U.S. patent application number 10/857201 was filed with the patent office on 2004-12-16 for expandable medical device for delivery of beneficial agent.
Invention is credited to Eigler, Neal L., Shanley, John F..
Application Number | 20040254635 10/857201 |
Document ID | / |
Family ID | 46301357 |
Filed Date | 2004-12-16 |
United States Patent
Application |
20040254635 |
Kind Code |
A1 |
Shanley, John F. ; et
al. |
December 16, 2004 |
Expandable medical device for delivery of beneficial agent
Abstract
An expandable medical device has a plurality of elongated struts
joined together to form a substantially cylindrical device which is
expandable from a cylinder having a first diameter to a cylinder
having a second diameter. At least one of the plurality of struts
includes at least one opening extending at least partially through
a thickness of the strut. A beneficial agent is loaded into the
opening within the strut in layers to achieve desired temporal
release kinetics of the agent. Alternatively, the beneficial agent
is loaded in a shape which is configured to achieve the desired
agent delivery profile. A wide variety of delivery profiles can be
achieved including zero order, pulsatile, increasing, decrease,
sinusoidal, and other delivery profiles.
Inventors: |
Shanley, John F.; (Redwood
City, CA) ; Eigler, Neal L.; (Pacific Palisades,
CA) |
Correspondence
Address: |
CINDY A. LYNCH
CONOR MEDSYSTEMS, INC.
1003 HAMILTON COURT
MENLO PARK
CA
94025
US
|
Family ID: |
46301357 |
Appl. No.: |
10/857201 |
Filed: |
May 27, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10857201 |
May 27, 2004 |
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10668430 |
Sep 22, 2003 |
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10857201 |
May 27, 2004 |
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10253020 |
Sep 23, 2002 |
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10253020 |
Sep 23, 2002 |
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09948989 |
Sep 7, 2001 |
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10253020 |
Sep 23, 2002 |
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09688092 |
Oct 16, 2000 |
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09688092 |
Oct 16, 2000 |
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09183555 |
Oct 29, 1998 |
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6241762 |
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60412489 |
Sep 20, 2002 |
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60314259 |
Aug 20, 2001 |
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60079881 |
Mar 30, 1998 |
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Current U.S.
Class: |
623/1.17 |
Current CPC
Class: |
A61F 2002/821 20130101;
A61L 31/146 20130101; A61F 2/91 20130101; A61F 2/856 20130101; A61L
2300/602 20130101; A61F 2002/91525 20130101; A61F 2250/0068
20130101; A61F 2002/91533 20130101; A61F 2002/91508 20130101; A61L
2300/416 20130101; A61L 31/10 20130101; A61F 2/915 20130101; A61L
31/148 20130101; A61F 2002/91516 20130101; A61F 2002/91541
20130101; A61L 31/16 20130101; A61F 2250/0035 20130101; A61F
2002/91558 20130101 |
Class at
Publication: |
623/001.17 |
International
Class: |
A61F 002/06 |
Claims
We claim:
1. A device for the controlled release of one or more drugs
comprising: an implantable stent; at least two reservoirs in the
stent; and a release system contained in each of the at least two
reservoirs, wherein the release system comprises one or more drugs
for release.
2. The device of claim 1, where the release system provides
continuous release of the one or more drugs from the at least two
reservoirs.
3. The device of claim 1, wherein the release system provides
pulsatile release of the one or more drugs from the at least two
reservoirs.
4. The device of claim 1, wherein the release system comprises drug
molecules in a matrix formed of a degradable material.
5. The device of claim 1, wherein the drug is homogeneously
distributed within the release system.
6. The device of claim 1, wherein the drug is heterogeneously
distributed within the release system.
7. The device of claim 1, wherein the reservoirs contains two or
more layers, at least one of which comprises the release
system.
8. The device of claim 1, wherein the release system further
comprises a synthetic biodegradable polymer.
9. The device of claim 8, wherein the synthetic biodegradable
polymer is selected from the group consisting of polyanhydrides and
polyorthoesters.
10. The device of claim 1, wherein the release system further
comprises a bioerodible hydrogel.
11. The device of claim 1, wherein the one or more drugs are in the
form of a solid or gel.
12. The device of claim 1, wherein the release system further
comprises at least one excipient.
13. The device of claim 1, wherein the at least two reservoirs are
each covered by a reservoir cap.
14. The device of claim 13, wherein the drug is released from the
reservoirs by passive means.
15. The device of claim 14, wherein the reservoir cap is formed of
a material that degrades or dissolves over time.
16. The device of claim 13, wherein the reservoir cap comprises a
polymeric material.
17. The device of claim 14, wherein at least one reservoir cap is
formed of a first material and at least one other reservoir cap is
formed of a second material, wherein the first material has a
different degradation rate, a different dissolution rate, or a
different permeability to the drug molecules compared to the second
material.
18. The device of claim 13, wherein the drug is released from the
reservoirs by active means for disintegrating or rupturing the
reservoir cap.
19. The device of claim 1, wherein a first drug is in at least one
of the reservoirs and a second drug is in at least one other of the
reservoirs, the first drug and the second drug being different in
kind or dose.
20. The device of claim 1, wherein the one or more drugs comprise a
protein, a polysaccharide, or a nucleic acid.
21. The device of claim 1, wherein the one or more drugs comprise
an anesthetic.
22. The device of claim 1, wherein the one or more drugs comprise
an antibiotic.
23. The device of claim 1, wherein the one or more drugs comprise
an anti-inflammatory agent.
24. The device of claim 1, wherein the one or more drugs comprise
an anti-hypertensive agent.
25. The device of claim 1, wherein the one or more drugs comprise a
chemotherapeutic agent.
26. The device of claim 1, wherein the one or more drugs comprise a
hormone.
27. The device of claim 1, wherein the one or more drugs comprise
an immunomodulator.
28. The device of claim 1, wherein the implantable stent is an
arterial or vascular stent.
29. The device of claim 1, wherein the implantable stent comprises
a metal.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of pending U.S.
application Ser. No. 10/668,430, filed Sep. 22, 2003, which claims
priority to U.S. Provisional Application Ser. No. 60/412,489, filed
Sep. 20, 2002. This application is also a continuation-in-part of
pending U.S. application Ser. No. 10/253,020, filed on Sep. 23,
2002, which is a continuation-in-part of U.S. application Ser. No.
09/948,989, filed on Sep. 7, 2001, which claims priority to U.S.
Provisional Application Ser. No. 60/314,259, filed Aug. 20, 2001
and which is a continuation-in-part of U.S. application Ser. No.
09/688,092, filed Oct. 16, 2000 which is a continuation-in-part of
U.S. application Ser. No. 09/183,555, filed Oct. 29, 1998, now U.S.
Pat. No. 6,241,762, which claims priority to U.S. Provisional
Application Ser. No. 60/079,881, filed Mar. 30, 1998.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to tissue-supporting medical
devices, and more particularly to expandable, non-removable devices
that are implanted within a bodily lumen of a living animal or
human to support the organ and maintain patency, and that can
deliver a beneficial agent to the intervention site.
[0004] 2. Summary of the Related Art
[0005] In the past, permanent or biodegradable devices have been
developed for implantation within a body passageway to maintain
patency of the passageway. These devices are typically introduced
percutaneously, and transported transluminally until positioned at
a desired location. These devices are then expanded either
mechanically, such as by the expansion of a mandrel or balloon
positioned inside the device, or expand themselves by releasing
stored energy upon actuation within the body. Once expanded within
the lumen, these devices, called stents, become encapsulated within
the body tissue and remain a permanent implant.
[0006] Known stent designs include monofilament wire coil stents
(U.S. Pat. No. 4,969,458); welded metal cages (U.S. Pat. Nos.
4,733,665 and 4,776,337); and, most prominently, thin-walled metal
cylinders with axial slots formed around the circumference (U.S.
Pat. Nos. 4,733,665; 4,739,762; and 4,776,337). Known construction
materials for use in stents include polymers, organic fabrics and
biocompatible metals, such as, stainless steel, gold, silver,
tantalum, titanium, and shape memory alloys such as Nitinol.
[0007] U.S. Pat. Nos. 4,733,665; 4,739,762; and 4,776,337 disclose
expandable and deformable interluminal vascular grafts in the form
of thin-walled tubular members with axial slots allowing the
members to be expanded radially outwardly into contact with a body
passageway. After insertion, the tubular members are mechanically
expanded beyond their elastic limit and thus permanently fixed
within the body. U.S. Pat. No. 5,545,210 discloses a thin-walled
tubular stent geometrically similar to those discussed above, but
constructed of a nickel-titanium shape memory alloy ("Nitinol"),
which can be permanently fixed within the body without exceeding
its elastic limit. All of these stents share a critical design
property: in each design, the features that undergo permanent
deformation during stent expansion are prismatic, i.e., the cross
sections of these features remain constant or change very gradually
along their entire active length. These prismatic structures are
ideally suited to providing large amounts of elastic deformation
before permanent deformation commences, which in turn leads to
sub-optimal device performance in important properties including
stent expansion force, stent recoil, strut element stability, stent
securement on delivery catheters, and radiopacity.
