U.S. patent application number 11/009657 was filed with the patent office on 2005-06-16 for apparatus and methods for controlled substance delivery from implanted prostheses.
This patent application is currently assigned to Avantec Vascular Corporation. Invention is credited to Sirhan, Motasim, Yan, John.
Application Number | 20050131532 11/009657 |
Document ID | / |
Family ID | 26670600 |
Filed Date | 2005-06-16 |
United States Patent
Application |
20050131532 |
Kind Code |
A1 |
Sirhan, Motasim ; et
al. |
June 16, 2005 |
Apparatus and methods for controlled substance delivery from
implanted prostheses
Abstract
The present invention provides improved stents and other
prostheses for delivering substances to vascular and other luminal
and intracorporeal environments. In particular, the present
invention provides luminal prostheses which allow for a programmed
and controlled substance delivery protocols for a variety of
purposes. The prostheses comprise a scaffold which is implantable
within a body lumen and a substance reservoir present over at least
a portion of the scaffold. Usually, a rate-controlling element will
be formed over the substance-containing reservoir to provide for a
number of different substance release characteristics.
Inventors: |
Sirhan, Motasim; (Sunnyvale,
CA) ; Yan, John; (Los Gatos, CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Avantec Vascular
Corporation
Sunnyvale
CA
|
Family ID: |
26670600 |
Appl. No.: |
11/009657 |
Filed: |
December 10, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11009657 |
Dec 10, 2004 |
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10017500 |
Dec 14, 2001 |
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10017500 |
Dec 14, 2001 |
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10002595 |
Nov 1, 2001 |
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10017500 |
Dec 14, 2001 |
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09783253 |
Feb 13, 2001 |
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10017500 |
Dec 14, 2001 |
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09782927 |
Feb 13, 2001 |
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6471980 |
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10017500 |
Dec 14, 2001 |
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09783254 |
Feb 13, 2001 |
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10017500 |
Dec 14, 2001 |
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09782804 |
Feb 13, 2001 |
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60308381 |
Jul 26, 2001 |
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60258024 |
Dec 22, 2000 |
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Current U.S.
Class: |
623/1.42 |
Current CPC
Class: |
A61F 2002/91583
20130101; A61L 31/16 20130101; A61L 2300/602 20130101; A61L
2300/416 20130101; A61L 27/54 20130101; A61F 2/95 20130101; A61F
2250/0068 20130101; A61F 2002/91558 20130101; A61F 2/91 20130101;
A61F 2250/0067 20130101; A61F 2/915 20130101; A61F 2002/91533
20130101; A61F 2230/0054 20130101 |
Class at
Publication: |
623/001.42 |
International
Class: |
A61F 002/06 |
Claims
What is claimed is:
1. A device for intracorporeal use within a patient's body,
comprising: an implantable scaffold; at least one source of at
least one therapeutic capable agent associated with the scaffold
and configured to release the therapeutic capable agent within the
patient's body at a controlled rate; and a rate-controlling element
layer covering at least a portion of the source and including at
least one therapeutic capable agent and providing for an initial
relatively more rapid release of the at least one therapeutic
capable agent therapeutic from the rate-controlling element layer
as well as a sustained, controlled release of the at least one
therapeutic capable agent from the source.
2. A device for intracorporeal use within a patient's body,
comprising: an implantable scaffold; at least one source of at
least one therapeutic capable agent associated with the scaffold;
and a rate-controlling element disposed adjacent at least a portion
of the source and being configured to control the release of the
therapeutic capable agent in the patient's body at an initial rate
and at a subsequent rate relatively slower than the initial
rate.
3. A device as in claim 1 or 2 wherein the rate-controlling element
covers only a portion of the source.
4. A device as in claim 1 or 2 wherein the source comprises a
reservoir.
5. A device as in claim 4 wherein the reservoir is at least
partially disposed over the expandable structure.
6. A device as in claim 5 wherein the reservoir is disposed
adjacent the luminal facing surface.
7. A device as in claim 5 wherein the reservoir is disposed
adjacent the tissue facing surface.
8. A device for intracorporeal use within a patient's body,
comprising: a radially expansible implantable scaffold having a
plurality of regions exhibiting different mechanical profiles
during the expansion of the scaffold and including relatively lower
and relatively higher mechanical profiles; and a source of at least
one therapeutic capable agent comprising a plurality of segments
and disposed adjacent at least a portion of the scaffold.
9. A device as in claim 8 wherein the segments are disposed
adjacent the relatively lower mechanical profile regions.
10. A device as in claim 8 wherein the segments are disposed
adjacent the relatively higher mechanical profile regions.
11. A device as in claim 8 wherein the segments are disposed
adjacent only the regions that do not undergo substantial bending,
flexing, stretching, or compressing upon the expansion of the
scaffold.
12. A device as in claim 8 wherein the segments are disposed
adjacent only the regions that do not undergo more than about 5% of
bending, flexing, stretching, or compressing upon the expansion of
the scaffold.
13. A device as in claim 8 wherein the segments are disposed
adjacent only the regions that undergo substantial bending,
flexing, stretching, compressing upon the expansion of the
scaffold.
14. A device as in claim 8 wherein the areas exhibiting relatively
higher mechanical profile are configured to be in a direct flow of
body fluids flowing through the intracorporeal body.
15. A device as in claim 8 further comprising a rate-controlling
element disposed adjacent the scaffold.
16. A device as in claim 15 wherein the rate-controlling element is
disposed adjacent at least a portion of the source.
17. A device as in claim 15 wherein the rate-controlling element is
formed from a nonporous material.
18. A device as in claim 15 wherein the rate-controlling element
has a variable thickness.
19. A device as in claim 15 wherein the rate-controlling element
has a greater thickness adjacent scaffold regions having relatively
higher mechanical profile.
20. A device for intracorporeal use within a patient's body,
comprising: an implantable scaffold; at least one source of at
least one therapeutic capable agent associated with at least a
portion of the scaffold and configured to release the therapeutic
capable agent within the patient's body; and a rate-controlling
element disposed adjacent at least a portion of the source and
including at least one disruption sufficiently large to permit
material transport to or from the source.
21. A device as in claim 20 wherein the at least one disruption is
an aperture.
22. A device as in claim 20 wherein the at least one disruption is
preformed.
23. A device as in claim 20 wherein the at least one disruption is
formed in the patient's body.
24. A device as in claim 20 wherein the transport comprises at
least one of transport of native fluids to the source or of the
therapeutic capable agent from the source.
25. A device for intracorporeal use within a patient's body,
comprising: an implantable scaffold; at least one source of at
least one therapeutic capable agent associated with at least a
portion of the scaffold and configured to release the therapeutic
capable agent within the patient's body; and a rate-controlling
element disposed adjacent at least a portion of the source and
being configured to mechanically change upon application of
mechanical stress or strain.
26. A device as in claim 25 wherein the mechanical stress or strain
is applied upon the bending of the scaffold.
27. A device as in claim 25 wherein the mechanical stress or strain
is applied upon the expansion of the scaffold.
28. A device for intracorporeal use within a patient's body,
comprising: an implantable scaffold; at least one source of at
least one therapeutic capable agent associated with at least a
portion of the scaffold and configured to release the therapeutic
capable agent within the patient's body; and a rate-controlling
element disposed adjacent at least a portion of the source and
which undergoes a mechanical change upon being implanted in the
patient's body.
29. A device as in claim 25 or 28 wherein the mechanical change is
one of mechanical fracture.
30. A device as in claim 25 or 28 wherein the mechanical change is
one of change in surface characteristic.
31. A device as in claim 25 or 28 wherein the mechanical change is
one of change in porosity.
32. A device as in any one of claims 8, 20, or 25 wherein the
device comprises a stent.
33. A device as in claim 32 wherein the source comprises a
matrix.
34. A device as in claim 33 wherein the matrix includes a matrix
material.
35. A luminal prosthesis comprising: a scaffold which is
implantable within a body lumen; a substance-containing reservoir
positioned over at least a portion of a surface of the scaffold;
and a rate-controlling element layer covering at least a portion of
the substance-containing reservoir, the rate-controlling element
layer having the substance dispersed therein and providing for an
initial rapid release of the substance from the rate-controlling
element layer as well as a sustained, controlled release of the
substance from the reservoir.
36. A luminal prosthesis comprising: a scaffold which is
implantable in a body lumen, said scaffold being radially
expansible and having regions which undergo greater and lesser
mechanical stress or strain during radial expansion; and a
substance-containing reservoir or layer comprising individual
portions which are preferentially positioned over the regions which
undergo lesser stress or strain.
37. A luminal prosthesis as in claim 36 wherein the
substance-containing layer is positioned only on those portions of
the scaffold that do not substantially bend, stretch, or compress
when the scaffold is expanded.
38. A luminal prosthesis as in claim 36 further comprising a
rate-controlling element layer formed over at least a portion of
the scaffold.
39. A luminal prosthesis as in claim 38 wherein the
rate-controlling element layer is thicker over regions of greater
mechanical profile.
40. A luminal prosthesis comprising: a scaffold which is
implantable within a body lumen; a substance-containing reservoir
positioned over at least a portion of a surface of the scaffold;
and a rate-controlling element layer covering at least a portion of
the substance-containing reservoir, the rate-controlling element
layer having at least one preformed aperture which is sufficiently
large to permit the transport of body fluids to the
substance-containing reservoir and/or the release of substance from
the reservoir.
41. A luminal prosthesis comprising: a scaffold which is
implantable within a body lumen; a substance-containing reservoir
positioned over at least a portion of a surface of the scaffold,
and a rate-controlling element layer covering at least a portion of
the substance containing reservoir, the rate-controlling element
layer being configured to fracture when stressed by substantially
bending, expanding, stretching, or compressing of the scaffold.
42. A luminal prosthesis comprising: a scaffold which is
implantable within a body lumen; a substance-containing reservoir
positioned over at least a portion of a surface of the scaffold;
and a rate-controlling element layer covering at least a portion of
the substance containing reservoir, the rate-controlling element
layer being configured to swell to permit release of substance from
the reservoir when exposed to a luminal environment.
43. A luminal prosthesis comprising: a scaffold which is
implantable within a body lumen; a substance-containing reservoir
positioned over at least a portion of a surface of the scaffold;
and a rate-controlling element positioned over at least a portion
of the surface of the scaffold and covering less than all of the
substance containing reservoir.
44. A luminal prosthesis as in any of claims 35 through 43 wherein
the luminal prosthesis comprises a metal stent.
45. A luminal prosthesis as in claim 44 wherein the metal stent is
balloon expandable.
46. A luminal prosthesis as in claim 44 wherein the metal stent is
self-expanding.
47. A luminal prosthesis as in any of claims 35 through 43 wherein
the substance-containing reservoir comprises a matrix layer
including the substance dispersed in a matrix material.
48. A luminal prosthesis as in claim 47 wherein the substance and
the matrix material have been vapor deposited on the scaffold.
49. A luminal prosthesis as in any of claim 35 through 43 wherein
the substance-containing layer consists essentially of a
homogeneous layer of the substance.
50. A luminal prosthesis as in claim 49 wherein the substance has
been vapor deposited on the scaffold.
51. A luminal prosthesis as in any of claims 35 through 43 wherein
the scaffold comprises structural elements having rectangular
cross-sections defining four orthogonal surfaces, wherein the drug
is positioned on fewer than all of the surfaces.
52. A luminal prosthesis as in any of claims 35 through 43 wherein
the rate-controlling element is porous.
53. A luminal prosthesis as in any of claim 35 through 43 wherein
the rate-controlling element is nonporous.
54. A luminal prosthesis as in any of claims 35 through 43 further
comprising a base layer over at least a portion of the scaffold and
at least a portion of the substance-containing layer.
55. A luminal prosthesis as in any of claims 35 through 43 wherein
the rate-controlling element layer comprises a parylene polymer or
copolymer.
56. A luminal prosthesis as in claim 55 wherein the parylene has
been vapor deposited over the scaffold or a portion thereof.
57. A luminal prosthesis as in claim 55 wherein the parylene
comprises parylene C.
58. A luminal prosthesis as in claim 55 wherein the parylene is
nonporous.
