately, a charge can be
applied to facilitate bonding of the medicament or therapeutic
agent to the polymer coated expansion member.
[0076] Preferably, the coated expansion member 35 should have a
diameter that is only slightly greater than the tubular member 12,
as for example by 1.0-2.3 millimeters. The first and second collars
41 and 42 also have been sized so they only have a diameter that is
slightly greater than the outer diameter of the outer flexible
elongate tubular member 12. To bring the cylindrical expansion
member 31 to its lowest configuration, the linear movement
mechanism 46 has been adjusted so that there is a maximum spacing
between the distal extremity 23 of the inner flexible elongate
tubular member 21 and the distal extremity 14 of the outer flexible
elongate tubular member 12. In this position of the expansion
member 31, the flexible elongate elements 36 cross each other at
nearly right angles so that the interstices or openings 37
therebetween are elongated with respect to the longitudinal
axis.
[0077] If applicable, the present invention has the flexible
elongate elements of the catheter coated with a liposome or
micelle-encapsulated medicament or therapeutic agent that can be
subjected to an electrical current that renders the flexible
elongate members to have a charge opposite to that of the
therapeutic agent or medicament. Applicable liposome or
micelle-encapsulated therapeutic agents or medicaments will have
inherent charge potentials that when opposite charges are applied
to the expansion member, an electrical bond is established between
the surface of the expansion member and the liposome or
micelle-encapsulated therapeutic agent or medicament. Electrical
energy or current may be applied from an electrical connector
located on the proximal end of the catheter, through the leads 45
and to the coated expansion member 35. This would create a
significant bonding of the liposome or micelle-encapsulated
therapeutic agent or medicament 40 to the flexible elongate
elements 36. The continuously charged mesh with the attached
liposome or micelle-encapsulated therapeutic agent or medicament 40
could then be advanced through the patient's vasculature to the
site of dilatation and therapy without significant loss of the
medicament in the bloodstream.
[0078] The mechanical dilatation and medicament delivery device 11
is then inserted into a guiding catheter (not shown) typically used
in such a procedure and introduced into the femoral artery and
having its distal extremity in engagement with the ostium of the
selected coronary artery.
[0079] Thereafter, the guide wire 26 can be inserted independently
of the mechanical dilatation and medicament delivery device 11. If
desired the guide wire 26 can be inserted along with the mechanical
dilatation and medicament delivery device 11 with its distal
extremity extending beyond the distal extremity of device 11. The
guide wire 26 is then advanced in a conventional manner by the
physician undertaking the procedure and is advanced into the vessel
containing a stenosis. The progress of the distal extremity of the
guide wire 26 is observed fluoroscopically and is advanced until
its distal extremity extends distally of the stenosis. With the
expansion member 31 in its diametrically contracted position and
the liposome or micelle-encapsulated medicament or therpeutic agent
coated thereon, the mechanical dilatation and medicament delivery
device 11 is advanced over the guide wire 26. The distal extremity
23 of the second or inner flexible elongate tubular member 21 is
advanced through the stenosis over the guide wire 26 until it is
distal to the stenosis and so that the distal extremity 14 of the
first or outer flexible elongate tubular member 12 is just proximal
of the stenosis.
[0080] After the expansion member 31 is in a desired position in
the stenosis, the expansion member 31 is expanded from its
diametrically contracted position to an expanded position by moving
the distal extremities 14 and 23 closer to each other by operation
of the screw mechanism 46. This can be accomplished by holding one
distal extremity stationary and moving the other distal extremity
towards it or by moving both distal extremities closer to each
other simultaneously. This movement of the distal extremities 14
and 23 causes collars 41 and 42 to move closer to each other and to
cause the central flexible elongate elements 36 forming the double
helix mesh of the intermediate portion 31a of the flexible
cylindrical expansion member 31 to move relative to each other to
progressively decrease the vertical crossing angle of the double
helically wound flexible elongate elements 36 from approximately
140.degree. to 170.degree. in its extended state to 5.degree. to
20.degree. in its axially contracted state and to progressively
change the interstices or openings 37 from diamond-shaped openings
with long axes parallel to the central longitudinal axis of the
catheter in its extended state to substantially square-shaped
openings in its intermediately contracted state to elongate
diamond-shaped interstices or openings with the longitudinal axes
extending in directions perpendicular to the central longitudinal
axis with the flexible elongate elements 36 coming into close
apposition to each other while at the same time causing radial
expansion of the expansion member and to progressively increase the
diameter of the central flow passage 34. The enlargement of
expansion member 31 in addition to being viewed fluoroscopically
can also be ascertained by the indicia 68 carried by the threaded
member 67.