[0008] U.S. Pat. No. 6,241,762, which is incorporated herein by
reference in its entirety, discloses a non-prismatic stent design
which remedies the above mentioned performance deficiencies of
previous stents. In addition, preferred embodiments of this patent
provide a stent with large, non-deforming strut and link elements,
which can contain holes without compromising the mechanical
properties of the strut or link elements, or the device as a whole.
Further, these holes may serve as large, protected reservoirs for
delivering various beneficial agents to the device implantation
site.
[0009] Of the many problems that may be addressed through
stent-based local delivery of beneficial agents, one of the most
important is restenosis. Restenosis is a major complication that
can arise following vascular interventions such as angioplasty and
the implantation of stents. Simply defined, restenosis is a wound
healing process that reduces the vessel lumen diameter by
extracellular matrix deposition and vascular smooth muscle cell
proliferation, and which may ultimately result in renarrowing or
even reocclusion of the lumen. Despite the introduction of improved
surgical techniques, devices and pharmaceutical agents, the overall
restenosis rate is still reported in the range of 25% to 50% within
six to twelve months after an angioplasty procedure. To treat this
condition, additional revascularization procedures are frequently
required, thereby increasing trauma and risk to the patient.
[0010] Some of the techniques under development to address the
problem of restenosis include irradiation of the injury site and
the use of conventional stents to deliver a variety of beneficial
or pharmaceutical agents to the wall of the traumatized vessel. In
the latter case, a conventional stent is frequently surface-coated
with a beneficial agent (often a drug-impregnated polymer) and
implanted at the angioplasty site. Alternatively, an external
drug-impregnated polymer sheath is mounted over the stent and
co-deployed in the vessel.
[0011] While acute outcomes from radiation therapies appeared
promising initially, long term beneficial outcomes have been
limited to reduction in restenosis occurring within a previously
implanted stent, so-called `in-stent` restenosis. Radiation
therapies have not been effective for preventing restenosis in de
novo lesions. Polymer sheaths that span stent struts have also
proven problematic in human clinical trials due to the danger of
blocking flow to branch arteries, incomplete apposition of stent
struts to arterial walls and other problems. Unacceptably high
levels of MACE (Major Adverse Cardiac Events that include death,
heart attack, or the need for a repeat angioplasty or coronary
artery bypass surgery) have resulted in early termination of
clinical trials for sheath covered stents.
[0012] Conventional stents with surface coatings of various
beneficial agents, by contrast, have shown promising early results.
U.S. Pat. No. 5,716,981, for example, discloses a stent that is
surface-coated with a composition comprising a polymer carrier and
paclitaxel (a well-known compound that is commonly used in the
treatment of cancerous tumors). The patent offers detailed
descriptions of methods for coating stent surfaces, such as
spraying and dipping, as well as the desired character of the
coating itself: it should "coat the stent smoothly and evenly" and
"provide a uniform, predictable, prolonged release of the
anti-angiogenic factor." Surface coatings, however, can provide
little actual control over the release kinetics of beneficial
agents. These coatings are necessarily very thin, typically 5 to 8
microns deep. The surface area of the stent, by comparison is very
large, so that the entire volume of the beneficial agent has a very
short diffusion path to discharge into the surrounding tissue.
[0013] Increasing the thickness of the surface coating has the
beneficial effects of improving drug release kinetics including the
ability to control drug release and to allow increased drug
loading. However, the increased coating thickness results in
increased overall thickness of the stent wall. This is undesirable
for a number of reasons, including increased trauma to the vessel
wall during implantation, reduced flow cross-section of the lumen
after implantation, and increased vulnerability of the coating to
mechanical failure or damage during expansion and implantation.
Coating thickness is one of several factors that affect the release
kinetics of the beneficial agent, and limitations on thickness
thereby limit the range of release rates, durations, and the like
that can be achieved.
[0014] In addition to sub-optimal release profiles, there are
further problems with surface coated stents. The fixed matrix
polymer carriers frequently used in the device coatings typically
retain approximately 30% of the beneficial agent in the coating
indefinitely. Since these beneficial agents are frequently highly
cytotoxic, sub-acute and chronic problems such as chronic
inflammation, late thrombosis, and late or incomplete healing of
the vessel wall may occur. Additionally, the carrier polymers
themselves are often highly inflammatory to the tissue of the
vessel wall. On the other hand, use of bio-degradable polymer
carriers on stent surfaces can result in the creation of "virtual
spaces" or voids between the stent and tissue of the vessel wall
after the polymer carrier has degraded, which permits differential
motion between the stent and adjacent tissue. Resulting problems
include micro-abrasion and inflammation, stent drift, and failure
to re-endothelialize the vessel wall.
[0015] Another significant problem is that expansion of the stent
may stress the overlying polymeric coating causing the coating to
plastically deform or even to rupture, which may therefore effect
drug release kinetics or have other untoward effects. Further,
expansion of such a coated stent in an atherosclerotic blood vessel
will place circumferential shear forces on the polymeric coating,
which may cause the coating to separate from the underlying stent
surface. Such separation may again have untoward effects including
embolization of coating fragments causing vascular obstruction.
SUMMARY OF THE INVENTION
[0016] In view of the drawbacks of the prior art, it would be
advantageous to provide a stent capable of delivering a relatively
large volume of a beneficial agent to a traumatized site in a
vessel while avoiding the numerous problems associated with surface
coatings containing beneficial agents, without increasing the
effective wall thickness of the stent, and without adversely
impacting the mechanical expansion properties of the stent.
[0017] It would further be advantageous to have such a stent, which
also significantly increases the available depth of the beneficial
agent reservoir.
[0018] It would also be advantageous to have methods of loading
various beneficial agents or combinations of beneficial agents into
these deep reservoirs, which provided control over the temporal
release kinetics of the agents.
[0019] In accordance with one aspect of the invention, a device for
the controlled release of one or more drugs comprises an
implantable stent, at least two reservoirs in the stent, and a
release system contained in each of the at least two reservoirs,
wherein the release system comprises one or more drugs for
release.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The invention will now be described in greater detail with
reference to the preferred embodiments illustrated in the
accompanying drawings, in which like elements bear like reference
numerals, and wherein:
[0021] FIG. 1 is a perspective view of a tissue supporting device
in accordance with a first preferred embodiment of the present
invention;
[0022] FIG. 2 is an enlarged side view of a portion of the device
of FIG. 1;
[0023] FIG. 3 is an enlarged side view of a tissue supporting
device in accordance with a further preferred embodiment of the
present invention;
[0024] FIG. 4 is an enlarged side view of a portion of the stent
shown in FIG. 3;
[0025] FIG. 5 is an enlarged cross section of an opening;
[0026] FIG. 6 is an enlarged cross section of an opening
illustrating beneficial agent loaded into the opening;
[0027] FIG. 7 is an enlarged cross section of an opening
illustrating a beneficial agent loaded into the opening and a thin
coating of a beneficial agent;
[0028] FIG. 8 is an enlarged cross section of an opening
illustrating a beneficial agent loaded into the opening and thin
coatings of different beneficial agents on different surfaces of
the device;
[0029] FIG. 9 is an enlarged cross section of an opening
illustrating a beneficial agent provided in a plurality of
layers;
[0030] FIG. 10 is an enlarged cross section of an opening
illustrating a beneficial agent and a barrier layer loaded into the
opening in layers;
[0031] FIG. 11A is an enlarged cross section of an opening
illustrating a beneficial agent, a biodegradable carrier, and a
barrier layer loaded into the opening in layers;
[0032] FIG. 11B is a graph of the release kinetics of the device of
FIG. 11A;
[0033] FIG. 12 is an enlarged cross section of an opening
illustrating different beneficial agents, carrier, and barrier
layers loaded into the opening;
[0034] FIG. 13 is an enlarged cross section of an opening
illustrating a beneficial agent loaded into the opening in layers
of different concentrations;
[0035] FIG. 14 is an enlarged cross section of an opening
illustrating a beneficial agent loaded into the opening in layers
of microspheres of different sizes;
[0036] FIG. 15A is an enlarged cross section of a tapered opening
illustrating a beneficial agent loaded into the opening;
[0037] FIG. 15B is an enlarged cross section of the tapered opening
of FIG. 15A with the beneficial agent partially degraded;
[0038] FIG. 15C is a graph of the release kinetics of the device of
FIGS. 15A and 15B;
[0039] FIG. 16A is an enlarged cross section of an opening
illustrating a beneficial agent loaded into the opening in a shape
configured to achieve a desired agent delivery profile;
[0040] FIG. 16B is an enlarged cross section of the opening of FIG.