59. A method for making a device for intracorporeal use,
comprising: providing an implantable structure having a first
residual stress and including a scaffold; and at least one source
of at least one therapeutic capable agent associated with the
scaffold and configured to release the therapeutic capable agent at
a targeted tissue site within the patient's body; changing the
structure residual stress to a second residual stress; disposing a
rate-controlling element adjacent at least a portion of the source
and being configured to control the release of the therapeutic
capable agent in the patient's body.
60. A method as in claim 59 wherein the changing step comprises
reducing the residual stress.
61. A method as in claim 59 wherein the changing step comprises
exposing the structure to ultrasound energy for a period of
time.
62. A method as in claim 59 wherein the changing step comprises
exposing the structure to vibrational energy for a period of
time.
63. A method as in claim 59 wherein the changing step comprises
heating the structure to a first temperature for a period of
time.
64. A method as in claim 63 wherein the first temperature is less
than the melting point of the therapeutic capable agent.
65. A method as in claim 63 wherein the first temperature is about
the same as the melting point of the therapeutic capable agent.
66. A method as in claim 63 wherein the at least one therapeutic
capable agent comprises a plurality of therapeutic capable agents
and the first temperature is about the same as the melting point of
the therapeutic capable agent with the lowest melting point.
67. A method as in claim 63 wherein the first temperature is more
than the melting point of the therapeutic capable agent.
68. A method as in claim 63 wherein the at least one therapeutic
capable agent comprises a plurality of therapeutic capable agents
and the first temperature is more than the melting point of the
therapeutic capable agent with the lowest melting point.
69. A method as in claim 63 wherein the first temperature is about
the glass transition temperature of the rate-controlling
element.
70. A method as in claim 63 wherein the first temperature is more
than the glass transition temperature of the rate-controlling
element
71. A method as in claim 59 wherein the changing step is performed
before the disposing step.
72. A method as in claim 59 wherein the changing step is performed
after the disposing.
73. A method as in claim 59 wherein the changing step comprises
heating the structure to a second temperature for a period of time
and is performed after the disposing step.
74. A method as in claim 73 wherein the heating of the structure to
a second temperate is performed under vacuum.
75. A method as in claim 73 wherein the heating of the structure to
a second temperate is performed in the absence of oxygen.
76. A method as in claim 73 wherein the second temperature is less
than the glass transition temperature of the rate-controlling
element.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/017,500, filed on Dec. 14, 2001, which is a
continuation-in-part of U.S. patent application Ser. No.
10/002,595, filed Nov. 1, 2001, which claims the benefit of
Provisional U.S. Patent Application 60/258,024, filed on Dec. 22,
2000; and which is a continuation-in-part of U.S. patent
application Ser. Nos. 09/783,253, 09/782,927 (now U.S. Pat. No.
6,471,980), Ser. Nos. 09/783,254, and 09/782,804, all filed on Feb.
13, 2001; and which claims the benefit of Provisional U.S. Patent
Application 60/308,381, filed on Jul. 26, 2001. Each of these
applications is assigned to the assignee of the present
application. The full disclosures of each of the above applications
is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to medical devices
and methods. More particularly, the present invention provides
luminal prostheses, such as vascular stents and grafts for reducing
or inhibiting restenosis.
[0004] The present invention relates generally to medical devices
and methods. More particularly, the present invention provides
luminal prostheses, such as vascular stents and grafts for reducing
or inhibiting restenosis.
[0005] A number of percutaneous intravascular procedures have been
developed for treating stenotic atherosclerotic regions of a
patient's vasculature to restore adequate blood flow. The most
successful of these treatments is percutaneous transluminal
angioplasty (PTA). In PTA, a catheter, having an expandable distal
end usually in the form of an inflatable balloon, is positioned in
the blood vessel at the stenotic site. The expandable end is
expanded to dilate the vessel to restore adequate blood flow beyond
the diseased region. Other procedures for opening stenotic regions
include directional arthrectomy, rotational arthrectomy, laser
angioplasty, stenting, and the like. While these procedures have
gained wide acceptance (either alone or in combination,
particularly PTA in combination with stenting), they continue to
suffer from significant disadvantages. A particularly common
disadvantage with PTA and other known procedures for opening
stenotic regions is the frequent occurrence of restenosis.
[0006] Restenosis refers to the re-narrowing of an artery after an
initially successful angioplasty. Restenosis afflicts approximately
up to 50% of all angioplasty patients and is the result of injury
to the blood vessel wall during the lumen opening angioplasty
procedure. In some patients, the injury initiates a repair response
that is characterized by smooth muscle cell proliferation referred
to as "hyperplasia" in the region traumatized by the angioplasty.
This proliferation of smooth muscle cells re-narrows the lumen that
was opened by the angioplasty within a few weeks to a few months,
thereby necessitating a repeat PTA or other procedure to alleviate
the restenosis.
[0007] A number of strategies have been proposed to treat
hyperplasia and reduce restenosis. Previously proposed strategies
include prolonged balloon inflation during angioplasty, treatment
of the blood vessel with a heated balloon, treatment of the blood
vessel with radiation following angioplasty, stenting of the
region, and other procedures. While these proposals have enjoyed
varying levels of success, no one of these procedures is proven to
be entirely successful in substantially or completely avoiding all
occurrences of restenosis and hyperplasia.
[0008] As an alternative or adjunctive to the above mentioned
therapies, the administration of therapeutic agents following PTA
for the inhibition of restenosis has also been proposed.
Therapeutic treatments usually entail pushing or releasing a
therapeutic capable agent through a catheter or from a stent. While
holding great promise, the delivery of therapeutic agents for the
inhibition of restenosis has not been entirely successful.
[0009] As an alternative or adjunctive to the above mentioned
therapies, the administration of therapeutic agents following PTA
for the inhibition of restenosis has also been proposed.
Therapeutic treatments usually entail pushing or releasing a drug
through a catheter or from a stent. While holding great promise,
the delivery of therapeutic agents for the inhibition of restenosis
has not been entirely successful.
[0010] Accordingly, it would be a significant advance to provide
improved devices and methods for reducing, inhibiting, or treating
restenosis and hyperplasia which may follow angioplasty and other
interventional treatments. This invention satisfies at least some
of these and other needs.
[0011] 2. Description of the Background Art
[0012] Local drug delivery for the prevention of restenosis is
described in Lincoff et al. (1994) Circulation 90:2070-2084. A full
description of an exemplary luminal prosthesis for use in the
present invention is described in co-pending application Ser. No.
09/565,560 filed May 4, 2000, the full disclosure of which is
incorporated herein by reference. Method and apparatus for
releasing active substances from implantable and other devices are
described in U.S. Pat. Nos. 6,096,070; 5,824,049; 5,624,411;
5,609,629; 5,569,463; 5,447,724; and 5,464,650. The use of stents
for drug delivery within the vasculature are described in PCT
Publication No. WO 01/01957 and U.S. Pat. Nos. 6,099,561;
6,071,305; 6,063,101; 5,997,468; 5,980,551; 5,980,566; 5,972,027;
5,968,092; 5,951,586; 5,893,840; 5,891,108; 5,851,231; 5,843,172;
5,837,008; 5,769,883; 5,735,811; 5,700,286; 5,679,400; 5,649,977;
5,637, 113; 5,591,227; 5,551,954; 5,545,208; 5,500,013; 5,464,450;
5,419,760; 5,411,550; 5,342,348; 5,286,254; and 5,163,952.
Biodegradable materials are described in U.S. Pat. Nos. 6,051,276;
5,879,808; 5,876,452; 5,656,297; 5,543,158; 5,484,584; 5,176,907;
4,894,231; 4,897,268; 4,883,666; 4,832,686; and 3,976,071. The use
of hydrocylosiloxane as a rate limiting barrier is described in
U.S. Pat. No. 5,463,010. Methods for coating of stents is described
in U.S. Pat. No. 5,356,433. Coatings to enhance biocompatibility of
implantable devices are described in U.S. Pat. Nos. 5,463,010;
5,112,457; and 5,067,491. Porous and non-porous materials for drug
delivery, coating, and other uses are described in U.S. Pat. Nos.
5,488,015; 5,470,802; 5,428,123; 5,288,504; 5,270,047; 5,243,756;
5,130,889; 4,788,063; 3,993,072; and 3,854,480. Energy-based
devices are described in U.S. Pat. Nos. 6,031,375; 5,928,145;
5,735,811; 5,728,062; 5,725,494; 5,409,000, 5,368,557; 5,000,185;
and 4,936,281. Magnetic processes, some of which have been used in
drug delivery systems, are described in U.S. Pat. Nos. 5,427,767;
5,225,282; 5,206,159; 5,069,216; 4,904,479; 4,871,716; 4,501,726;
4,357,259; 4,345,588; and 4,335,094.
[0013] The disclosure of this application is related to the
disclosures of the following applications: Ser. No. 09/782,927
(Attorney Docket No. 20460-000920); Ser. No. 09/783,254 (Attorney
Docket No. 20460-000930); and Ser. No. 09/782,804 (Attorney Docket
No. 20460-000940).
[0014] The full disclosures of each of the above references are
incorporated herein by reference.
BRIEF SUMMARY OF THE INVENTION
[0015] The present invention is directed to improved devices for
preparation or treatment of susceptible tissue sites, and methods
making and using the same. In particular, the present invention is
directed to corporeal, more particularly intracorporeal devices. In
one embodiment, the present devices and methods reduce the
formation or progression of restenosis and/or hyperplasia which may
follow an intravascular intervention. In an embodiment, the device
provides a therapeutic capable agent to the susceptible tissue
site. Preferably, the therapeutic capable agent is provided to the
therapeutic capable agent in a manner as to become available,
immediately or after a delay period, to the susceptible tissue site
upon introduction of the device to the corporeal body.
[0016] As used herein, "susceptible tissue site" refers to a tissue
site that is injured, or may become injured as a result of an
impairment (e.g., disease, medical condition), or may become
injured during or following an interventional procedure such as an
intravascular intervention. The term "intravascular intervention"
includes a variety of corrective procedures that may be performed
to at least partially resolve a stenotic, restenotic, or thrombotic
condition in a blood vessel, usually an artery, such as a coronary
artery. Usually, the corrective procedure will comprise balloon
angioplasty. The corrective procedure may also comprise directional
atherectomy, rotational atherectomy, laser angioplasty, stenting,
or the like, where the lumen of the treated blood vessel is
enlarged to at least partially alleviate a stenotic condition which
existed prior to the treatment. The susceptible tissue site may
include tissues associated with intracorporeal lumens, organs, or
localized tumors. As used herein, the term "intracorporeal body"
refers to body lumens or internal corporeal tissues and/or organs,
within a corporeal body. The body lumen may be any blood vessel in
the patient's vasculature, including veins, arteries, aorta, and
particularly including coronary and peripheral arteries, as well as
previously implanted grafts, shunts, fistulas, and the like. It
will be appreciated that the present invention may also be applied
to other body lumens, such as the biliary duct, which are subject
to excessive neoplastic cell growth. Examples of internal corporeal
tissues and organs, include various organs, nerves, glands, ducts,
and the like. In an embodiment, the device includes luminal
prostheses such as vascular stents or grafts. In another
embodiment, the device may include, cardiac pacemaker leads or lead
tips, cardiac defibrillator leads or lead tips, heart valves,
sutures, or needles, pacemakers, orthopedic devices, appliances,
implants or replacements, or portions of any of the above.
[0017] As used herein the term "therapeutic capable agent" includes
at least one compound which is either therapeutic as it is
introduced to the corporeal body (e.g., human subject) under
treatment, or becomes therapeutic after entering the corporeal body
of the subject (or exposed to the surface of the corporeal body as
the case may be), by for example, reaction with a native or
non-native substance or condition. Examples of native conditions
include pH (e.g. acidity), chemicals, temperature, salinity,
conductivity, contractile or expansive changes of the body
lumen/organ, and pulsating nature of the body fluids as they flow
through or come in contact with the device; with non-native
conditions including those such as magnetic fields, and ultrasound.
In the present application, the chemical name of any of the
therapeutic capable agents or other compounds is used to refer to
the compound itself and to pro-drugs (precursor substances that are
converted into an active form of the compound in the body), and/or
pharmaceutical derivatives, analogues, or metabolites thereof
(bioactive compound to which the compound converts within the body
directly or upon introduction of other agents or conditions (e.g.,
enzymatic, chemical, energy), or environment (e.g., pH)).