[0081] The intermediate portion 31a of the cylindrical expansion
member 31 when fully expanded is almost a solid tubular mass which
has significant radial strength to fully expand a stenosis or
alternatively a stent or prosthesis. In addition, because of
spring-like properties of the enlarged expansion member being
comprised of helically wound flexible elongate elements 36, the
expansion member 31 can conform to a curve within the blood vessel
while still exerting significant radial force to the stenosis or
alternatively a stent or prosthesis and to make possible
compression of the stenosis without tending to straighten the curve
in the vessel which typically occurs with standard straight
angioplasty balloon systems. Since the expansion member or
alternatively a stent or prosthesis is coated with a therapeutic
agent or medicament one or more therapeutic agents or medicaments
can be delivered to the vessel during the time of device expansion
while blood is permitted to flow unobstructed to the distal vessel
(see FIGS. 11-16).
[0082] Additionally an electrical charge can be provided to the
dilatation member or mesh that is opposite in charge to that used
to bind the liposome or micelle-encapsulated medicament to the mesh
or expansion member. This charge will then tend to drive the
liposome or micelle-encapsulated medicament or therapeutic agent
into the tissue through iontophoretic means. The iontophoretic
process is known to facilitate or assist the transport of the
liposome or micelle-encapsulated medicament or therapeutic agent
across the selectively permeable membranes and enhance tissue
penetration. Since the present invention involves the use of
electrical energy, there are many possible waveforms contemplated
for use. As depicted in FIGS. 8a-8f, square waves 61, rectangular
waves 63, saw toothed waves 64, sinusoidal waves that do not
reverse polarity 65, rectified sinusoidal waves, 72 and modified
rectangular or other waves 73. The primary characteristic of the
preferred waveforms is that they all provide a net flow of current
to the coated expansion member 35. It must be appreciated by those
skilled in the art, that the waveforms with frequencies and duty
cycles must be capable of delivering the desired current under
varying impedances encountered by the expansion member 35 and the
surrounding vessel wall 17 and fluids.
[0083] After a predetermine time, the electrical current can be
altered to achieve another purpose or terminated. Since blood flows
continuously through the dilatation and medicament delivery device
11 during the dilatation and medicament delivery procedure, there
is minimal danger of ischemia occurring. This makes it possible to
maintain dilatation and medicament delivery 11 of the obstruction
over extended periods of time when desired. One particularly
advantage for the mechanical dilatation and medicament delivery
device 11 is that it could be used with patients which have
obstructions of a critical nature that cannot even tolerate
relatively short periods of balloon dilatation without leading to
ischemia and creating permanent damage or shock to the patient.
Another advantage of the present invention is the increased contact
area of the cylindrical expansion member with the vessel wall can
lead to increased adsorption of the medicament or therapeutic agent
by the tissues.
[0084] After dilatation and medicament delivery of the lesion has
been carried out for an appropriate length of time, the expansion
member 31 can be moved from its expanded position to a contracted
position by, for example, operation of the screw mechanism 46 in a
reverse direction to cause separation of the distal extremities 14
and 23 to thereby cause elongation of the expansion member 31 with
a concurrent reduction in diameter.
[0085] After the expansion member 31 has been reduced to its
contracted or minimum diameter, the mechanical dilatation and
medicament delivery device 11 can be removed along with the guide
wire 26 after which the guiding catheter (not shown) can be removed
and the puncture site leading to the femoral artery closed in a
conventional manner. Alternately, the previously used mechanical
dilatation and medicament delivery device 11 can be replaced and
another mechanical dilatation and medicament delivery device 11
which has fresh medicaments, different medicaments, or different
expansion member 31 diameters for subsequent treatment of the
site.
[0086] Describe below are some examples of experiments conducted
using the present invention.
EXAMPLE 1
Local delivery of 7-Amino Actinomycin D
[0087] 7-Amino Actinomycin D is a fluorescent (emits at 610 nm,
[red]) analog of Actinomycin D, a potent inhibitor of cellular
proliferation. It is very lipophilic and poorly soluble in water.
Liposome or micelles were prepared by mixing 3.0 mg of
phosphatidylcholine, 3.0 mg of cholesterol and 0.3 mg of
phosphatidylserine in a test tube. Chloroform (200 microliters) was
added and the solution was evaporated to dryness in a test tube.