16A with the beneficial agent partially degraded;
[0041] FIG. 16C is a graph of the release kinetics of the device of
FIGS. 16A and 16B;
[0042] FIG. 17A is an enlarged cross section of an opening
illustrating the beneficial agent loaded into the opening and a
spherical shape;
[0043] FIG. 17B is a graph of the release kinetics of the device of
FIG. 17A;
[0044] FIG. 18A is an enlarged cross section of an opening
illustrating a plurality of beneficial agent layers and a barrier
layer with an opening for achieving a desired agent delivery
profile;
[0045] FIG. 18B is an enlarged cross section of the opening of FIG.
18A with the agent layers beginning to degraded;
[0046] FIG. 18C is an enlarged cross section of the opening of FIG.
18A with the agent layers further degraded;
[0047] FIG. 19 is an enlarged cross section of an opening
illustrating a plurality of cylindrical beneficial agent
layers;
[0048] FIG. 20 is an isometric view of an expandable tissue
supporting device with different beneficial agents in different
holes;
[0049] FIG. 21 is an isometric view of an expandable tissue
supporting device with different beneficial agents in alternating
holes; and
[0050] FIG. 22 is an enlarged side view of a portion of an
expandable tissue supporting device with beneficial agent openings
in the bridging elements.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0051] Referring to FIGS. 1 and 2, a tissue supporting device in
accordance with one preferred embodiment of the present invention
is shown generally by reference numeral 10. The tissue supporting
device 10 includes a plurality of cylindrical tubes 12 connected by
S-shaped bridging elements 14. The bridging elements 14 allow the
tissue supporting device to bend axially when passing through the
tortuous path of the vasculature to the deployment site and allow
the device to bend when necessary to match the curvature of a
vessel wall to be supported. Each of the cylindrical tubes 12 has a
plurality of axial slots 16 extending from an end surface of the
cylindrical tube toward an opposite end surface.
[0052] Formed between the slots 16 is a network of axial struts 18
and links 22. The struts 18 and links 22 are provided with openings
for receiving and delivering a beneficial agent. As will be
described below with respect to FIGS. 9-17, the beneficial agent is
loaded into the openings in layers or other configurations which
provide control over the temporal release kinetics of the
agent.
[0053] Each individual strut 18 is preferably linked to the rest of
the structure through a pair of reduced sections 20, one at each
end, which act as stress/strain concentration features. The reduced
sections 20 of the struts function as hinges in the cylindrical
structure. Since the stress/strain concentration features are
designed to operate into the plastic deformation range of generally
ductile materials, they are referred to as ductile hinges 20. The
ductile hinges 20 are described in further detail in U.S. Pat. No.
6,241,762, which has been incorporated herein by reference.
[0054] With reference to the drawings and the discussion, the width
of any feature is defined as its dimension in the circumferential
direction of the cylinder. The length of any feature is defined as
its dimension in the axial direction of the cylinder. The thickness
of any feature is defined as the wall thickness of the
cylinder.
[0055] The presence of the ductile hinges 20 allows all of the
remaining features in the tissue supporting device to be increased
in width or the circumferentially oriented component of their
respective rectangular moments of inertia--thus greatly increasing
the strength and rigidity of these features. The net result is that
elastic, and then plastic deformation commence and propagate in the
ductile hinges 20 before other structural elements of the device
undergo any significant elastic deformation. The force required to
expand the tissue supporting device 10 becomes a function of the
geometry of the ductile hinges 20, rather than the device structure
as a whole, and arbitrarily small expansion forces can be specified
by changing hinge geometry for virtually any material wall
thickness. The ability to increase the width and thickness of the
struts 18 and links 22 provides additional area and depth for the
beneficial agent receiving openings.
[0056] In the embodiment of FIGS. 1 and 2, it is desirable to
increase the width of the individual struts 18 between the ductile
hinges 20 to the maximum width that is geometrically possible for a
given diameter and a given number of struts arrayed around that
diameter. The only geometric limitation on strut width is the
minimum practical width of the slots 16 which is about 0.002 inches
(0.0508 mm) for laser machining. Lateral stiffness of the struts 18
increases as the cube of strut width, so that relatively small
increases in strut width significantly increase strut stiffness.
The net result of inserting ductile hinges 20 and increasing strut
width is that the struts 18 no longer act as flexible leaf springs,
but act as essentially rigid beams between the ductile hinges. All
radial expansion or compression of the cylindrical tissue
supporting device 10 is accommodated by mechanical strain in the
hinge features 20, and yield in the hinge commences at very small
overall radial expansion or compression.
[0057] The ductile hinge 20 illustrated in FIGS. 1 and 2 is
exemplary of a preferred structure that will function as a
stress/strain concentrator. Many other stress/strain concentrator
configurations may also be used as the ductile hinges in the
present invention, as shown and described by way of example in U.S.
Pat. No. 6,241,762. The geometric details of the stress/strain
concentration features or ductile hinges 20 can be varied greatly
to tailor the exact mechanical expansion properties to those
required in a specific application.
[0058] Although a tissue supporting device configuration has been
illustrated in FIG. 1 which includes ductile hinges, it should be
understood that the beneficial agent may be contained in openings
in stents having a variety of designs including the designs
illustrated in U.S. Provisional Patent Application Ser. No.
60/314,360, filed on Aug. 20, 2001 and U.S. patent application Ser.
No. 09/948,987, filed on Sep. 7, 2001 (Attorney Docket No.
032304-033), which are incorporated herein by reference. The
present invention incorporating beneficial agent openings may also
be used with other known stent designs.
[0059] As shown in FIGS. 1-4, at least one and more preferably a
series of openings 24 are formed by laser drilling or any other
means known to one skilled in the art at intervals along the
neutral axis of the struts 18. Similarly, at least one and
preferably a series of openings 26 are formed at selected locations
in the links 22. Although the use of openings 24 and 26 in both the
struts 18 and links 22 is preferred, it should be clear to one
skilled in the art that openings could be formed in only one of the
struts and links. Openings may also be formed in the bridging
elements 14. In the embodiment of FIGS. 1 and 2, the openings 24,
26 are circular in nature and form cylindrical holes extending
through the width of the tissue supporting device 10. It should be
apparent to one skilled in the art, however, that openings of any
geometrical shape or configuration could of course be used without
departing from the scope of the present invention. In addition,
openings having a depth less than the thickness of the device may
also be used.
[0060] The behavior of the struts 18 in bending is analogous to the
behavior of an I-beam or truss. The outer edge elements 32 of the
struts 18, shown in FIG. 2, correspond to the I-beam flange and
carry the tensile and compressive stresses, whereas the inner
elements 34 of the struts 18 correspond to the web of an I-beam
which carries the shear and helps to prevent buckling and wrinkling
of the faces. Since most of the bending load is carried by the
outer edge elements 32 of the struts 18, a concentration of as much
material as possible away from the neutral axis results in the most
efficient sections for resisting strut flexure. As a result,
material can be judiciously removed along the axis of the strut so
as to form openings 24, 26 without adversely impacting the strength
and rigidity of the strut. Since the struts 18 and links 22 thus
formed remain essentially rigid during stent expansion, the
openings 24, 26 are also non-deforming.
[0061] The openings 24, 26 in the struts 18 may promote the healing
of the intervention site by promoting regrowth of the endothelial
cells. By providing the openings 24, 26 in the struts, 18, the
cross section of the strut is effectively reduced without
decreasing the strength and integrity of the strut, as described
above. As a result, the overall distance across which endothelial
cell regrowth must occur is also reduced to approximately
0.0025-0.0035 inches, which is approximately one-half of the
thickness of a conventional stent. It is further believed that
during insertion of the expandable medical device, cells from the
endothelial layer may be scraped from the inner wall of the vessel
by the openings 24, 26 and remain therein after implantation. The
presence of such endothelial cells would thus provide a basis for
the healing of the vessel wall.
[0062] The openings 24, 26 are loaded with an agent, most
preferably a beneficial agent, for delivery to the vessel wall
which the tissue supporting device 10 is supporting.
[0063] The terms "agent" and "beneficial agent" as used herein are
intended to have their broadest possible interpretation and are
used to include any therapeutic agent or drug, as well as inactive
agents such as barrier layers or carrier layers. The terms "drug"
and "therapeutic agent" are used interchangeably to refer to any
therapeutically active substance that is delivered to a bodily
conduit of a living being to produce a desired, usually beneficial,
effect. The present invention is particularly well suited for the
delivery of antiproliferatives (anti-restenosis agents) such as
paclitaxel and rapamycin for example, and antithrombins such as
heparin, for example.