[0018] In an embodiment, the device comprises a structure and at
least one source of at least one therapeutic capable agent
associated with the structure. In one embodiment, the device
further comprises a rate-controlling element disposed or formed
adjacent at least a portion of the structure. The therapeutic
capable agent is associated at least in part with either or both
the structure and the rate-controlling element in a manner as to
become available, immediately or after a delay period, to the
susceptible tissue site upon introduction of the device to the
corporeal body. As used herein the term "associated with" refers to
any form of association such as directly or indirectly being
coupled to, connected to, disposed on, disposed within, attached
to, adhered to, bonded to, adjacent to, entrapped in, and like
configurations.
[0019] In an embodiment, the device is implantable within a
corporeal body including an intracorporeal target site (e.g., body
organs or lumens). The intracorporeal target site may include the
susceptible tissue site or in the alternative it may be a supply
site such as an artery which supplies blood to the susceptible
tissue site.
[0020] In one embodiment the structure may be an expandable
structure. In another embodiment, the structure may have a
substantially constant size or diameter, or alternatively depending
on the application and use, may be a contractable structure. The
expandable structure may be in the form of a stent, which
additionally maintains luminal patency, or in the form of a graft,
which additionally protects or enhances the strength of a luminal
wall. The device, may comprise at least in part, a scaffold,
preferably formed at least in part from an open lattice.
Optionally, the scaffold comprises an at least substantially closed
surface. The expandable structure may be radially expandable. The
structure may be self-expanding or expandable by another object
such as a balloon. In an embodiment, the structure includes at
least one surface, usually, a tissue facing surface. In another
embodiment, the structure includes a tissue facing surface, another
surface usually a luminal surface, and two edge surfaces. In an
embodiment, the structure may have an interior disposed between two
surfaces, usually, the tissue facing and the luminal surfaces. In
an embodiment, the structure includes portions having different
mechanical stress or strain profiles upon expansion or contraction,
or areas which are substantially in the direct line of fluid (e.g.,
blood or other bodily fluids) flow through the body. By way of
example, the different portions of the structure may exhibit
different stress characteristics during expansion of the device
when implanted within the intracorporeal body. In one embodiment,
the structure includes portions having relatively lower and
portions having relatively higher mechanical stress or strain
profiles with respect to one another. The term "having different
mechanical profile" will herein be used to refer to this
characteristic of the structure or prosthesis. In an embodiment,
when the device may include an axially different coating profile
such that the prosthesis comprises a different profile of the
therapeutic capable agent and/or the rate-controlling element which
will be in the direct flow of the body fluids thus subject to more
turbulent flow.
[0021] The source may be disposed or formed adjacent at least a
portion of the structure. The source may be disposed or formed
adjacent at least a portion of either or both surfaces of the
expandable structure, within the interior of the structure disposed
between the two surfaces, adjacent either or both the edges, or any
combination thereof. The association of the therapeutic capable
agent with either or both the structure and the rate-controlling
element may be continuous or in discrete segments. In one
embodiment, the source is disposed or formed adjacent only a
portion of the structure and/or the rate-controlling element,
preferably, areas having lower mechanical stress profiles.
[0022] The expandable structure may be formed of any suitable
material such as metals, polymers, or a combination thereof. In one
embodiment, the expandable structure may be formed of an at least
partially biodegradable material, selected from the group
consisting of polymeric material, metallic materials, or
combinations thereof. The at least partially biodegradable
material, preferably degrades over time. Examples of polymeric
material include poly-L-lactic acid, having a delayed degradation
to allow for the recovery of the vessel before the structure is
degraded. Example of metallic material include metals or alloys
degradable in the corporeal body, such as stainless steel. An
exemplary stent for use in the present invention is described in
co-pending application Ser. No. 09/565,560, the full disclosure of
which is incorporated herein by reference.
[0023] In an embodiment, the device is a stent generally including
a cylindrical frame having proximal and distal ends, and tissue and
luminal facing surfaces. The device usually further comprises a
plurality of radially expansible unit segments including rings. The
rings preferably have a serpentine shape. In an embodiment, the
unit segments, preferably include segments having different
mechanical profiles, as for example may be exhibit as a result of
expansion. In an embodiment, some of the rings may be joined with
at least one axially adjacent ring through expansion links. The
links preferably have a sigmoidal shape, more preferably, an S
shape having a relatively smooth profile along its length to
minimize or reduce kinking upon expansion. Similarly, the links may
comprise segments having different mechanical profiles along their
length. For example, the joint and/or links may have relatively
lower mechanical profile portions along their lengths with
relatively higher mechanical profile portions at bends, points,
intersections, joints, or areas exposed to flow turbulence.
Preferably, the source is positioned adjacent the tissue facing
surface of the structure. Preferably, the portion is an area of the
structure having relatively lower mechanical profile.
[0024] In one embodiment, the source and/or the rate-controlling
element are independently disposed only on a portion of the
structure, preferably, the portion having relatively lower
mechanical profile. In another embodiment, the source may be
disposed on the relatively lower mechanical profile areas while the
rate-controlling element is disposed over either the lower
mechanical profile areas or the lower and higher mechanical profile
areas.
[0025] The therapeutic capable agent may be associated with either
or both the structure (e.g., expandable structure) and the
rate-controlling element in one or more ways as described above.
The therapeutic capable agent may be disposed adjacent (e.g., on or
within) the expandable structure. Alternatively or additionally,
the therapeutic capable agent may be disposed adjacent (e.g., on or
within) the rate-controlling element, or in an interface between
structure and the rate-controlling element, in a pattern that
provides the desired performance (e.g., release rate). In another
embodiment, the device includes an outer layer including the
therapeutic capable agent. In an embodiment, the therapeutic
capable agent outer layer provides for a bulous release of the
therapeutic capable agent upon introduction of the device to the
corporeal body. In one embodiment, the source may comprise a
plurality of compounds, as for example the therapeutic capable
agent and another compound such as another therapeutic capable
agent or an enabling compound. Each of the plurality of compounds
may be in the same or different area of the source.
[0026] The rate-controlling element may be formed of a
non-degradable, partially degradable, substantially degradable
material, or a combination thereof. The material may be synthetic
or natural; non-polymeric, polymeric, ceramic, or metallic; or a
combination thereof. The rate-controlling element may have a
porous, microporous, nanoporous, or nonporous morphology, or any
combinations thereof. Preferably, when the device comprise a porous
rate-controlling element, at least one layer of a nonporous
rate-controlling element is disposed between the source and the
porous rate-controlling element.
[0027] In a preferred embodiment the rate-controlling element is
formed from a nonporous material, usually a nonporous conformal
material. Example of suitable non-porous material include, but not
limited to: plasma deposited polymers; sputtered, evaporated,
electroplated metals and/or alloys; glow discharge coating;
polyethylene; polyurethanes; silicone rubber; cellulose; and
parylene including parylene C, N, D, F, or combinations thereof,
usually parylene C. In an embodiment, the device comprises a layer
of another rate-controlling element which is configured to bind, at
least partially, with the therapeutic capable agent. In an
embodiment Bovine Serum Albumin (BSA) is disposed adjacent the
nonporous rate-controlling element (e.g., parylene) such that as
the therapeutic capable agent (e.g., mycophenolic acid) diffuses or
elutes out of the nonporous rate-controlling element, the
therapeutic capable agent binds with the BSA, further delaying or
controlling the release of therapeutic capable agent. Other
examples of another rate-controlling element capable of binding
with the therapeutic capable agent include quartemary ammonium
compounds such as polyethylene imine. In one embodiment a hydrogel
compound is disposed under either or both the therapeutic capable
agent and the rate-controlling element or in the matrix. As body
fluids come in contact with the hydrogel compound, the hydrogel
compound swells causing a change in the flow or diffusion
properties of the therapeutic capable agent through the
rate-controlling element, as for example by causing disruptions in
the rate-controlling element layer.
[0028] As defined herein, "porous material" refers to a polymeric
material or structure having an open cell structure. Such material
can be classified as macroporous, microporous (e.g., having
cell/pore size ranging from about 1 to about 100 microns), or
nanoporous (e.g., having cell/pore size in nanometer range and
larger than the actual length of the polymer chains making up the
polymer). The typical chain length of such porous material ranges
from about 2 to about 100 angstroms (A). As used herein, "nonporous
material" refers to materials including coatings, which have no
pores or have pore size less than the normal free volume of the
material. The free volume is associated with the space between
molecules in a material accessible to segmental motions. In an
embodiment the rate-controlling element has a free volume equal or
less than twice the volume of the rate-controlling element
molecule.
[0029] At the molecular level most, if not all, of the solid and/or
nonporous polymers have at least some free volume which allows for
chain motion. The dimension of the free volume space is usually in
the order of fractions of the molecular chain length, thus the term
nonporous. As temperature increases so does the chain motion and
the free volume.
[0030] In an embodiment, the rate of release of the therapeutic
capable agent from the source through the rate-controlling element
(as an external layer covering the source and/or as a matrix
material), is affected by the "partition coefficient" and
diffusivity of the therapeutic capable agent molecule and the
thickness of the rate-controlling element.
[0031] The solubility of different therapeutic capable agents in
the same nonporous polymeric rate-controlling element varies
greatly. Therapeutic capable agent-polymeric rate-controlling
element solubility depends on several factors including any one or
more of the following: the difference in the chemical structure of
the therapeutic capable agent and the nonporous polymeric
rate-controlling element, the presence and characteristic of the
functional groups of the therapeutic capable agent and the
rate-controlling element, hydrogen, ionic, or other bonding between
the two, molecular weight, stereochemical configurations of the
therapeutic capable agent and the nonporous polymeric
rate-controlling element, crystalline/amorphous state, temperature
of the system, activity coefficient of the therapeutic capable
agent solute in the polymeric rate-controlling element, the molar
heat of fusion absorbed when the therapeutic capable agent crystals
dissolve or solubilize into the polymeric rate-controlling
element.
[0032] The diffusion of the therapeutic capable agent through the
nonporous polymeric rate-controlling element depends on a number of
factors such as the molecular energy (e.g., vibration, rotation,
translation), and intermolecular attraction/repulsion (between the
portion of the same material or that of between the two different
material). The conformation of the polymer and the therapeutic
capable agent and/or rate-controlling element depends on a variety
of factors including the chain length, molecular structure,
crystallinity, and degree of cross-linking.
[0033] In an embodiment, where the rate-controlling element is
formed from a nonporous material, upon expansion of the structure
within the intracorporeal body, the rate-controlling element may at
least partially form areas of disruption on or within the
rate-controlling element. The disruptions allow the transport of
either or both the elution medium (e.g., bodily fluids such as
blood, water, serum, tissue, interstitial fluid) to the source, or
the therapeutic capable agent from the source to the targeted
intracorporeal site. The transport of the body fluids to the source
assists in the transport of the therapeutic capable agent back to
the targeted intracorporeal site. In one embodiment, the
disruptions may be formed in the implanted device, at least in
portions of the device which are in the direct line of fluid
flow.
[0034] By way of examples, a metallic material that at least
partially degrades with time may be used as the rate-controlling
element; as well as non-polymers having large molecular weight,
polar or non-polar functional groups, electrical charge, steric
hindrance groups, hydrophobic, hydrophilic, or amphiphilic
moieties. It should be appreciated that the device may comprise a
plurality of rate-controlling elements, each having same or
different chemical and physical profiles and characteristics, each
being present at similar or different locations, and including
none, same, or different therapeutic capable agents. In another
embodiment, the device may include areas (e.g., distal and proximal
ends of the device) having variable thickness of both the source
and the rate-controlling element to allow for slower or faster
release.
[0035] Suitable nondegradable or slow degrading rate-controlling
element materials include, but are not limited to, polyurethane,
polyethylenes imine, cellulose acetate butyrate, ethylene vinyl
alcohol copolymer, silicone, polytetrafluorethylene (PTFE),
parylene, parylast, poly(methyl methacrylate butyrate),
poly-N-butyl methacrylate, poly(methyl methacrylate), poly
2-hydroxy ethyl methacrylate, poly ethylene glycol methacrylates,
poly vinyl chloride, poly(dimethyl siloxane),
poly(tetrafluoroethylene), poly(ethylene oxide), poly ethylene
vinyl acetate, poly carbonate, poly acrylamide gels,
N-vinyl-2-pyrrolidone, maleic anhydride, Nylon, quartemary ammonium
compounds including stearyl ammonium chloride and benzyl ammonium
chloride, cellulose acetate butyrate (CAB) and the like, including
other synthetic or natural polymeric substances; mixtures,
copolymers, and combinations thereof. In an embodiment the
rate-controlling element is formed from a material selected from
the group consisting of silicone, polytetrafluoroethylene,
parylast, polyurethane, parylene, cellulose acetate butyrate;
mixtures, copolymers and combinations thereof.