7-Amino Actinomycin D (500 mg) was dissolved in 8 mM CaCl.sub.2 for
a final concentration of 0.5 mg/ml. The 7-Amino Actinomycin D
solution was added to the lipid mixture in small aliquots with
constant stirring. The hydrogel-coated metal mesh catheter was
placed in the 7-amino Actinomycin D/liposome or micelle mixture and
then used for drug delivery in the following manner: The
hydrogel-coated metal mesh catheter was placed in the 7-Amino
Actinomycin D/liposome or micelle mixture and then removed. In some
cases, the hydrogel-coated mesh portion of the catheter was covered
with a retractable sheath to prevent loss of the compound during
the transport of the catheter from the arterial access site to the
target site. When the catheter was positioned at the target site
the sheath was retracted and the mesh was expanded against the
arterial wall. Iontophoersis was performed by applying an
electrical current to the mesh. The circuit was completed by pacing
a patch on the skin that was connected to the circuit and had an
opposite charge than the mesh. In this example the iontophoresis
parameters were 5 mA, and 8 V, applied for 10 minutes. The results
also show 7-Amino Actinomycin D throughout the vessel wall and in
the outer layer of the vessel. There is also evidence of
localization of the 7-Amino Actinomycin D in the nuclei of the
cells.
EXAMPLE 2
Local Delivery of Paclitaxel
[0088] Paclitaxel is one of the most potent inhibitors of cellular
proliferation in clinical use and has been shown to be efficacious
in a large number of cancers. Paclitaxel is very lipophilic and
essentially insoluble in water. Liposome or micelles were prepared
by mixing 0.72 mg phosphatidylcholine and 0.8 mg of
phosphatidylserine in a test tube with 800 microliters of
chloroform. The solution was evaporated to dryness. Paclitaxel
labeled with a fluorescent probe (Oregon Green) was dissolved in
methanol to obtain a 20 1 mg/1 ml solution. Twenty-five microliters
of this solution was combined with 975 microliters of 8 mM
CaCl.sub.2. The paclitaxel solution was added to the dried lipid
mixture in small aliquots with constant stirring. The
hydrogel-coated metal mesh catheter was placed in the
paclitaxel/liposome or micelle mixture and then removed. In some
cases, the hydrogel-coated mesh portion of the catheter is covered
with a retractable sheath to prevent loss of the compound during
the transport of the catheter from the arterial access site to the
target site. When the catheter was positioned at the target site
the sheath was retracted and the mesh was expanded against the
arterial wall. Iontophoersis was performed by applying an
electrical current to the mesh. The circuit was completed by pacing
a patch on the skin that was connected to the circuit and had an
opposite charge than the mesh. In this example the iontophoresis
parameters were 7 mA and 8 V, applied for 20 minutes. The results
showed the paclitaxel throughout the vessel wall and in the outer
layer of the vessel.
[0089] Although, the procedure hereinbefore described was for
treatment of a single stenosis, it should be appreciated that if
desired during the same time that the mechanical dilatation and
medicament delivery device 11 is within the guiding catheter, other
vessels of the patient having stenoses therein can be treated in a
similar manner merely by retracting the distal extremity of the
mechanical dilatation and medicament delivery device 11 from the
stenosis being treated, placing another prosthesis over the
expansion member, and then advancing it into another stenosis in
another vessel in a similar manner.
[0090] The advantages of using the present invention is the ability
to deliver a liposome or micelle-encapsulated therapeutic agent or
medicament to a vascular segment for prolonged periods while
allowing continuous perfusion of blood into the distal to the
treatment area.
[0091] From the foregoing, it can be seen that there has been
provided a mechanical dilatation and medicament delivery device
which can be used in a similar manner to a balloon catheter in
dilating a vessel segment or deploying a stent during an
interventional procedure with the outstanding advantage that blood
can continue to flow to the distal blood vessel during the
procedure while delivery of a liposome or micelle-encapsulated
medicament or therapeutic agent is also accomplished. This permits
a longer vessel dilatation and medicament delivery without tissue
ischemia. Furthermore, the dilatation and medicament delivery
device provides either passive or active delivery of a medicament
or therapeutic agent to the affected vessel walls via the coated
expansion member or via a stent or prostheis coated with such an
agent. Furthermore, the mechanical dilatation and medicament
delivery device also provides the advantages of known expanded
non-compliant diameter and therefore exact sizing.
* * * * *