[0064] Additional uses, however, include therapeutic agents in all
the major therapeutic areas including, but not limited to:
anti-infectives such as antibiotics and antiviral agents;
analgesics, including fentanyl, sufentanil, buprenorphine and
analgesic combinations; anesthetics; anorexics; antiarthritics;
antiasthmatic agents such as terbutaline; anticonvulsants;
antidepressants; antidiabetic agents; antidiarrheals;
antihistamines; anti-inflammatory agents; antimigraine
preparations; antimotion sickness preparations such as scopolamine
and ondansetron; antinauseants; antineoplastics; antiparkinsonism
drugs; antipruritics; antipsychotics; antipyretics; antispasmodics,
including gastrointestinal and urinary; anticholinergics;
sympathomimetrics; xanthine derivatives; cardiovascular
preparations, including calcium channel blockers such as
nifedipine; beta blockers; beta-agonists such as dobutamine and
ritodrine; antiarrythmics; antihypertensives such as atenolol; ACE
inhibitors such as ranitidine; diuretics; vasodilators, including
general, coronary, peripheral, and cerebral; central nervous system
stimulants; cough and cold preparations; decongestants;
diagnostics; hormones such as parathyroid hormone; hypnotics;
immunosuppressants; muscle relaxants; parasympatholytics;
parasympathomimetrics; prostaglandins; proteins; peptides;
psychostimulants; sedatives; and tranquilizers.
[0065] The beneficial agents used in the present invention include
classical small molecular weight therapeutic agents commonly
referred to as drugs including all classes of action as exemplified
by, but not limited to: antiproliferatives, antithrombins,
antiplatelet, antilipid, anti-inflammatory, angiogenic,
anti-angiogenic, vitamins, ACE inhibitors, vasoactive substances,
antimitotics, metello-proteinase inhibitors, NO donors, estradiols,
anti-sclerosing agents, alone or in combination. Beneficial agent
also includes larger molecular weight substances with drug like
effects on target tissue sometimes called biologic agents including
but not limited to: peptides, lipids, protein drugs, enzymes,
oligonucleotides, ribozymes, genetic material, prions, virus,
bacteria, and eucaryotic cells such as endothelial cells,
monocyte/macrophages or vascular smooth muscle cells to name but a
few examples. The therapeutic agent may also be a pro-drug, which
metabolizes into the desired drug when administered to a host.
Other beneficial agents may include but not be limited to physical
agents such as microcapsules, microspheres, microbubbles,
liposomes, niosomes, radioactive isotopes, emulsions, dispersions,
or agents activated by some other form of energy such as light or
ultrasonic energy, or by other circulating molecules that can be
systemically administered.
[0066] The embodiment of the invention shown in FIGS. 1 and 2 can
be further refined by using Finite Element Analysis and other
techniques to optimize the deployment of the beneficial agent
within the openings of the struts and links. Basically, the shape
and location of the openings 24, 26 can be modified to maximize the
volume of the voids while preserving the relatively high strength
and rigidity of the struts 18 with respect to the ductile hinges
20.
[0067] FIG. 3 illustrates a further preferred embodiment of the
present invention, wherein like reference numerals have been used
to indicate like components. The tissue supporting device 100
includes a plurality of cylindrical tubes 12 connected by S-shaped
bridging elements 14. Each of the cylindrical tubes 12 has a
plurality of axial slots 16 extending from an end surface of the
cylindrical tube toward an opposite end surface. Formed between the
slots 16 is a network of axial struts 18 and links 22. Each
individual strut 18 is linked to the rest of the structure through
a pair of ductile hinges 20, one at each end, which act as
stress/strain concentration features. Each of the ductile hinges 20
is formed between an arc surface 28 and a concave notch surface
29.
[0068] At intervals along the neutral axis of the struts 18, at
least one and more preferably a series of openings 24' are formed
by laser drilling or any other means known to one skilled in the
art. Similarly, at least one and preferably a series of openings
26' are formed at selected locations in the links 22. Although the
use of openings 24', 26' in both the struts 18 and links 22 is
preferred, it should be clear to one skilled in the art that
openings could be formed in only one of the struts and links. In
the illustrated embodiment, the openings 24' in the struts 18 are
generally rectangular whereas the openings 26' in the links 22 are
polygonal. It should be apparent to one skilled in the art,
however, that openings of any geometrical shape or configuration
could of course be used, and that the shape of openings 24, 24' may
be the same or different from the shape of openings 26, 26',
without departing from the scope of the present invention. As
described in detail above, the openings 24', 26' may be loaded with
an agent, most preferably a beneficial agent, for delivery to the
vessel in which the tissue support device 100 is deployed. Although
the openings 24', 26' are preferably through openings, they may
also be recesses extending only partially through the thickness of
the struts and links.
[0069] The relatively large, protected openings 24, 24', 26, 26',
as described above, make the expandable medical device of the
present invention particularly suitable for delivering agents
having more esoteric larger molecules or genetic or cellular
agents, such as, for example, protein drugs, enzymes, antibodies,
antisense oligonucleotides, ribozymes, gene/vector constructs, and
cells (including but not limited to cultures of a patient's own
endothelial cells). Many of these types of agents are biodegradable
or fragile, have a very short or no shelf life, must be prepared at
the time of use, or cannot be pre-loaded into delivery devices such
as stents during the manufacture thereof for some other reason. The
large through-openings in the expandable device of the present
invention form protected areas or receptors to facilitate the
loading of such an agent either at the time of use or prior to use,
and to protect the agent from abrasion and extrusion during
delivery and implantation.
[0070] The volume of beneficial agent that can be delivered using
through openings is about 3 to 10 times greater than the volume of
a 5 micron coating covering a stent with the same stent/vessel wall
coverage ratio. This much larger beneficial agent capacity provides
several advantages. The larger capacity can be used to deliver
multi-drug combinations, each with independent release profiles,
for improved efficacy. Also, larger capacity can be used to provide
larger quantities of less aggressive drugs and to achieve clinical
efficacy without the undesirable side-effects of more potent drugs,
such as retarded healing of the endothelial layer.
[0071] Through openings also decrease the surface area of the
beneficial agent bearing compounds to which the vessel wall surface
is exposed. For typical devices with beneficial agent openings,
this exposure decreases by a factors ranging from about 6:1 to 8:1,
by comparison with surface coated stents. This dramatically reduces
the exposure of vessel wall tissue to polymer carriers and other
agents that can cause inflammation, while simultaneously increasing
the quantity of beneficial agent delivered, and improving control
of release kinetics.
[0072] FIG. 4 shows an enlarged view of one of the struts 18 of
device 100 disposed between a pair of ductile hinges 20 having a
plurality of openings 24'. FIG. 5 illustrates a cross section of
one of the openings 24' shown in FIG. 4. FIG. 6 illustrates the
same cross section when a beneficial agent 36 has been loaded into
the opening 24' of the strut 18. Optionally, after loading the
opening 24' and/or the opening 26' with a beneficial agent 36, the
entire exterior surface of the stent can be coated with a thin
layer of a beneficial agent 38, which may be the same as or
different from the beneficial agent 36, as schematically shown in
FIG. 7. Still further, another variation of the present invention
would coat the outwardly facing surfaces of the stent with a first
beneficial agent 38 while coating the inwardly facing surfaces of
the stent with a different beneficial agent 39, as illustrated in
FIG. 8. The inwardly facing surface of the stent would be defined
as at least the surface of the stent which, after expansion, forms
the inner passage of the vessel. The outwardly facing surface of
the stent would be defined as at least the surface of the stent
which, after expansion, is in contact with and directly supports
the inner wall of the vessel. The beneficial agent 39 coated on the
inner surfaces may be a barrier layer which prevents the beneficial
agent 36 from passing into the lumen of the blood vessel and being
washed away in the blood stream.
[0073] FIG. 9 shows a cross section of an opening 24 in which one
or more beneficial agents have been loaded into the opening 24 in
discrete layers 50. One method of creating such layers is to
deliver a solution comprising beneficial agent, polymer carrier,
and a solvent into the opening and evaporating the solvent to
create a thin solid layer of beneficial agent in the carrier. Other
methods of delivering the beneficial agent can also be used to
create layers. According to another method for creating layers, a
beneficial agent may be loaded into the openings alone if the agent
is structurally viable without the need for a carrier. The process
can then be repeated until each opening is partially or entirely
filled.
[0074] In a typical embodiment, the total depth of the opening 24
is about 125 to about 140 microns, and the typical layer thickness
would be about 2 to about 50 microns, preferably about 12 microns.
Each typical layer is thus individually about twice as thick as the
typical coating applied to surface-coated stents. There would be at
least two and preferably about ten to twelve such layers in a
typical opening, with a total beneficial agent thickness about 25
to 28 times greater than a typical surface coating. According to
one preferred embodiment of the present invention, the openings
have an area of at least 5.times.10.sup.-6 square inches, and
preferably at least 7.times.10.sup.-6 square inches.
[0075] Since each layer is created independently, individual
chemical compositions and pharmacokinetic properties can be
imparted to each layer. Numerous useful arrangements of such layers
can be formed, some of which will be described below. Each of the
layers may include one or more agents in the same or different
proportions from layer to layer. The layers may be solid, porous,
or filled with other drugs or excipients.