[0036] Suitable biodegradable rate-controlling element materials
include, but are not limited to, poly(lactic acid), poly(glycolic
acid) and copolymers, poly dioxanone, poly(ethyl glutamate),
poly(hydroxybutyrate), polyhydroxyvalerate and copolymers,
polycaprolactone, polyanhydride, poly(ortho esters);
poly(iminocarbonates), polyester amides, polyester amines,
polycyanoacrylates, polyphosphazenes, copolymers and other
aliphatic polyesters, or suitable copolymers thereof including
copolymers of poly-L-lactic acid and poly-e-caprolactone; mixtures,
copolymers, and combinations thereof. Other examples of suitable
material include polymers, as disclosed in U.S. Pat. No. 5,610,241
and issued to Lee et al., and incorporated herein by reference in
its entirety. Lee discloses graft polymers having a biodegradable
backbone and side chains with reactive amino acid groups and/or
protected amino acid groups. The graft polymers are obtained from a
biodegradable homopolymer or copolymer starting material having
carbonyl group and carbon alpha to carbon of the carbonyl group and
having H atom on carbon alpha to carbonyl carbon and consisting
essentially of biodegradable homopolymer or copolymer backbone
joined at backbone carbon alpha to backbone carbonyl group, to the
chain amino acid pendant group at a carbonyl moiety of the pendant
group, which side chain amino acid pendant group contains reactive
amino acid group(s) and/or protected amino acid groups.
[0037] The graft polymers are prepared by reacting amino acid
halide having other reactive groups protected, with biodegradable
polymer containing carbanion on carbon alpha to carbon of carbonyl
group, and then deprotecting the protected groups.
[0038] Suitable natural material include: fibrin, albumin,
collagen, gelatin, glycosoaminoglycans, oligosaccharides & poly
saccharides, chondroitin, phosholipids, phosphorylcholine,
glycolipids, proteins, amino acids, cellulose, and mixtures,
copolymers, or combinations thereof. In an embodiment, the
rate-controlling element comprises Bovine Serum Albumin (BSA).
[0039] Other suitable material include, titanium, chromium,
Nitinol, gold, stainless steel, metal alloys, ceramics, or a
combination thereof; and other compounds that may release the
therapeutic capable agent as a result of interaction (e.g.,
chemical reaction, high molecular weight, steric hindrance,
hyrophobicity, hydrophilicity, amphilicity, heat) of the
therapeutic capable agent with the rate-controlling element
material (e.g, a non-polymer compound). By way of example, a
combination of two or more metals or metal alloys with different
galvanic potentials to accelerate corrosion by galvanic corrosion
pathways may also be used.
[0040] The degradable material may degrade by bulk degradation or
hydrolysis. In an embodiment, the rate-controlling element degrades
or hydrolyzes throughout, or preferably, by surface degradation or
hydrolysis, in which a surface of the rate-controlling element
degrades or hydrolyzes over time while maintaining bulk integrity.
In another embodiment, hydrophobic rate-controlling elements are
preferred as they tend to release therapeutic capable agent at
desired release rate. A non-degradable rate-controlling element may
release therapeutic capable agent by diffusion.
[0041] In an embodiment, the therapeutic capable agent itself is a
rate-controlling element, as for example, when the therapeutic
capable agent is a polymeric material. In an embodiment, the
therapeutic capable agent, alone or in combination with a matrix
material, forms a matrix. The term "matrix" as used herein refers
to an association between the therapeutic capable agent and the
rate-controlling element and/or other compounds. In an embodiment,
the matrix comprises a matrix interface formed between the
rate-controlling element and the therapeutic capable agent and/or
other compound/s. In an embodiment, the rate-controlling element
may comprise multiple adjacent layers formed from the same or
different material. The therapeutic capable agent may be present
adjacent one or more of the rate-controlling element layers.
Additionally and/or alternatively, the therapeutic capable agent
may form a matrix and/or matrix interface with one or more of the
rate-controlling element layers.
[0042] The therapeutic capable agent may be selected from a group
consisting of immunosuppressants, anti-inflammatories,
anti-proliferatives, anti-migratory agents, anti-fibrotic agents,
proapoptotics, calcium channel blockers, anti-neoplastics,
anti-cancer agents, antibodies, anti-thrombotic agents,
anti-platelet agents, IIb/IIIa agents, antiviral agents, and a
combination thereof.
[0043] Specific examples of therapeutic capable agent include:
mycophenolic acid, mycophenolate mofetil, mizoribine,
methylprednisolone, dexamethasone, Certican.TM., rapamycin,
Triptolide.TM., Methotrexate.TM., Benidipine.TM., Ascomycin.TM.,
Wortmannin.TM., LY294002, Camptothecin.TM., Topotecan.TM.,
hydroxyurea, Tacrolimus.TM. (FK 506), cyclophosphamide,
cyclosporine, daclizumab, azathioprine, prednisone,
Gemcitabine.TM., cilostazol (Pletal.TM.), tranilast, quercetin,
suramin; metabolites, derivatives, and combinations thereof.
[0044] In an embodiment, the source of the therapeutic capable
agent is a polymeric material including therapeutic capable agent
moieties as a structural subunit of the polymer. The therapeutic
capable agent moieties are polymerized and associated to one
another through suitable linkages (e.g. ethylenic) forming
polymeric therapeutic capable agent. Once the polymeric therapeutic
capable agent is brought into contact with tissue or fluid such as
blood, the polymeric therapeutic capable agent subunits
disassociate. Alternatively, the therapeutic capable agent may be
released as the polymeric therapeutic capable agent degrades or
hydrolyzes, preferably, through surface degradation or hydrolysis,
making the therapeutic capable agent available to the susceptible
tissue site, preferably over a period of time. Examples of methods
and compounds for polymerizing therapeutic capable agents are
described in WO 99/12990 Patent Application by Kathryn Uhrich,
entitled "Polyanhydrides With Therapeutically Useful Degradation
Products," and assigned to Rutgers University, the full disclosure
of which is incorporated herein by reference. An example of a
therapeutic capable agents and a suitable reaction ingredient unit
includes, mycophenolic acid with adipic acid and/or salicylic acid
in acid catalyzed esterification reaction; mycophenolic acid with
aspirin and/or adipic acid in acid catalyzed esterification
reaction, mycophenolic acid with other NSAIDS, and/or adipic acid
in acid catalyzed esterification reaction. In an embodiment, the
polymeric therapeutic capable agent may be associated with a
polymeric and/or metallic backbone.
[0045] The devices of the present invention may be configured to
release or make available the therapeutic capable agent at one or
more phases, the one or more phases having similar or different
performance (e.g., release) profiles. The therapeutic capable agent
may be made available to the tissue at amounts which may be
sustainable, intermittent, or continuous; in one or more phases
and/or rates of delivery; effective to reduce any one or more of
smooth muscle cell proliferation, inflammation, immune response,
hypertension, or those complementing the activation of the same.
Any one of the at least one therapeutic capable agents may perform
one or more functions, including preventing or reducing
proliferative/restenotic activity, reducing or inhibiting thrombus
formation, reducing or inhibiting platelet activation, reducing or
preventing vasospasm, or the like.
[0046] The release rate may be further controlled by the size,
quantity, location, elasticity of the rate-controlling element
(i.e., as the polymeric rate-controlling element stretches or
relaxes during flexing of the device), and the hydrophobicity of
the therapeutic capable agent. By way of example, a
methyprednisolone (MP) therapeutic capable agent being more
hydrophobic than mycophenolic acid (MPA) releases at a slower rate
into the surrounding intracorporeal site or elusion medium than
mycophenolic acid.
[0047] The total amount of therapeutic capable agent made available
to the tissue depends in part on the level and amount of desired
therapeutic result. The therapeutic capable agent may be made
available at one or more phases, each phase having similar or
different release rate and duration as the other phases. The
release rate may be pre-defined. In an embodiment, the rate of
release may provide a sustainable level of therapeutic capable
agent to the susceptible tissue site. In another embodiment, the
rate of release is substantially constant. The rate may decrease
and/or increase over time, and it may optionally include a
substantially non-release period. The release rate may comprise a
plurality of rates. In an embodiment the plurality of release rates
include at least two rates selected from the group consisting of
substantially constant, decreasing, increasing, substantially
non-releasing.
[0048] The total amount of therapeutic capable agent made available
or released will typically be in an amount ranging from about 0.1
.mu.g to about 10 g, generally from about 0.1 .mu.g to about 10 mg,
preferably from about 1 .mu.g to about 10 mg, more preferably from
about 1 .mu.g to about 2 mg, from 10 .mu.g to about 2 mg, or from
about 50 .mu.g to about 1 mg.
[0049] In an embodiment, the therapeutic capable agent may be
released in a time period, as measured from the time of implanting
of the device, ranging from about 1 day to about 200 days; from
about 1 day to about 45 days; or from about 7 days to about 21
days.
[0050] In an embodiment the release rate of the therapeutic capable
agent per day may range from about 0.001 micrograms (.mu.g) to
about 1000 .mu.g, usually from about 0.001 .mu.g to about 200
.mu.g, normally from about 0.5 .mu.g to about 200 .mu.g, and
typically from about 1 .mu.g to about 60 .mu.g.
[0051] In one embodiment, the rate-controlling element is
configured to have properties, physical and/or chemical properties
(e.g., physical dimensions such as thickness and chemical
properties such as polymer chemical structure) such that the flux
density of the therapeutic capable agent across the
rate-controlling element (or through the matrix as the case may be)
to the targeted tissue site ranges from about 1.71.times.10-14
g/(cm.sup.2s) to about 1.71.times.10-8 g/(cm.sup.2s), usually from
about 1.71.times.10-14 g/(cm.sup.2s) to about 1 3.43.times.10-9
g/(cm.sup.2s), normally from about 8.57.times.10-12 g/(cm.sup.2s)
to about 3.43.times.10-9 g/(cm.sup.2s), and typically from about
1.7.times.10-11 g/(cm.sup.2s) to about 1.03.times.10-9
g/(cm.sup.2s). The desired flux density is affected by the total
interfacial area between the therapeutic capable agent and the
rate-controlling element, the diffusion coefficient of the
therapeutic capable agent across (or through the matrix) the
rate-controlling element. Thus, depending on the nature of the drug
and the desired therapeutic dosages (e.g., total flux (.mu.g/day))
and the design of the device (e.g., total area of the device
including therapeutic capable agent), the various properties (e.g.,
physical and/or chemical) may be configured to bring about the
desired result.
[0052] The therapeutic capable agent may be made available at an
initial phase and one or more subsequent phases. When the
therapeutic capable agent is delivered at different phases, the
initial delivery rate will typically be from about 0 to about 99%
of the subsequent release rates, usually from about 0% to about
90%, preferably from about 0% to 75%. In an embodiment a mammalian
tissue concentration of the substance at an initial phase will
typically be within a range from about 0.001 nanogram (ng)/mg of
tissue to about 100 .mu.g/mg of tissue; from about 1 ng/mg of
tissue to about 100 .mu.g/mg of tissue; from about 1 ng/mg of
tissue to about 10 .mu.g/mg of tissue. A mammalian tissue
concentration of the substance at a subsequent phase will typically
be within a range from about 0.001 ng/mg of tissue to about 600
.mu.g/mg of tissue, preferably from about 1 ng/mg of tissue to
about 10 .mu.g/mg of tissue.
[0053] The rate of delivery during the initial phase will typically
range from about 0.001 ng to about 50 .mu.g per day, usually from
about 0.1 .mu.g to about 30 .mu.g per day, more preferably, from
about 1 .mu.g per day to about 20 .mu.g per day. The rate of
delivery at the subsequent phase may range from about 0.01 .mu.g
per day to about 200 .mu.g per day, usually from about 1 .mu.g per
day to about 100 .mu.g per day. In one embodiment, the therapeutic
capable agent is made available to the susceptible tissue site in a
programmed and/or controlled manner with increased efficiency
and/or efficacy. Moreover, the present invention provides limited
or reduced hindrance to endothelialization of the vessel wall.
[0054] The duration of the initial, subsequent, and any other
additional phases may vary. For example, the release of the
therapeutic capable agent may be delayed from the initial
implantation of the device. Typically the delay is sufficiently
long to allow the generation of sufficient cellularization or
endothelialization at the treated site. Typically, the duration of
the initial phase will be sufficiently long to allow initial
cellularization or endothelialization at, at least part of the
device. Typically, the duration of the initial phase whether being
a delayed phase or a release phase, is usually less than about 12
weeks, more usually from about 1 hour to about 8 weeks, more
preferably from about 12 hours to about 4 weeks, from about 12
hours to about 2 weeks, from about 1 day to about 2 weeks, or from
about 1 day to about 1 week.
[0055] The durations of the one or more subsequent phases may also
vary, typically being from about 4 hours to about 24 weeks, from
about 1 day to about 12 weeks, from about 2 days to about 8 weeks,
more preferably in from about of 3 days to about 50 days. In an
embodiment, the duration specified relates to a vascular
environment. The more than one phase may include similar or
different durations, amounts, and/or rates of release. For example,
in one scenario, there may be an initial phase of delay, followed
by a subsequent phase of release a first subsequent rate, and
second subsequent phase at a second subsequent rate of release, and
the like.
[0056] When the device includes the source including a plurality of
compounds (e.g., first therapeutic capable agent and an another
compound such as another therapeutic capable agent or enabling
compound), the plurality of compounds may be released at different
times and/or rates, from the same or different layers when present.
Each of the plurality of compounds may be made available
independently of another, simultaneous with, or subsequent to the
interventional procedure, and may be simultaneous or sequential
with one another. For example, a first therapeutic capable agent
(e.g., Triptolide.TM. may be released within a time period of 1 day
to 45 days with the second therapeutic capable agent (e.g,
mycophenolic acid) released within a time period of 2 days to 3
months, from the time of interventional procedure.
[0057] Furthermore, a biocompatible (e.g., blood compatible) layer
may be formed over the source and/or the most outer layer of the
device, to make or enhance the biocompatibility of the device.
Suitable biocompatible material for use as the biocompatible layer
include, but are not limited to, polyethylene glycol (PEG),
polyethylene oxide (PEO), hydrogels, silicone, polyurethanes,
heparin coatings.
[0058] In an embodiment, the device further includes another
compound, such as another therapeutic capable agent, or another
compound enabling and/or enhancing either or both the release and
efficacy of the therapeutic capable agent. The another therapeutic
capable agent may be associated with expandable structure in the
same or different manner as the first therapeutic capable
agent.
[0059] The another therapeutic capable agent may act in synergy
with the therapeutic capable agent, in ways such as compensating
for the possible reactions and by-products that can be generated by
the therapeutic capable agent. By way of example, the therapeutic
capable agent may reduce generation of desired endothelial cells,
thus by including a suitable another therapeutic capable agent,
more endothelialization may be achieved.
[0060] The another therapeutic capable agent may comprise at least
one compound selected from the group consisting of anti-cancer
agents; chemotherapeutic agents; thrombolytics; vasodilators;
antimicrobials or antibiotics antimitotics; growth factor
antagonists; free radical scavengers; biologic agents;
radiotherapeutic agents; radiopaque agents; radiolabelled agents;
anti-coagulants such as heparin and its derivatives;
anti-angiogenesis therapeutic capable agents such as
Thalidomide.TM.; angiogenesis therapeutic capable agents; PDGF-B
and/or EGF inhibitors; anti-inflamatories including psoriasis
therapeutic capable agents; riboflavin; tiazofurin; zafurin;
anti-platelet agents including cyclooxygenase inhibitors such as
acetylsalicylic acid, ADP inhibitors such as clopidogrel (e.g.,
Plavix.TM.) and ticlopdipine (e.g., Ticlid.TM.), phosphodiesterase
III inhibitors such as cilostazol (e.g., Pletal.TM.), glycoprotein
IIb/IIIa agents such as abciximab (e.g., Rheopro.TM.); eptifibatide
(e.g., Integrilin.TM.), and adenosine reuptake inhibitors such as
dipyridmoles; healing and/or promoting agents including
anti-oxidants, nitrogen oxide donors; antiemetics; antinauseants;
derivatives and combinations thereof. The another therapeutic agent
may be released prior to, concurrent with, or subsequent to, the
therapeutic capable agent, at similar or different rates and
phases.
[0061] In an embodiment, the another compound comprises, an
enabling compound respondable to an external form of energy, or
native condition, to affect the release of the therapeutic capable
agent. The respondable compound may be associated with the
therapeutic capable agent, the rate-controlling element, the
expandable structure, or a combination thereof. The second enabling
compound may be formed from magnetic particles coupled to the
therapeutic capable agent. The energy source may be a magnetic
source for directing a magnetic field at the prosthesis after
implantation to effect release of the therapeutic capable
agent.
[0062] In an embodiment of a method for making the devices of the
present invention, an implantable structure is provided with a
source of therapeutic capable agent. The therapeutic capable
agent-coated structure is then heated to a temperature, usually to
a temperature about the same as the melting point of the
therapeutic capable agent or less, for a period of time. Lower or
higher temperatures may also be used depending on the duration of
the heating step. In an embodiment, the heating helps in a change
in the crystallinity of the therapeutic capable agent, thus
providing for a more uniform surface under the rate-controlling
element. In an alternate embodiment, the therapeutic capable
agent-coated structure is heated after the rate-controlling element
has also be provided on the structure.
[0063] In another embodiment, the therapeutic capable
agent/rate-controlling element-coated structure is heated to a
temperature about the same or lower than the glass transition
temperature (Tg) of the rate-controlling element. Higher or lower
temperatures may also be used with appropriate adjustment of the
duration of the heating step. In one embodiment, the heating is
performed under vacuum and/or in the absence of oxygen. The heating
of the coated device to this temperature, assists in reducing the
residual stress of the device, thus reducing the likelihood of
formation of undesirable disruption in the rate-controlling element
coating. It should be noted, that in some embodiments, the presence
of disruptions before and/or after the device is implanted in the
intracorporeal body may be purposefully designed into the device.
Other forms of energy other than heat, may also be used in the
reduction of the residual stress, for example, ultrasound, or
vibrational energy.
[0064] The present invention still further provides intracorporeal
devices comprising an implantable scaffold having at least one
source of at least one therapeutic capable agent associated
therewith and configured to be released when the scaffold is
implanted. A rate-controlling element comprising a non-porous
material covers at least a portion of the source. Preferably, the
non-porous material comprises parylene, more preferably consisting
essentially of paralyne, and often consisting of parylene. Other
non-porous materials, however, may also find use, such as plasma
deposited polymers, sputtered materials, evaporated materials,
electroplated metals, electroplated alloys, glow discharge coating,
polyethylenes, polyurethanes, silicone rubber, cellulose, and the
like. Usually, the non-porous layers will become at least partially
porous when exposed to the conditions in the implanted region,
typically a blood vessel. Alternatively, the rate controlling
member may become disrupted, e.g., crack or form holes, when
implanted. Often, a therapeutic capable agent will be present in
the rate-controlling element, usually being the same substance as
in the source.
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] FIGS. 1A through 1C are cross-sectional views of a device
embodying features of the present invention and implanted in a body
lumen.
[0066] FIGS. 2A through 2N are cross-sectional views of various
embodiments of the delivery prosthesis of FIGS. 1A-1C taken along
line 2-2.
[0067] FIG. 3 is a schematic representation of an exemplary stent
for use as the device of the present invention.
[0068] FIGS. 4A and 4B are schematic representations of an expanded
view of a portion of the Stent of FIG. 3 showing areas having
different mechanical profiles.
[0069] FIGS. 5A through and 8D are schematic representations of
different embodiments of the stent of FIG. 4A.
[0070] FIGS. 9A through 9D is a schematic representation of an
embodiment of the stent of FIG. 4A having an aperture in the
rate-controlling element.
[0071] FIGS. 10A through 10D are schematic representation of
different embodiments of methods for making the stent of FIG.
9.
[0072] FIGS. 1A and 1B are schematic representations of an
embodiment of the stent of FIG. 4A having deliberate disrupted
areas.
[0073] FIG. 12 is a schematic representation of an embodiment of a
method of making the stent of FIG. 4A disposed on a rotating
mandrel.
[0074] FIGS. 13A through 13D are schematic representation of
different embodiments of apparatus and methods for making the
stents of FIG. 4A.
[0075] FIGS. 14A through 14C are schematic representations of
another embodiment of masking apparatus and methods for making the
stent of FIG. 4A.
[0076] FIGS. 15A and 15B are schematic representations of spray
apparatus and methods for making the stent of FIG. 4A.
[0077] FIG. 16 is a graphical representation of the release of a
therapeutic capable agent over a predetermined time period.
[0078] FIGS. 17A, 17B, 18A, 18B, 19A through 19E, 20A, 20B, 21A,
and 21B are graphical representations of the performance of various
therapeutic capable agents.
[0079] FIG. 22 are graphical representations of the performance of
stents having different thicknesses of rate-controlling
element.
[0080] FIGS. 23A and 23B are graphical representation of different
embodiments of stents showing the effect of apertures in the
rate-controlling element on release rate of therapeutic capable
agent.
[0081] FIG. 24 is a graphical representation of the stent of FIG.
4A showing the effect of masking during coating of the therapeutic
capable agent.
[0082] FIG. 25 is a graphical representation of the stent of FIG.
4A showing the effect of heating of stent on the release of
therapeutic capable agent.
DETAILED DESCRIPTION OF THE INVENTION
[0083] FIGS. 1A-1C, and cross-sectional drawings FIGS. 2A-2N,
illustrate a device 10, such as a prosthesis 13, embodying features
of the invention and generally including an expandable structure 16
implantable in an intracorporeal body, such as body lumen 19
including a susceptible tissue site 22, and a source 25 adjacent
the expandable structure 16 including a therapeutic capable agent
28. The device 10, as shown, is disposed in the body lumen 19. It
should be appreciated, that although the source 25 as depicted in
the figures is disposed adjacent a surface of the expandable
structure, the word adjacent is not intended to be limited by the
exemplary figures or descriptions.
[0084] As used herein the term "therapeutic capable agent" includes
at least one compound which is either therapeutic as it is
introduced to the corporeal body (e.g., human subject) under
treatment, or becomes therapeutic after entering the corporeal body
of the subject (or exposed to the surface of the corporeal body as
the case may be), by for example, reaction with a native or
non-native substance or condition. Examples of native conditions
include pH (e.g. acidity), chemicals, temperature, salinity,
conductivity, contractile or expansive changes of the body
lumen/organ, and pulsating nature of the body fluids as they flow
through or come in contact with the device; with non-native
conditions including those such as magnetic fields, and ultrasound.
In the present application, the chemical name of any of the
therapeutic capable agents or other compounds is used to refer to
the compound itself and to pro-drugs (precursor substances that are
converted into an active form of the compound in the body), and/or
pharmaceutical derivatives, analogues, or metabolites thereof
(bioactive compound to which the compound converts within the body
directly or upon introduction of other agents or conditions (e.g.,
enzymatic, chemical, energy), or environment (e.g., pH)).
[0085] The expandable structure may be formed of any suitable
material such as metals, polymers, or a combination thereof. In one
embodiment, the expandable structure may be formed of an at least
partially biodegradable material, selected from the group
consisting of polymeric material, metallic materials, or
combinations thereof. The at least partially biodegradable
material, preferably degrades over time. Examples of polymeric
material include poly-L-lactic acid, having a delayed degradation
to allow for the recovery of the vessel before the structure is
degraded. Example of metallic material include metals or alloys
degradable in the corporeal body, such as stainless steel.
[0086] The therapeutic capable agent may be selected from a group
consisting of immunosuppressants, anti-inflammatories,
anti-proliferatives, anti-migratory agents, anti-fibrotic agents,
proapoptotics, calcium channel blockers, anti-neoplastics,
anti-cancer agents, antibodies, anti-thrombotic agents,
anti-platelet agents, IIb/IIIa agents, antiviral agents, and a
combination thereof.