[0076] FIG. 9 shows the simplest arrangement of layers including
identical layers 50 that together form a uniform, homogeneous
distribution of beneficial agent. If the carrier polymer were
comprised of a biodegradable material, then erosion of the
beneficial agent containing carrier would occur on both faces of
the opening at the same time, and beneficial agent would be
released at an approximately linear rate over time corresponding to
the erosion rate of the carrier. This linear or constant release
rate is referred to as a zero order delivery profile. Use of
biodegradable carriers in combination with through openings is
especially useful, to guarantee 100% discharge of the beneficial
agent within a desired time without creating virtual spaces or
voids between the radially outermost surface of the stent and
tissue of the vessel wall. When the biodegradable material in the
through openings is removed, the openings may provide a
communication between the strut-covered vessel wall and the blood
stream. Such communication may accelerate vessel healing and allow
the ingrowth of cells and extracellular components that more
thoroughly lock the stent in contact with the vessel wall.
Alternatively, some through-openings may be loaded with beneficial
agent while others are left unloaded. The unloaded holes could
provide an immediate nidus for the ingrowth of cells and
extracellular components to lock the stent into place, while loaded
openings dispense the beneficial agent.
[0077] The advantage of complete erosion using the through openings
over surface coated stents opens up new possibilities for
stent-based therapies. In the treatment of cardiac arrhythmias,
such as atrial fibrillation both sustained and paroxysmal,
sustained ventricular tachycardia, super ventricular tachycardia
including reentrant and ectopic, and sinus tachycardia, a number of
techniques under development attempt to ablate tissue in the
pulmonary veins or some other critical location using various
energy sources, e.g. microwaves, generally referred to as
radio-frequency ablation, to create a barrier to the propagation of
undesired electrical signals in the form of scar tissue. These
techniques have proven difficult to control accurately. A stent
based therapy using through openings, biodegradable carriers, and
associated techniques described herein could be used to deliver a
chemically ablative agent in a specific, precise pattern to a
specific area for treatment of atrial fibrillation, while
guaranteeing that none of the inherently cytotoxic ablating agent
could be permanently trapped in contact with the tissue of the
vessel wall.
[0078] If, on the other hand, the goal of a particular therapy is
to provide a long term effect, beneficial agents located in
openings provide an equally dramatic advantage over surface coated
devices. In this case, a composition comprising a beneficial agent
and a non-biodegradable carrier would be loaded into the through
openings, preferably in combination with a diffusion barrier layer
as described below. To continue the cardiac arrhythmias example, it
might be desirable to introduce a long-term anti-arrhythmic drug
near the ostia of the pulmonary veins or some other critical
location. The transient diffusion behavior of a beneficial agent
through a non-biodegradable carrier matrix can be generally
described by Fick's second law: 1 C x t = x [ D C x x ]
[0079] Where C is the concentration of beneficial agent at cross
section x, x is either the thickness of a surface coating or depth
of a through opening, D is the diffusion coefficient and t is time.
The solution of this partial differential equation for a through
opening with a barrier layer will have the form of a normalized
probability integral or Gaussian Error Function, the argument of
which will contain 2 x 2 Dt
[0080] the term
[0081] To compare the time intervals over which a given level of
therapy can be sustained for surface coatings vs. through openings,
we can use Fick's Second Law to compare the times required to
achieve equal concentrations at the most inward surfaces of the
coating and opening respectively, i.e. the values of x and t for
which the arguments 3 x 1 2 Dt 1 = x 2 2 Dt 2 x 1 2 x 2 2 = t 1 t
2
[0082] of the Error Function are equal:
[0083] The ratio of diffusion times to achieve comparable
concentrations thus varies as the square of the ratio of depths. A
typical opening depth is about 140 microns while a typical coating
thickness is about 5 micron; the square of this ratio is 784,
meaning that the effective duration of therapy for through openings
is potentially almost three orders of magnitude greater for through
openings than for surface coatings of the same composition. The
inherent non-linearity of such release profiles can in part be
compensated for in the case of through openings, but not in thin
surface coatings, by varying the beneficial agent concentration of
layers in a through opening as described below. It will be recalled
that, in addition to this great advantage in beneficial agent
delivery duration, through openings are capable of delivering a 3
to 10 times greater quantity of beneficial agent, providing a
decisive overall advantage in sustained therapies. The diffusion
example above illustrates the general relationship between depth
and diffusion time that is characteristic of a wider class of solid
state transport mechanisms.
[0084] Beneficial agent that is released to the radially innermost
or inwardly facing surface known as the lumen facing surface of an
expanded device may be rapidly carried away from the targeted area,
for example by the bloodstream, and thus lost. Up to half of the
total agent loaded in such situations may have no therapeutic
effect due to being carried away by the bloodstream. This is
probably the case for all surface coated stents as well as the
through opening device of FIG. 9.
[0085] FIG. 10 shows a device in which the first layer 52 is loaded
into a through opening 24 such that the inner surface of the layer
is substantially co-planar with the inwardly facing surface 54 of
the cylindrical device. The first layer 52 is comprised of a
material called a barrier material which blocks or retards
biodegradation of subsequent layers in the inwardly facing
direction toward the vessel lumen, and/or blocks or retards
diffusion of the beneficial agent in that direction. Biodegradation
of other layers or beneficial agent diffusion can then proceed only
in the direction of the outwardly facing surface 56 of the device,
which is in direct contact with the targeted tissue of the vessel
wall. The barrier layer 52 may also function to prevent hydration
of inner layers of beneficial agent and thus prevent swelling of
the inner layers when such layers are formed of hygroscopic
materials. The barrier layer 52 may further be comprised of a
biodegradable material that degrades at a much slower rate than the
biodegradable material in the other layers, so that the opening
will eventually be entirely cleared. Providing a barrier layer 52
in the most inwardly facing surface of a through-opening thus
guarantees that the entire load of beneficial agent is delivered to
the target area in the vessel wall. It should be noted that
providing a barrier layer on the inwardly facing surface of a
surface-coated stent without openings does not have the same
effect; since the beneficial agent in such a coating cannot migrate
through the metal stent to the target area on the outer surface, it
simply remains trapped on the inner diameter of the device, again
having no therapeutic effect.
[0086] Barrier layers can be used to control beneficial agent
release kinetics in more sophisticated ways. A barrier layer 52
with a pre-determined degradation time could be used to
deliberately terminate the beneficial agent therapy at a
pre-determined time, by exposing the underlying layers to more
rapid bio-degradation from both sides. Barrier layers can also be
formulated to be activated by a separate, systemically applied
agent. Such systemically applied agent could change the porosity of
the barrier layer and/or change the rate of bio-degradation of the
barrier layer or the bulk beneficial agent carrier. In each case,
release of the beneficial agent could be activated by the physician
at will by delivery of the systemically applied agent. A further
embodiment of physician activated therapy would utilize a
beneficial agent encapsulated in micro-bubbles and loaded into
device openings. Application of ultrasonic energy from an exterior
of the body could be used to collapse the bubbles at a desired
time, releasing the beneficial agent to diffuse to the outwardly
facing surface of the reservoirs. These activation techniques can
be used in conjunction with the release kinetics control techniques
described herein to achieve a desired drug release profile that can
be activated and/or terminated at selectable points in time.
[0087] FIG. 11A shows an arrangement of layers provided in a
through opening in which layers 50 of a beneficial agent in a
biodegradable carrier material, are alternated with layers 58 of
the biodegradable carrier material alone, with no active agent
loaded, and a barrier layer 52 is provided at the inwardly facing
surface. As shown in the release kinetics plot of FIG. 11B, such an
arrangement releases beneficial agent in three programmable bursts
or waves achieving a stepped or pulsatile delivery profile. The use
of carrier material layers without active agent creates the
potential for synchronization of drug release with cellular
biochemical processes for enhanced efficacy.
[0088] Alternatively, different layers could be comprised of
different beneficial agents altogether, creating the ability to
release different beneficial agents at different points in time, as
shown in FIG. 12. For example, in FIG. 12, a layer 60 of
anti-thrombotic agent could be deposited at the inwardly facing
surface of the stent, followed by a barrier layer 52 and
alternating layers of anti-proliferatives 62 and anti-inflamatories
64. This configuration could provide an initial release of
anti-thrombotic agent into the bloodstream while simultaneously
providing a gradual release of anti-proliferatives interspersed
with programmed bursts of anti-inflammatory agents to the vessel
wall. The configurations of these layers can be designed to achieve
the agent delivery bursts at particular points in time coordinated
with the body's various natural healing processes.
[0089] A further alternative is illustrated in FIG. 13. Here the
concentration of the same beneficial agent is varied from layer to
layer, creating the ability to generate release profiles of
arbitrary shape. Progressively increasing the concentration of
agent in the layers 66 with increasing distance from the outwardly
facing surface 56, for example, produces a release profile with a
progressively increasing release rate, which would be impossible to
produce in a thin surface coating.
[0090] Another general method for controlling beneficial agent
release kinetics is to alter the beneficial agent flux by changing
the surface area of drug elution sources as a function of time.
This follows from Fick's First Law, which states that the
instantaneous molecular flux is proportional to surface area, among
other factors: 4 J = D C x N t = AD c x
[0091] Where .differential.N/.differential.t is the number of
molecules per unit time, A is the instantaneous drug eluting
surface area, D is the diffusivity, and C is the concentration. The
drug eluting surface area of a surface coated stent is simply the
surface area of the stent itself. Since this area is fixed, this
method of controlling release kinetics is not available to surface
coated devices. Through openings, however, present several
possibilities for varying surface area as a function of time.