[0087] Specific examples of therapeutic capable agent include:
mycophenolic acid, mycophenolate mofetil, mizoribine,
methylprednisolone, dexamethasone, Certican.TM., rapamycin,
Triptolide.TM., Methotrexate.TM., Benidipine.TM., Ascomycin.TM.,
Wortmannin.TM., LY294002, Camptothecin.TM., Topotecan.TM.,
hydroxyurea, Tacrolimus.TM. (FK 506), cyclophosphamide,
cyclosporine, daclizumab, azathioprine, prednisone,
Gemcitabine.TM., cilostazol (Pletal.TM.), tranilast, quercetin,
suramin; metabolites, derivatives, and combinations thereof.
[0088] In an embodiment, the source of the therapeutic capable
agent is a polymeric material including therapeutic capable agent
moieties as a structural subunit of the polymer. The therapeutic
capable agent moieties are polymerized and associated to one
another through suitable linkages (e.g. ethylenic) forming
polymeric therapeutic capable agent. Once the polymeric therapeutic
capable agent is brought into contact with tissue or fluid such as
blood, the polymeric therapeutic capable agent subunits
disassociate. Alternatively, the therapeutic capable agent may be
released as the polymeric therapeutic capable agent degrades or
hydrolyzes, preferably, through surface degradation or hydrolysis,
making the therapeutic capable agent available to the susceptible
tissue site, preferably over a period of time. Examples of methods
and compounds for polymerizing therapeutic capable agents are
described in WO 99/12990 Patent Application by Kathryn Uhrich,
entitled "Polyanhydrides With Therapeutically Useful Degradation
Products," and assigned to Rutgers University, the full disclosure
of which is incorporated herein by reference. An example of a
therapeutic capable agents and a suitable reaction ingredient unit
includes, mycophenolic acid with adipic acid and/or salicylic acid
in acid catalyzed esterification reaction; mycophenolic acid with
aspirin and/or adipic acid in acid catalyzed esterification
reaction, mycophenolic acid with other NSAIDS, and/or adipic acid
in acid catalyzed esterification reaction. In an embodiment, the
polymeric therapeutic capable agent may be associated with a
polymeric and/or metallic backbone.
[0089] The expandable structure 16, as shown without intending any
limitation, has a tissue facing surface 31 and luminal facing
surface 34, and optionally an interior 37 which may include a lumen
as shown in FIG. 2B. It will be appreciated that the following
depictions are for illustration purposes only and do not
necessarily reflect the actual shape, size, configuration, or
distribution of the prosthesis 13. The prosthesis may have a
continuous structure or an intermittent structure as the case may
be with many stents (e.g., the cross section of the stent does not
entirely include a substrate forming the expandable structure--for
example, some stents have a screen or mesh like cross section). The
source may be disposed or formed adjacent at least a portion of
either or both the luminal facing surface, as shown in FIG. 1B; and
the tissue facing surface, as shown in FIG. 1C; within the interior
of the expandable structure, or any combination thereof.
[0090] The source 25 for making the therapeutic capable agent
available to therapeutic capable agent is associated with
expandable structure, in one or more configurations. The source as
shown in FIGS. 2A and 2B is within the expandable structure 16, as
for example, when a matrix 40 is formed by the expandable structure
16 and the therapeutic capable agent 28, or when the therapeutic
capable agent 28 is disposed within the interior (or the exterior
of the expandable structure 16 as the case may be), 37 of the
expandable structure 16. In an embodiment, the source 25 has a
thickness typically in a range from about 1 angstroms (A) to about
50 microns (.mu.m), from about 100 angstroms to about 20 microns,
usually from about 100 angstroms to about 10 microns, normally from
about 5000 angstroms to about 5 microns, and nominally from abut
7500 angstroms to about 2 microns.
[0091] Now referring to FIG. 2C, the device further comprises a
rate-controlling element 43. The rate-controlling element may be
formed over at least a portion of the expandable structure 16 for
controlling the release of the therapeutic capable agent 28 from
the matrix 40 or the interior 37 of the expandable structure. The
source may be the rate-controlling element itself when the
therapeutic capable agent is a polymeric therapeutic capable
agent.
[0092] In an embodiment, the source may comprise a matrix
comprising the therapeutic capable agent and a matrix forming
material. By way of example, the source may comprise a matrix
comprising mycophenolic acid and albumin (e.g., Bovine Serum
Albumin or BSA). The presence of the matrix material for which the
therapeutic capable agent has an affinity for, as for example BSA,
reduces the rate of elusion (thus release) of mycophenolic acid to
the susceptible tissue site.
[0093] The rate-controlling element may be formed of a
non-degradable, partially degradable, substantially degradable
material, or a combination thereof. The material may be synthetic
or natural; non-polymeric, polymeric, ceramic, or metallic; or a
combination thereof. The rate-controlling element may have a
porous, microporous, nanoporous, or nonporous morphology, or any
combinations thereof. Preferably, when the device comprise a porous
rate-controlling element, at least one layer of a nonporous
rate-controlling element is disposed between the source and the
porous rate-controlling element.
[0094] In a preferred embodiment the rate-controlling element is
formed from a nonporous material, usually a nonporous conformal
material. Example of suitable non-porous material include, but not
limited to: plasma deposited polymers; sputtered, evaporated,
electroplated metals and/or alloys; glow discharge coating;
polyethylene; polyurethanes; silicone rubber; cellulose; and
parylene including parylene C, N, D, F, or combinations thereof,
usually parylene C.
[0095] Suitable nondegradable or slow degrading rate-controlling
element materials include, but are not limited to, polyurethane,
polyethylenes imine, cellulose acetate butyrate, ethylene vinyl
alcohol copolymer, silicone, polytetrafluorethylene (PTFE),
parylene, parylast, poly(methyl methacrylate butyrate),
poly-N-butyl methacrylate, poly(methyl methacrylate), poly
2-hydroxy ethyl methacrylate, poly ethylene glycol methacrylates,
poly vinyl chloride, poly(dimethyl siloxane),
poly(tetrafluoroethylene), poly(ethylene oxide), poly ethylene
vinyl acetate, poly carbonate, poly acrylamide gels,
N-vinyl-2-pyrrolidone, maleic anhydride, Nylon, quarternary
ammonium compounds including stearyl ammonium chloride and benzyl
ammonium chloride, cellulose acetate butyrate (CAB) and the like,
including other synthetic or natural polymeric substances;
mixtures, copolymers, and combinations thereof. In an embodiment
the rate-controlling element is formed from a material selected
from the group consisting of silicone, polytetrafluoroethylene,
parylast, polyurethane, parylene, cellulose acetate butyrate;
mixtures, copolymers and combinations thereof.
[0096] Suitable biodegradable rate-controlling element materials
include, but are not limited to, poly(lactic acid), poly(glycolic
acid) and copolymers, poly dioxanone, poly(ethyl glutamate),
poly(hydroxybutyrate), polyhydroxyvalerate and copolymers,
polycaprolactone, polyanhydride, poly(ortho esters);
poly(iminocarbonates), polyester amides, polyester amines,
polycyanoacrylates, polyphosphazenes, copolymers and other
aliphatic polyesters, or suitable copolymers thereof including
copolymers of poly-L-lactic acid and poly-e-caprolactone; mixtures,
copolymers, and combinations thereof. Other examples of suitable
material include polymers, as disclosed in U.S. Pat. No. 5,610,241
and issued to Lee et al., and incorporated herein by reference in
its entirety. Lee discloses graft polymers having a biodegradable
backbone and side chains with reactive amino acid groups and/or
protected amino acid groups. The graft polymers are obtained from a
biodegradable homopolymer or copolymer starting material having
carbonyl group and carbon alpha to carbon of the carbonyl group and
having H atom on carbon alpha to carbonyl carbon and consisting
essentially of biodegradable homopolymer or copolymer backbone
joined at backbone carbon alpha to backbone carbonyl group, to the
chain amino acid pendant group at a carbonyl moiety of the pendant
group, which side chain amino acid pendant group contains reactive
amino acid group(s) and/or protected amino acid groups.
[0097] The graft polymers are prepared by reacting amino acid
halide having other reactive groups protected, with biodegradable
polymer containing carbanion on carbon alpha to carbon of carbonyl
group, and then deprotecting the protected groups.
[0098] Suitable natural material include: fibrin, albumin,
collagen, gelatin, glycosoaminoglycans, oligosaccharides & poly
saccharides, chondroitin, phosholipids, phosphorylcholine,
glycolipids, proteins, amino acids, cellulose, and mixtures,
copolymers, or combinations thereof. In an embodiment, the
rate-controlling element comprises Bovine Serum Albumin (BSA).
[0099] Other suitable material include, titanium, chromium,
Nitinol, gold, stainless steel, metal alloys, ceramics, or a
combination thereof; and other compounds that may release the
therapeutic capable agent as a result of interaction (e.g.,
chemical reaction, high molecular weight, steric hindrance,
hyrophobicity, hydrophilicity, amphilicity, heat) of the
therapeutic capable agent with the rate-controlling element
material (e.g, a non-polymer compound). By way of example, a
combination of two or more metals or metal alloys with different
galvanic potentials to accelerate corrosion by galvanic corrosion
pathways may also be used.
[0100] The degradable material may degrade by bulk degradation or
hydrolysis. In an embodiment, the rate-controlling element degrades
or hydrolyzes throughout, or preferably, by surface degradation or
hydrolysis, in which a surface of the rate-controlling element
degrades or hydrolyzes over time while maintaining bulk integrity.
In another embodiment, hydrophobic rate-controlling elements are
preferred as they tend to release therapeutic capable agent at
desired release rate. A non-degradable rate-controlling element may
release therapeutic capable agent by diffusion.
[0101] FIG. 2D illustrates features of an embodiment having the
therapeutic capable agent 28 disposed between one of the tissue or
luminal facing surfaces of the expandable structure and the
rate-controlling element 43.
[0102] As shown in FIG. 2E, the source 25 includes the
rate-controlling element 43 formed adjacent at least a portion of
one of the tissue or luminal facing surfaces of the expandable
structure 16 and forming the matrix 40 with the therapeutic capable
agent 28. As noted earlier, the therapeutic capable agent 28 may
itself act as a rate-controlling element, as for example, when the
polymeric therapeutic capable agent forms a matrix.
[0103] The matrix may be formed between the rate-controlling
element 43 and the expandable structure 16 and forming a matrix
interface 46 therebetween and/or between the therapeutic capable
agent 28 and the rate-controlling element 43, as shown in FIGS. 2F
and 2G. The matrix interface may formed as a result of the physical
disposition of the two layers (e.g., rate-controlling element and
the therapeutic capable agent. Alternatively and/or additionally,
the matrix interface may be formed as a result of chemical reaction
between the therapeutic capable agent and a polymer, oligomer,
coupling agent, or small molecule. The matrix interface,
preferably, further provides controlling of the release of the
therapeutic capable agent to the susceptible tissue site.
[0104] In an embodiment, features of which are shown in FIG. 2H,
the outer most layer of the prosthesis 13 may be formed of the
therapeutic capable agent with or without a matrix interface 46
formed between the outer most layer and the other layers. It should
be noted, that the therapeutic capable agent 28, although as shown
in most figures as discrete particles, may form a smooth layer or a
layer of particles, as for example as part of matrix interface 46
as shown in FIG. 2H.
[0105] In an alternate embodiment, features of which are shown in
FIG. 21, at least one layer of a second rate-controlling element 49
is formed over the matrix 40, further affecting the release rate of
the therapeutic capable agent 28 to the susceptible tissue site.
The second rate-controlling element 49 may be of the same or
different material than that forming the first rate-controlling
element 43.
[0106] Now referring now to FIGS. 2J and 2K, the source may
comprise, a plurality of compounds, as for example the first
therapeutic capable agent 28 and another compound 50 such as
another therapeutic capable agent 50 or an enabling compound 61
(FIG. 2N). Each of the plurality of compounds may be in the same or
different area of the source. For example, as shown in FIG. 2K, the
first therapeutic capable agent 28 may be present in matrix 40
while the second therapeutic capable agent 50 is in a second matrix
52 formed by the second therapeutic capable agent 50 and a second
rate-controlling element 55. The rate-controlling elements 43 and
55 may be formed from the same or different material.
[0107] The another therapeutic capable agent may comprise at least
one compound selected from the group consisting of anti-cancer
agents; chemotherapeutic agents; thrombolytics; vasodilators;
antimicrobials or antibiotics antimitotics; growth factor
antagonists; free radical scavengers; biologic agents;
radiotherapeutic agents; radiopaque agents; radiolabelled agents;
anti-coagulants such as heparin and its derivatives;
anti-angiogenesis therapeutic capable agents such as
Thalidomide.TM.; angiogenesis therapeutic capable agents; PDGF-B
and/or EGF inhibitors; anti-inflamatories including psoriasis
therapeutic capable agents; riboflavin; tiazofurin; zafurin;
anti-platelet agents including cyclooxygenase inhibitors such as
acetylsalicylic acid, ADP inhibitors such as clopidogrel (e.g.,
Plavix.TM.) and ticlopdipine (e.g., Ticlid.TM.), phosphodiesterase
III inhibitors such as cilostazol (e.g., Pletal.TM.), glycoprotein
IIb/IIIa agents such as abciximab (e.g., Rheopro.TM.); eptifibatide
(e.g., Integrilin.TM.), and adenosine reuptake inhibitors such as
dipyridmoles; healing and/or promoting agents including
anti-oxidants, nitrogen oxide donors; antiemetics; antinauseants;
derivatives and combinations thereof. The another therapeutic agent
may be released prior to, concurrent with, or subsequent to, the
therapeutic capable agent, at similar or different rates and
phases.
[0108] In another embodiment, features of which are shown in FIGS.
2L and 2M, the therapeutic capable agent 28 is disposed within or
on the expandable structure 16 within a reservoir 58. The
rate-controlling element 43 may be disposed adjacent the reservoir
58 and/or the therapeutic capable agent 28 for affecting the
release of the therapeutic capable agent. As stated earlier, the
exemplary figures and descriptions are not meant to limit the term
"adjacent."
[0109] In a further embodiment, features of which are shown in FIG.
2N, the another compound comprises the enabling compound 61
respondable to an external form of energy, or native condition, to
affect the release of the therapeutic capable agent. The
respondable compound may be associated with the therapeutic capable
agent, the rate-controlling element, the expandable structure, or a
combination thereof. As shown in FIG. 2N, the respondable compound
is associated with the therapeutic capable agent. The enabling
compound 61 may be formed from magnetic particles coupled to the
therapeutic capable agent 28. The energy source may be a magnetic
source for directing a magnetic field at the prosthesis 13 after
implantation to effect release of the therapeutic capable agent 28.
The magnetic particles 61 may be formed from magnetic beads and
will typically have a size in a range from about 1 nm to about 100
nm. The magnetic source exposes the prosthesis 13 to its magnetic
field at an intensity typically in the range from about 0.01 T to
about 2 T, which will activate the magnetic particles 61 and
thereby effect release of the therapeutic capable agent from the
prosthesis. The another enabling compound may be present in other
configurations of prosthesis 13 as described above.
[0110] Other suitable external energy sources, which may or may not
require another compound or their performance may not be affected
by the presence or absence of another compound, include ultrasound,
magnetic resonance imaging, magnetic field, radio frequency,
temperature change, electromagnetic, x-ray, radiation, heat, gamma,
vibration, microwave, or a combination thereof.
[0111] By way of example, an ultrasound external energy source may
be used having a frequency in a range from 20 kHz to 100 MHz,
preferably in a range from 0.1 MHz to 20 MHz, and an intensity
level in a range from 0.05 W/cm2 to 10 W/cm2, preferably in a range
from 0.5 W/cm2 to 5 W/cm2. The ultrasound energy would be directed
at the prosthesis 13 from a distance in a range from 1 mm to 30 cm,
preferably in a range from 1 cm to 20 cm. The ultrasound may be
continuously applied or pulsed, for a time period in a range from 5
sec to 30 minutes, preferably in a range from 1 minute to 15
minutes. The temperature of the prosthesis 13 during this period
will be in a range from 36.degree. C. to 48.degree. C. The
ultrasound may be used to increase a porosity of the prosthesis 13,
thereby allowing release of the therapeutic capable agent 28 from
the prosthesis 13. Other sources of energy, for example, heat or
vibrational, may also be used to increase the porosity of the
prosthesis or a portion thereof, or alter the configuration of the
same.
[0112] Furthermore, a biocompatible (e.g., blood compatible) layer
may be formed over the source and/or the most outer layer of the
device, to make or enhance the biocompatibility of the device.
Suitable biocompatible material for use as the biocompatible layer
include, but are not limited to, polyethylene glycol (PEG),
polyethylene oxide (PEO), hydrogels, silicone, polyurethanes,
heparin coatings.
[0113] The dimensions of the expandable structure will depend on
its intended use. Typically, the expandable structure will have a
length in a range from about 5 mm to about 100 mm, usually being
from about 8 mm to about 50 mm, for vascular applications. The
diameter of a cylindrically shaped expandable structure for
vascular applications, in a non-expanded configuration, usually
ranges from about 0.5 mm to about 10 mm, more usually from about
0.8 mm to about 8 mm; with the diameter in an expanded
configuration ranging from about 1.0 mm to about 100 mm, preferably
from about 2.0 mm to about 30 mm. The expandable structure usually
will have a thickness in a range from about 0.025 mm to 2.0 mm,
preferably from about 0.05 mm to about 0.5 mm.
[0114] The ring segments, and other components of structures such
as the expandable structure 16, may be formed from conventional
materials used for body lumen stents and grafts, typically being
formed from malleable metals or alloyes, such as 300 series
stainless steel, or from resilient metals, such as superelastic and
shape memory alloys, e.g., Nitinol.TM. alloys, spring stainless
steels, and the like; non-metallic materials, such as ceramics or
polymeric materials, or a combination thereof. The polymeric
materials may include those polymeric materials that are
substantially non-degradable, such as those described in relation
to the materials of choice for the rate-controlling element.
Alternatively, the polymeric material may be a biodegradable or
substantially biodegradable polymer such as those described in
reference with the biodegradable rate-controlling element material.
When the expandable structure material is formed of the
rate-controlling element material, the expandable structure may
function both as the prosthesis and the direct source of the
therapeutic capable agent. Additional structures for the body or
unit segments of the present invention are illustrated in U.S. Pat.
Nos. 5,195,417; 5,102,417; and 4,776,337, the full disclosures of
which are incorporated herein by reference.
[0115] Other suitable material for use as the structure include,
carbon or carbon fiber, cellulose acetate, cellulose nitrate,
silicone, polyethylene terphthalate, polyurethane, polyamide,
polyester, polyorthoester, polyanhydride, polyether sulfone,
polycarbonate, polytetrafluoroethylene, or another biocompatible
polymeric materials, or mixtures or copolymers thereof, a
polyanhydride, polycaprolactone, polyhydroxybutyrate valerate or
another biodegradable polymer, or mixtures or copolymers thereof; a
protein, an extracellular matrix component, collagen, fibrin or
another biologic agent, or a suitable mixture of any of the
material listed above, degradable, non-degradable, metallic, or
otherwise. In an embodiment, device may comprise a biodegradable
structure with a polymeric source, such as a polymeric therapeutic
capable agent.
[0116] The expandable structure 16 may be a stent 70 or, a graft.
When the expandable structure is a stent, the expandable structure
16 will usually comprise at least two radially expandable, usually
cylindrical, ring segments 73 as shown in FIG. 3. Typically, the
expandable structure 16 will have at least four, and often five,
six, seven, eight, ten, or more ring segments. At least some of the
ring segments will be adjacent to each other but others may be
separated by other non-ring structures. The description of
exemplary stent structures are not intended to be exhaustive, and
it should be appreciate that other variations of stent designs
usable in the present invention are known to those skilled in the
art.
[0117] Referring back to FIG. 3, the exemplary stent 70 (embodying
features of a stent described in more detail in co-pending U.S.
patent application Ser. No. 08/968,319 and assigned to the assignee
of the present invention, the disclosure of which in its entirety
is incorporated herein by reference) for use in the present
invention comprises from 4 to 50 ring segments 73 (with eight being
illustrated). Each ring segment 73 is joined to the adjacent ring
segment by at least one of sigmoidal links 76. Each ring segment 73
includes a plurality, e.g., six strut/hinge units, and two out of
each six hinge/strut structures on each ring segment 73 will be
joined by the sigmoidal links 76 to the adjacent ring segment.
Stent 70 as shown in FIG. 3 shows the stent 70 is in a collapsed or
non-expanded configuration.
[0118] The term "radially expandable" as used herein includes
segments that can be converted from a small diameter configuration
to a radially expanded, usually cylindrical, configuration which is
achieved when the expandable structure 16 is implanted at a desired
target site. The expandable structure 16 may be minimally
resilient, e.g., malleable, thus requiring the application of an
internal force to expand and set it at the target site. Typically,
the expansive force can be provided by a balloon, such as the
balloon of an angioplasty catheter for vascular procedures. The
expandable structure 16 preferably provides sigmoidal links between
successive unit segments which are particularly useful to enhance
flexibility and crimpability of the stent.
[0119] Alternatively, the expandable structure 16 can be
self-expanding. Structures for use in the devices of the present
invention, including the expandable structure 16 (such as
self-expanding structures) are provided by utilizing a resilient
material, such as a tempered stainless steel, or a superelastic
alloy such as a Nitinol.TM. alloy, and forming the body segment so
that it possesses its desired, radially-expanded diameter when it
is unconstrained, i.e. released from the radially constraining
forces of a sheath. In order to remain anchored in the body lumen,
the expandable structure 16 will remain partially constrained by
the lumen. The self-expanding expandable structure 16 can be
tracked and delivered in its radially constrained configuration,
e.g., by placing the expandable structure 16 within a delivery
sheath or tube and removing the sheath at the target site.
[0120] Now referring back to FIG. 3, and to FIGS. 4A and 4B, the
exemplary stent 70 including features of the invention is shown to
generally include a cylindrical frame 79 having proximal and distal
ends, 82 and 85, tissue and luminal facing surfaces, 88 and 91, a
plurality of radially expansible unit segments including rings 73.
The unit segments, preferably, include segments having different
mechanical profiles, as for example may be exhibit as a result of
expansion. For example, the segments, may include relatively lower
mechanical profile portions their lengths with relatively higher
mechanical profile portions at bends, points, intersections,
joints, or areas exposed to flow turbulence. The areas exhibiting
relatively lower mechanical profiles, upon the expansion of the
scaffold, typically do not under substantial bending, flexing,
stretching, or compression, usually being less than about 5%. Some
of the rings 73, as shown, are joined with at least one axially
adjacent ring through expansion links 76, preferably having a
sigmoidal shape, more preferably, an S shape having a relatively
smooth profile along its length to minimize or reduce kinking upon
expansion. Preferably, the rings 73, as shown, have a serpentine
shape. Similarly, the links may comprise segments having different
mechanical profile profiles along their length. For example, the
links or joints may include relatively lower mechanical profile
portions along their lengths with relatively higher mechanical
profile portions at bends, points, intersections, joints, or areas
exposed to flow turbulence (i.e., areas which are substantially in
the direct line of fluid (e.g., blood or other bodily fluids) flow
through the body).
[0121] In an embodiment as shown in FIGS. 5A and 5B, the
therapeutic capable agent is disposed adjacent all of the surface
of at least one of the tissue facing and luminal facing surfaces of
the structure on both the higher and lower stress areas, 94 and 97.
As shown in FIGS. 6A through 6F, the source may be disposed on all
of at least one of the tissue or luminal facing surfaces or only on
the portions of the cylindrical frame, usually, only on those
portions of the ring and/or joints, 73 and 76, having relatively
lower mechanical profiles 97. The therapeutic capable agent may be
applied in discrete portions, the portions having relatively larger
areas (e.g., FIG. 6A), preferably on areas having relatively lower
mechanical profile. Alternatively or additionally, the therapeutic
capable agent may be present in smaller surface areas (e.g. FIG.
6B), preferably along the outer surfaces of the structure and away
from sides and/or edges of the rings and/or the links (FIGS. 6D,
6F).