[0092] In the embodiment of FIG. 14, beneficial agent is provided
in the openings 24 in the form of microspheres, particles or the
like. Individual layers 70 can then be created that contain these
particles. Further, the particle size can be varied from layer to
layer. For a given layer volume, smaller particle sizes increase
the total particle surface area in that layer, which has the effect
of varying the total surface area of the beneficial agent from
layer to layer. Since the flux of drug molecules is proportional to
surface area, the total drug flux can be adjusted from layer to
layer by changing the particle size, and the net effect is control
of release kinetics by varying particle sizes within layers.
[0093] A second general method for varying drug eluting surface
area as a function of time is to change the shape or
cross-sectional area of the drug-bearing element along the axis of
the opening. FIG. 15A shows an opening 70 having a conical shape
cut into the material of the stent itself. The opening 70 may then
be filled with beneficial agent 72 in layers as described above or
in another manner. In this embodiment, a barrier layer 74 may be
provided on the inwardly facing side of the opening 70 to prevent
the beneficial agent 72 from passing into the blood stream. In this
example, the drug eluting surface area A.sub.t would continuously
diminish (from FIG. 15A to FIG. 15B) as the bio-degradable carrier
material erodes, yielding the elution pattern of FIG. 15C.
[0094] FIG. 16A shows a simple cylindrical through-opening 80 in
which a preformed, inverted cone 82 of beneficial agent has been
inserted. The rest of the through opening 80 is then back-filled
with a biodegradable substance 84 with a much slower rate of
degradation or a non-biodegradable substance, and the inwardly
facing opening of the through opening is sealed with a barrier
layer 86. This technique yields the opposite behavior to the
previous example. The drug-eluting surface area A.sub.t
continuously increases with time between FIGS. 16A and 16B,
yielding the elution pattern of FIG. 16C.
[0095] The changing cross section openings 70 of FIG. 15A and the
non-biodegradable backfilling techniques of FIG. 16A may be
combined with any of the layered agent embodiments of FIGS. 9-14 to
achieve desired release profiles. For example, the embodiment of
FIG. 15A may use the varying agent concentration layers of FIG. 13
to more accurately tailor a release curve to a desired profile.
[0096] The process of preforming the beneficial agent plug 82 to a
special shape, inserting in a through opening, and back-filling
with a second material can yield more complex release kinetics as
well. FIG. 17A shows a through opening 90 in which a spherical
beneficial agent plug 92 has been inserted. The resulting
biodegradation of the sphere, in which the cross sectional surface
area varies as a sinusoidal function of depth, produces a flux
density which is roughly a sinusoidal function of time, FIG. 17B.
Other results are of course possible with other profiles, but none
of these more complex behaviors could be generated in a thin,
fixed-area surface coating.
[0097] An alternative embodiment of FIGS. 18A-18C use a barrier
layer 52' with an opening 96 to achieve the increasing agent
release profile of FIG. 16C. As shown in FIG. 18A, the opening 24
is provided with an inner barrier layer 52 and multiple beneficial
agent layers 50 as in the embodiment of FIG. 10. An additional
outer barrier layer 52' is provided with a small hole 96 for
delivery of the agent to the vessel wall. As shown in FIQS. 18B and
18C, the beneficial agent containing layers 50 degrade in a
hemispherical pattern resulting in increasing surface area for
agent delivery over time and thus, an increasing agent release
profile.
[0098] FIG. 19 illustrates an alternative embodiment in which an
opening in the tissue supporting device is loaded with cylindrical
layers of beneficial agent. According to one method of forming the
device of FIG. 19, the entire device is coated with sequential
layers 100, 102, 104, 106 of beneficial agent. The interior surface
54 and exterior surface 56 of the device are then stripped to
remove the beneficial agent on these surfaces leaving the
cylindrical layers of beneficial agent in the openings. In this
embodiment, a central opening remains after the coating layers have
been deposited which allows communication between the outer surface
56 and inner surface 54 of the tissue supporting device.
[0099] In the embodiment of FIG. 19, the cylindrical layers are
eroded sequentially. This can be used for pulsatile delivery of
different beneficial agents, delivery of different concentrations
of beneficial agents, or delivery of the same agent. As shown in
FIG. 19, the ends of the cylindrical layers 100, 102, 104, 106 are
exposed. This results in a low level of erosion of the underlying
layers during erosion of an exposed layer. Alternatively, the ends
of the cylindrical layers may be covered by a barrier layer to
prevent this low level continuous erosion. Erosion rates of the
cylindrical layers may be further controlled by contouring the
surfaces of the layers. For example, a ribbed or star-shaped
pattern may be provided on the radially inner layers to provide a
uniform surface area or uniform erosion rate between the radially
inner layers and the radially outer layers. Contouring of the
surfaces of layers may also be used in other embodiments to provide
an additional variable for controlling the erosion rates.
[0100] FIG. 20 illustrates a further alternative embodiment of the
invention in which different beneficial agents are positioned in
different holes of an expandable medical device 300. A first
beneficial agent is provided in holes 330a at the ends of the
device and a second beneficial agent is provided in holes 330b at a
central portion of the device. The beneficial agent may contain
different drugs, the same drugs in different concentrations, or
different variations of the same drug. The embodiment of FIG. 20
may be used to provide an expandable medical device 300 with either
"hot ends" or "cool ends."
[0101] Preferably, each end portion of the device 300 which
includes the holes 330a containing the first beneficial agent
extends at least one hole and up to about 15 holes from the edge.
This distance corresponds to about 0.005 to about 0.1 inches from
the edge of an unexpanded device. The distance from the edge of the
device 300 which includes the first beneficial agent is preferably
about one section, where a section is defined between the bridging
elements.
[0102] Different beneficial agents containing different drugs may
be disposed in different openings in the stent. This allows the
delivery of two or more beneficial agents from a single stent in
any desired delivery pattern. Alternatively, different beneficial
agents containing the same drug in different concentrations may be
disposed in different openings. This allows the drug to be
uniformly distributed to the tissue with a non-uniform device
structure.
[0103] The two or more different beneficial agents provided in the
devices described herein may contain (1) different drugs; (2)
different concentrations of the same drug; (3) the same drug with
different release kinetics, i.e., different matrix erosion rates;
or (4) different forms of the same drug. Examples of different
beneficial agents formulated containing the same drug with
different release kinetics may use different carriers to achieve
the elution profiles of different shapes. Some examples of
different forms of the same drug include forms of a drug having
varying hydrophilicity or lipophilicity.
[0104] In one example of the device 300 of FIG. 20, the holes 330a
at the ends of the device are loaded with a first beneficial agent
comprising a drug with a high lipophilicity while holes 330b at a
central portion of the device are loaded with a second beneficial
agent comprising the drug with a lower lipophilicity. The first
high lipophilicity beneficial agent at the "hot ends" will diffuse
more readily into the surrounding tissue reducing the edge effect
restenosis.
[0105] The device 300 may have an abrupt transition line at which
the beneficial agent changes from a first agent to a second agent.
For example, all openings within 0.05 inches of the end of the
device may contain the first agent while the remaining openings
contain the second agent. Alternatively, the device may have a
gradual transition between the first agent and the second agent.
For example, a concentration of the drug in the openings can
progressively increase (or decrease) toward the ends of the device.
In another example, an amount of a first drug in the openings
increases while an amount of a second drug in the openings
decreases moving toward the ends of the device.
[0106] FIG. 21 illustrates a further alternative embodiment of an
expandable medical device 400 in which different beneficial agents
are positioned in different openings 430a, 430b in the device in an
alternating or interspersed manner. In this manner, multiple
beneficial agents can be delivered to tissue over the entire area
or a portion of the area supported by the device. This embodiment
will be useful for delivery of multiple beneficial agents where
combination of the multiple agents into a single composition for
loading in the device is not possible due to interactions or
stability problems between the beneficial agents.
[0107] In addition to the use of different beneficial agents in
different openings to achieve different drug concentrations at
different defined areas of tissue, the loading of different
beneficial agents in different openings may be used to provide a
more even spatial distribution of the beneficial agent delivered in
instances where the expandable medical device has a non-uniform
distribution of openings in the expanded configuration.
[0108] For example, in many of the known expandable devices and for
the device illustrated in FIG. 22 the coverage of the device 500 is
greater at the cylindrical tube portions 512 of the device than at
the bridging elements 514. Coverage is defined as the ratio of the
device surface area to the area of the lumen in which the device is
deployed. When a device with varying coverage is used to deliver a
beneficial agent contained in openings in the device, the
beneficial agent concentration delivered to the tissue adjacent the
cylindrical tube portions 512 is greater that the beneficial agent
delivered to the tissue adjacent the bridging elements 514. In
order to address this longitudinal variation in device structure
and other variations in device coverage which lead to uneven
beneficial agent delivery concentrations, the concentration of the
beneficial agent may be varied in the openings at portions of the
device to achieve a more even distribution of the beneficial agent
throughout the tissue. In the case of the embodiment of FIG. 22,
the openings 530a in the tube portions 512 include a beneficial
agent with a lower drug concentration than the openings 530b in the
bridging elements 514. The uniformity of agent delivery may be
achieved in a variety of manners including varying the drug
concentration, the opening diameter or shape, the amount of agent
in the opening (i.e., the percentage of the opening filed), the
matrix material, or the form of the drug.
[0109] In addition to the delivery of different beneficial agents
to the mural side of the expandable medical device for treatment of
the vessel wall, beneficial agents may be delivered to the lumenal
side of the expandable medical device. Drugs which are delivered
into the blood stream from the lumenal side of the device can be
located at a proximal end of the device or a distal end of the
device.
[0110] The methods for loading different beneficial agents into
different openings in an expandable medical device may include
known techniques such as dipping and coating and also known
piezoelectric micro-jetting techniques. Micro-injection devices may
be computer controlled to deliver precise amounts of two or more
liquid beneficial agents to precise locations on the expandable
medical device in a known manner. For example, a dual agent jetting
device may deliver two agents simultaneously or sequentially into
the openings. When the beneficial agents are loaded into through
openings in the expandable medical device, a lumenal side of the
through openings may be blocked during loading by a resilient
mandrel allowing the beneficial agents to be delivered in liquid
form, such as with a solvent. The beneficial agents may also be
loaded by manual injection devices.
[0111] Therapeutic Layer Formulations
[0112] The therapeutic agent layers of the present invention are
beneficial agents comprised of a matrix and at least one
therapeutic agent. The term "matrix" or "biocompatible matrix" are
used interchangeably to refer to a medium or material that, upon
implantation in a subject, does not elicit a detrimental response
sufficient to result in the rejection of the matrix. The matrix
typically does not provide any therapeutic responses itself, though
the matrix may contain or surround a therapeutic agent, a
therapeutic agent, an activating agent or a deactivating agent, as
defined herein. A matrix is also a medium that may simply provide
support, structural integrity or structural barriers. The matrix
may be polymeric, non-polymeric, hydrophobic, hydrophilic,
lipophilic, amphiphilic, and the like.
[0113] The matrix of the therapeutic agent layers can be made from
pharmaceutically acceptable polymers, such as those typically used
in medical devices. The term "polymer" refers to molecules formed
from the chemical union of two or more repeating units, called
monomers. Accordingly, included within the term "polymer" may be,
for example, dimers, trimers and oligomers. The polymer may be
synthetic, naturally-occurring or semisynthetic. In preferred form,
the term "polymer" refers to molecules which typically have a
M.sub.w greater than about 3000 and preferably greater than about
10,000 and a M.sub.w that is less than about 10 million, preferably
less than about a million and more preferably less than about
200,000. Examples of polymers include but are not limited to,
poly-.alpha.-hydroxy acid esters such as, polylactic acid,
polyglycolic acid, polylactic-co-glycolic acid, polylactic
acid-co-caprolactone; polyethylene glycol and polyethylene oxide;
polyvinyl pyrrolidone; polyorthoesters; polysaccharides and
polysaccharide derivatives such as polyhyaluronic acid, polyalginic
acid, chitin, chitosan, cellulose, hydroxyehtylcellulose,
hydroxypropylcellulose, carboxymethylcellulose; polypeptides, and
proteins such as polylysine, polyglutamic acid, albumin;
polyanhydrides; polyhydroxy alkonoates such as polyhydroxy
valerate, polyhydroxy butyrate, and the like, and copolymers
thereof. The polymers and copolymers can be prepared by methods
well known in the art (see, for example, Rempp and Merril: Polymer
Synthesis, 1998, John Wiley and Sons) in or can be used as
purchased from Alkermes, in Cambridge, Mass. or Birmingham Polymer
Inc., in Birmingham, Ala.
[0114] The preferred co-polymer for use in the present invention
are poly(lactide-co-glycolide) (PLGA) polymers. The rate at which
the polymer erodes is determined by the selection of the ratio of
lactide to glycolide within the copolymer, the molecular weight of
each polymer used, and the crystallinity of the polymers used.
[0115] Bioerodible polymers may also be used to form barrier layers
that erode at a rate that can be predetermined base on the
composition and that contain no therapeutic agent.
[0116] Additives in Protective, Barrier, or Therapeutic Layer
Formulations
[0117] Typical additives that may be included in a bioerodible
matrix are well known to those skilled in the art (see Remington:
The Science and Practice of Pharmacy, Gennaro, ed., Mack Publishing
Co., Easton, Pa., 19th ed., 1995) and include but are not limited
to pharmaceutically acceptable excipients, adjuvants, carriers,
antioxidants, preservatives, buffers, antacids, emulsifiers, inert
fillers, fragrances, thickeners, tackifiers, opacifiers, gelling
agents, stabilizers, surfactants, emolliehts, coloring agents, and
the like.
[0118] Typical formulations for therapeutic agents incorporated in
these medical devices are well known to those skilled in the art
and include but are not limited to solid particle dispersions,
encapsulated agent dispersions, and emulsions, suspensions,
liposomes or microparticles, wherein said liposome or microparticle
comprise a homogeneous or heterogeneous mixture of the therapeutic
agent.
[0119] The term "homogeneously disposed" refers to a component
which is mixed uniformly in a matrix in such a manner that the
component is macroscopically indistinguishable from the matrix
itself. An example of a homogeneously disposed component is a drug
formulation such as a microemulsion in which small beads of oil are
dispersed uniformly in water.
[0120] The term "heterogeneously disposed" refers to a component
which is mixed non-uniformly into a matrix in such a manner that
the component is macroscopically distinguishable from the matrix
itself. An example of a heterogeneously disposed component is a
simple emulsion in which the beads of oil in the water are large
enough to cause a turbidity to the solution and can be seen
settling out of solution over time. Heterogeneously disposed
compositions also include encapsulated formulations where a
component, such as a protective layer, is layered onto or around a
therapeutic agent or a therapeutic layer, forming a protective
shell.
[0121] The amount of the drug that is present in the device, and
that is required to achieve a therapeutic effect, depends on many
factors, such as the minimum necessary dosage of the particular
drug, the condition to be treated, the chosen location of the
inserted device, the actual compound administered, the age, weight,
and response of the individual patient, the severity of the
patient's symptoms, and the like.
[0122] The appropriate dosage level of the therapeutic agent, for
more traditional routes of administration, are known to one skilled
in the art. These conventional dosage levels correspond to the
upper range of dosage levels for compositions, including a
physiologically active substance and traditional penetration
enhancer. However, because the delivery of the active substance
occurs at the site where the drug is required, dosage levels
significantly lower than a conventional dosage level may be used
with success. Ultimately, the percentage of therapeutic agent in
the composition is determined by the required effective dosage, the
therapeutic activity of the particular formulation, and the desired
release profile. In general, the active substance will be present
in the composition in an amount from about 0.0001% to about 99%,
more preferably about 0.01% to about 80% by weight of the total
composition depending upon the particular substance employed.
However, generally the amount will range from about 0.01% to about
75% by weight of the total composition, with levels of from about
25% to about 75% being preferred.
[0123] Protective and Barrier Layer Formulations
[0124] The protective and barrier layers of the present invention
are beneficial agents comprised of a bioerodible matrix and
optionally contain additional additives, therapeutic agents,
activating agents, deactivating agents, and the like. Either a
property of the chosen material of the protective or barrier layer,
or a chemical embedded in the protective or barrier layer provides
protection from deactivating processes or conditions for at least
one therapeutic agent. In addition to the polymer materials
described above, the protective or barrier layer may also be
comprised of pharmaceutically acceptable lipids or lipid
derivatives, which are well known in the art and include but are
not limited to fatty acids, fatty acid esters, lysolipids,
phosphocholines, (Avanti Polar Lipids, Alabaster, Ala.), including
1-alkyl-2-acetoyl-sn-gl- ycero 3-phosphocholines, and
1-alkyl-2-hydroxy-sn-glycero 3-phosphocholines; phosphatidylcholine
with both saturated and unsaturated lipids, including
dioleoylphosphatidylcholine; dimyristoyl-phosphatidylcholine;
dipentadecanoylphosphatidylcholine; dilauroylphosphatidyl-choline;
dipalmitoylphosphatidylcholine (DPPC);
distearoylphosphatidylcholine (DSPC); and
diarachidonylphosphatidylcholin- e (DAPC);
phosphatidyl-ethanolamines, such as dioleoylphosphatidylethanola-
mine, dipahnitoyl-phosphatidylethanolamine (DPPE) and
distearoylphosphatidylefhanolamine (D SPE); phosphatidylserine;
phosphatidylglycerols, including distearoylphosphatidylglycerol
(DSPG); phosphatidylinositol; sphingolipids such as sphingomyelin;
glucolipids; sulfatides; glycosphingolipids; phosphatidic acids,
such as dipahmitoylphosphatidic acid (DPPA) and
distearoylphosphatidic acid (DSPA); palmitic acid; stearic acid;
arachidonic acid; oleic acid; lipids bearing polymers, such as
chitin, hyaluronic acid, polyvinylpyrrolidone or polyethylene
glycol (PEG), also referred to herein as "pegylated lipids", with
preferred lipids bearing polymers including DPPE-PEG (DPPE-PEG),
which refers to the lipid DPPE having a PEG polymer attached
thereto, including, for example, DPPE-PEG5000, which refers to DPPE
having attached thereto a PEG polymer having a mean average
molecular weight of about 5000; lipids bearing sulfonated mono-,
di-, oligo- or polysaccharides; cholesterol, cholesterol sulfate
and cholesterol hemisuccinate; tocopherol hemisuccinate; lipids
with ether and ester-linked fatty acids; polymerized lipids (a wide
variety of which are well known in the art); diacetyl phosphate;
dicetyl phosphate; stearylamine; cardiolipin; phospholipids with
short chain fatty acids of about 6 to about 8 carbons in length;
synthetic phospholipids with asymmetric acyl chains, such as, for
example, one acyl chain of about 6 carbons and another acyl chain
of about 12 carbons; ceramides; non-ionic liposomes including
niosomes such as polyoxyethylene fatty acid esters, polyoxyethylene
fatty alcohols, polyoxyethylene fatty alcohol ethers,
polyoxyethylated sorbitan fatty acid esters, glycerol polyethylene
glycol oxystearate, glycerol polyethylene glycol ricinoleate,
ethoxylated soybean sterols, ethoxylated castor oil,
polyoxyethylene-polyoxypropylene polymers, and polyoxyethylene
fatty acid stearates; sterol aliphatic acid esters including
cholesterol sulfate, cholesterol butyrate, cholesterol
iso-butyrate, cholesterol palmitate, cholesterol stearate,
lanosterol acetate, ergosterol palmitate, and phytosterol
n-butyrate; sterol esters of sugar acids including cholesterol
glucuronide, lanosterol glucuronide, 7-dehydrocholesterol
glucuronide, ergosterol glucuronide, cholesterol gluconate,
lanosterol gluconate, and ergosterol gluconate; esters of sugar
acids and alcohols including lauryl glucuronide, stearoyl
glucuronide, myristoyl glucuronide, lauryl gluconate, myristoyl
gluconate, and stearoyl gluconate; esters of sugars and aliphatic
acids including sucrose acetate isobutyrate (SAIB), sucrose
laurate, fructose laurate, sucrose palritate, sucrose stearate,
glucuronic acid, gluconic acid and polyuronic acid; saponins
including sarsasapogenin, smilagenin, hederagenin, oleanolic acid,
and digitoxigenin; glycerol dilaurate, glycerol trilaurate,
glycerol monolaurate, glycerol dipalmitate, glycerol and glycerol
esters including glycerol tripalmitate, glycerol monopalmitate,
glycerol distearate, glycerol tristearate, glycerol monostearate,
glycerol monomyristate, glycerol dimyristate, glycerol
trimyristate; long chain alcohols including n-decyl alcohol, lauryl
alcohol, myristyl alcohol, cetyl alcohol, and n-octadecyl alcohol;
1,2-dioleoyl-sn-glycerol; 1,2-dipalmitoyl-sn-3-succinylglycerol;
1,3-dipalmitoyl-2-succinylglycerol;
1-hexadecyl-2-palmitoylglycerophospho- ethanolamine and
palmitoylhomocysteine, and/or combinations thereof.
[0125] If desired, a cationic lipid may be used, such as, for
example, N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium
chloride (DOTMA), 1,2-dioleoyloxy-3-(trimethylammonio)propane
(DOTAP); and
1,2-dioleoyl-3-(4'-trimethylammonio)butanoyl-sn-glycerol (DOTB). If
a cationic lipid is employed in the lipid compositions, the molar
ratio of cationic lipid to non-cationic lipid may be, for example,
from about 1:1000 to about 1:100. Preferably, the molar ratio of
cationic lipid to non-cationic lipid may be from about 1:2 to about
1:10, with a ratio of from about 1:1 to about 1:2.5 being
preferred. Even more preferably, the molar ratio of cationic lipid
to non-cationic lipid may be about 1:1.
[0126] These lipid materials are well known in the art and can be
used as purchased from Avanti, Burnaby, B.C. Canada.
[0127] The preferred lipids for use in the present invention are
phosphatidyl-choline, phosphatidylethanolamine, phosphatidylserine,
sphingomyelin as well as synthetic phospholipids such as
dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine,
distearoyl phosphatidylcholine, distearoyl phosphatidyl-glycerol,
dipalmitoyl phosphatidylglycerol, dimyristoyl phosphatidylserine,
distearoyl phosphatidylserine and dipalmitoyl
phosphatidylserine.
[0128] The rate at which the bioerodible matrix erodes is
determined by the choice of lipid, the molecular weight, and the
ratio of the chosen materials.
[0129] The protective or barrier layer can erode by either chemical
or physical erosion mechanisms. If the layer erodes by a physical
mechanism, the layer is typically a thin film from about 0.1 .mu.m
to about 3 .mu.m of a non-polymeric material embedded between two
polymeric layers. In this instance, the structural integrity of the
protective or barrier layer is maintained by the presence of both
of these polymeric layers. When the polymeric material closest to
the luminal surface erodes away, the protective or barrier layer
breaks apart by the physical forces exerted on it from the
remaining polymeric layer. In another embodiment, the protective or
barrier layer is eroded by chemical interactions, dissolution in
water, hydrolysis, or reaction with enzymes.
[0130] One function of the protective or barrier layer is to
protect one or more therapeutic agents from deactivating or
degrading conditions. The protection may come from the properties
of the material when, for example, a hydrophobic protective or
barrier layer would protect a water sensitive agent from water by
resisting the influx of moisture. The protective or barrier layer
may also act as a physical barrier. For example, a protective or
barrier layer comprised of a hydrogel may allow water to be
absorbed by the gel, and allow any agents contained within the gel
to diffuse out of the gel into the reaction environment. The
hydrogel, however, would prevent enzymes from penetrating the
layer, thereby protecting any agents contained within from the
enzyme. The term "hydrogel" refers to cross-linked polymeric
material in which the liquid component is water. Hydrogels may be
prepared by cross-linking certain polymers and lipids disclosed
herein.
[0131] Finally the protective or barrier layer does not have to act
as a barrier. The protective or barrier layer may protect a
therapeutic agent by releasing an agent, such as an activating
agent or a deactivating agent, into the reaction environment prior
to the release of the therapeutic agent.
[0132] A therapeutic agent may be incorporated directly in the
protective or barrier layer. The therapeutic agent can be
heterogeneously or homogeneously dispersed in the protective or
barrier layer. The therapeutic agent can be a drug, or a drug
formulated into a microcapsule, niosome, liposome, microbubble,
microsphere, or the like. In addition, the protective or barrier
layer may contain more than one therapeutic agent. For example, a
water sensitive drugs, such as a limus, or any other drug that must
be administered through intravenous, intramuscular, or
subcutaneously, could be incorporated in a hydrophobic matrix such
as SAIB, or fatty acid ester.
[0133] A therapeutic agent may also be disposed in a therapeutic
agent layer, separate from the protective or barrier layer. In this
case the protective or barrier layer may be adjacent to the
therapeutic agent layer and may serve to prevent or retard
processes that would degrade or deactivate the therapeutic agent
until the protective or barrier layer has substantially eroded. In
this instance the protective or barrier layer is a barrier between
a therapeutic layer and the reaction environment. This barrier may
be a hydrophobic barrier that resists water absorption. The
hydrophobic barrier would be used in conjunction with
water-sensitive drugs as described above. Alternatively, the
protective or barrier layer maybe a hydrogel that resists the
absorbance of enzymes. An enzyme resistant barrier would used to
protect an drug such as a DNA, RNA, peptide or protein based
therapeutic agent.
[0134] The protective or barrier layer may optionally include
activating and deactivating agents for the purpose of preparing the
reaction environment for the subsequent release of a therapeutic
agent. These activating and deactivating agents are well known to
those skilled in the art and include but are not limited to
antacids, buffers, enzyme inhibitors, hydrophobic additives, and
adjuvants. For example, Mg(OH).sub.2 in particles of about 0.5
.mu.m to about 5 .mu.m more preferably, about 1 .mu.m incorporated
in a PLGA polymer layer could be used in conjunction with any acid
senstive drug. An example of an activating agent is chymotrypsin,
which may be incorporated in polyvinyl pyrrolidone layer. The
chymotrypsin, could be used to convert a pro-drug to an active
drug.
[0135] While the invention has been described in detail with
reference to the preferred embodiments thereof, it will be apparent
to one skilled in the art that various changes and modifications
can be made and equivalents employed, without departing from the
present invention.
* * * * *