[0122] The source may vary in the amount of the therapeutic capable
agent it comprises. When the source is present in a plurality of
segments, as for example, when present in discrete portions, each
source may comprise same or different therapeutic capable agents,
at same or different amounts, and may make the therapeutic capable
agent available to the susceptible tissue site at same or different
phases and/or rates. The source may be the therapeutic capable
agent, as for example when the therapeutic capable agent is a
polymeric therapeutic capable agent, or may comprise a matrix as
for example one or more therapeutic capable agents with same or
different matrix forming material. The source may be present as a
layer, a matrix, as part of a matrix interface, on or within the
structure, or combinations thereof. The source may be present as a
single layer, or a plurality of layers immediately adjacent one
another or separated by another layer (such as another source or a
rate-controlling element layer).
[0123] In an embodiment features of which are shown in FIGS. 7A
through 7D, the stent further comprises a rate-controlling element
43 disposed adjacent (as for example, over) at least a portion of
the structure. The rate-controlling element may disposed adjacent
the structure on at least one of the tissue or luminal facing
surfaces (e.g. FIG. 7A) or only those areas of the stent including
the source 25 (e.g., FIG. 7B). When the rate-controlling element is
disposed only in some but not all of the areas of the structure,
the device may advantageously exhibit a relatively higher
flexibility as compared to a structure which is completely covered
with the rate-controlling element. In an alternate embodiment, the
rate-controlling element may be disposed only on those areas of the
structure having a relatively higher stress profile. This latter
embodiment may be particularly useful when a device with greater
overall coating thickness or one having a rate-controlling element
applied over the entire structure, is desired. It should be
appreciated that although the rate-controlling element as shown in
the figures covers the entire perimeter of the structure, the
rate-controlling element may cover only portions of the structure
on one or both luminal and tissue facing surfaces and/or the ends
of the device. Additionally, the rate-controlling element and/or
the therapeutic capable agent may have a different thickness at
various locations of the structure, as for example, on the sides
being in direct flow of the bodily fluids.
[0124] In another embodiment features of which are shown in FIGS.
8A through 8D, the device comprises segments with and without
therapeutic capable agent with the rate-controlling element 43
disposed adjacent both the segments including the therapeutic
capable agent and those which do not. Preferably, the segments
including the therapeutic capable agent are disposed adjacent the
relatively lower mechanical profile areas with the relatively
higher mechanical profile areas not including the therapeutic
capable agent. The rate-controlling element comprises portions
having different thicknesses.
[0125] Preferably, the thickness of the rate-controlling element
disposed adjacent those segments of the device including the
therapeutic capable agent (source as for example a reservoir) is
relatively thinner than the thickness at other segments of the
device. This variable rate-controlling element thickness profile
provides for lower likelihood of cracking or pinhole formation at
the higher stress areas while maintaining a relatively overall thin
thickness. The minimization of the formation of the crack and/or
pinhole formation at these segments even though no therapeutic
capable agent is present, minimizes the likelihood of the
uncontrolled rapid release of the therapeutic capable agent.
[0126] The thickness of the rate-controlling element, such as the
nonporous rate-controlling element layer can range from about 50
angstroms (A) to about 50 microns (.mu.m), from about 100 angstroms
to about 20 microns, usually from about 100 angstroms to about 10
microns, normally from about 5000 angstroms to about 5 microns, and
nominally from abut 7500 angstroms to about 2 microns.
[0127] Without intending any limitation, it is believed that the
nonporous rate-controlling layer when applied over those portions
of the structure experiencing relatively higher mechanical profile
upon expansion, are susceptible to cracking and/or formation of
pinholes upon expansion. The cracking and/or pinhole formation
results in gaps in the rate-controlling layer. The gaps, in turn,
will aid in the transport of the elution medium to the source, thus
resulting in a more rapid release of the therapeutic capable agent
to the corporeal body. Depending on the need and the desired
effect, this effect may be desired to be reduced or minimized when
it is necessary to release the therapeutic capable agent over a
period of time. The therapeutic capable agent source may be absent
from all or only portions of those segments of the stents which
exhibit relatively higher mechanical profile.
[0128] In an embodiment having device segments with and without
therapeutic capable agent, the thickness of the rate-controlling
element preferably ranges from about 100 angstroms to about 5
microns; preferably, ranging from about 100 angstroms to about 1
micron at device segments including the therapeutic capable agent,
and preferably ranging from about 0.5 to about 5 microns at device
segments not including the therapeutic capable agent (e.g., high
stress areas). Alternatively, the thickness of the rate-controlling
element preferably ranges from about 0.5 microns to about 5
microns; preferably, ranging from about 1 micron to about 5 micron
at device segments including the therapeutic capable agent, and
preferably ranging from about 0.5 to about 5 microns at device
segments not including the therapeutic capable agent (e.g., high
stress areas). Preferably when the rate-controlling element
comprises parlylene, more preferably, parylene C, the stress area
thickness of the rate-controlling element ranges from about 0.5
microns to about 10 microns.
[0129] In another embodiment, the device may include areas (e.g.,
distal and proximal ends of the device) having variable thickness
of either or both the source and the rate-controlling element to
allow for slower or faster release rates.
[0130] In an embodiment such as that shown in FIGS. 6A and 6B when
the source is not present in the areas having relatively higher
mechanical profile, the thickness of the nonporous rate-controlling
element layer, preferably, range from about 50 angstroms to 5
microns.
[0131] In another embodiment, as shown in FIGS. 9A through 9D, the
device may include apertures or orifices 100 in the therapeutic
capable agent reservoir, made and used by similar processes as
those described below, allowing for controlled release of the
therapeutic capable agent to the targeted intracorporeal site.
[0132] The apertures 100 may be positioned in the rate-controlling
element (e.g., nonporus rate-controlling element such as parylene)
either or both directly above and offset from the therapeutic
capable agent source, as for example shown in FIGS. 9B and 9C,
respectively.
[0133] The apertures may have depth running the entire thickness of
the rate-controlling element layer or one shorter than the entire
depth depending on the desired release rate. A single device may
include similar or different apertures, sizes, locations, patterns,
and depths in order to effectuate the desired release rate of the
therapeutic capable agent. The aperture may range in opening from
about 1 angstrom to about 100 microns, usually from about 1
angstrom to about 8 microns.
[0134] In an embodiment, as shown in FIG. 9D, the source and the
rate-controlling element have at least a portion emerging out of
the structure surface. The emerged portion 103 may include an
aperture (surface or one having a more substantial depth) allowing
for a capillary-like function. The emerged portion, advantageously,
will be relatively more in contact with the tissue at the targeted
intracorporeal site allowing for more direct release of the
therapeutic capable agent to the tissue and less into the blood
stream thus minimizing wash out of the therapeutic capable
agent.
[0135] The amount and type of the therapeutic capable agent in each
source (e.g., reservoir) may be the same or different. In an
example, to minimize or reduce edge effect, the therapeutic capable
agent is present at a greater amount at the ends of the device.
[0136] The embodiments including the at least one aperture may
particularly be helpful in controllably increase the release rate
of the therapeutic capable agent to greater than 2 .mu.g/day,
preferably greater than about 5 .mu.g/day, and more preferably
greater than about 10 .mu.g/day; where the rate without the
apertures may have been less than 50 .mu.g/day, preferably less
than 5 .mu.g/day, more preferably less than 2 .mu.g/day.
[0137] When using devices according to the present invention and
including apertures in the rate-controlling element, greater
consistency in the release rate of the therapeutic capable agent
may be achieved. Typically, the rate-controlling element produces a
relatively higher degree of variation in the release rate from
device to device. Examples of factors bringing about such variation
include, but are not limited to, the polymer's physical and
chemical parameters which may vary lot to lot (e.g., structure,
molecular weight, orientation, crystallinity, glass transition
temperature, porosity, moisture content). Furthermore, as the
therapeutic capable agent permeates through the polymeric
rate-controlling element, phase separation and swelling of the
therapeutic capable agent and the rate-controlling element may
occur changing the porosity of the rate-controlling element, and
thus resulting in a change in therapeutic capable agent release
characteristics.
[0138] The apertures and holes may be made using a variety of tools
and methods, including but not limited to: physical piercing tools
(e.g., needle, wire, thin wall or sharpen edge tube, tube with
different cross-sections and sharpen edge, beveled tube, pick);
beams including laser, electron beam, or ionic beam bombardment,
ion implantation, or the like to create one or more holes or
orifices at precise locations or randomly on the rate-controlling
element; inducing the formation of pinholes or orifices by applying
a thin layer of rate-controlling element such that the pinholes are
created during application of the coating and/or use of the
device.
[0139] In an embodiment of a method of creating the orifices, as
shown in FIGS. 10A through 10D, a small diameter wire, plastic or
wax (e.g., bee wax), beading, tube, or similar object 106 is
attached on the desired location of hole/orifice before applying
the rate-controlling element. During the coating process, the
object will be conformally coated along with the structure and
becomes fixed to the structure. The object is then either partially
(FIG. 10C) or fully (FIG. 10D) cut or removed (e.g., with a cutting
tool), resulting in the exposure of a portion of the structure
which is no longer coated. The object can be coated with microsoap,
oil, detergent in water, or other release agents if it is desired
to remove it after coating, leaving an orifice in its place.
[0140] In another embodiment, as shown in FIGS. 11A and 11B, the
device 70.quadrature. includes deliberate disrupted areas 109
created as a result of expansion during the implanting of the
device and/or subsequent exposure to targeted intracorporeal site
environment.
[0141] By way of example, when a hydrophobic therapeutic capable
agent layer is applied at the device areas having relatively higher
mechanical profile profile, in particular when the at high
therapeutic capable agent concentrations, the therapeutic capable
agent and/or the rate-controlling element layer disposed adjacent
(e.g., on the exterior surface of the therapeutic capable agent
layer), may crack, disrupt, and/or form pinholes during as the
device is expanded or exposed to the targeted intracorporeal site
environment. Consequently, the therapeutic capable agent is
released at a higher rate in this disrupted areas. As device is
aged upon usage, the profile of the rate-controlling element may
change (e.g., change in the size of the disrupted area, porosity
increase as a result of movement of elution fluid to and from the
therapeutic capable agent).
[0142] In yet another embodiment, the therapeutic capable agent has
a degree of crystallinity less than about 90%, usually less than
about 50%. The lower crystallinity may be achieved by heating any
of the embodiments of the therapeutic capable agent-coated device
(before or after the application of the rate-controlling element)
to higher temperature, usually about or greater than the melting
point of the therapeutic capable agent, for a period of time
sufficient to bring about the desired degree of crystallinity,
usually from about 1 minute to about 24 hours, typically from about
30 minutes to about 2 hours. As the therapeutic capable agent
melts, it becomes more amorphous, thus less brittle. The amorphous
(or semi-amorphous) nature of the therapeutic capable agent reduces
creation of pin holes or unwanted interruptions in the
rate-controlling element layer, thus a more controlled rate of
release.
[0143] The heating of the therapeutic capable agent-coated device
with or without the rate-controlling element may additionally serve
to change, as for example, reduce the residual stress of the device
due to the molecular rearrangement of the therapeutic capable agent
and/or the rate-controlling element.
[0144] In an embodiment, the therapeutic capable
agent/rate-controlling element-coated device is heated to a
temperature for a period of time sufficient to change, usually
reduce the residual stress in the rate-controlling element to about
less than 10%, usually to about less than 5%, typically to about
less than 1%, normally to about less than 0.5%. Typically, the
device is heated to a temperature about or greater than the Tg of
the rate-controlling element, usually between the Tg and the
melting point of the rate-controlling element. The period of time
ranges usually from about 1 minute to about 24 hours, typically
from about 30 minutes to about 2 hours.
[0145] The residual stress of the coated device due to the
rate-controlling element and/or the therapeutic capable agent may
be also be reduced by other means such as: heating the device to a
temperature below the Tg of the rate-controlling element or the
melting point of the therapeutic capable agent, respectively, for a
longer period of time; and using other sources of energy including
ultrasonic, magnetic, or vibrational.
[0146] In an embodiment, the device comprises a layer of another
rate-controlling element which is configured to bind, at least
partially, with the therapeutic capable agent. In an embodiment
Bovine Serum Albumin (BSA) is disposed adjacent the nonporous
rate-controlling element (e.g., parylene) such that as the
therapeutic capable agent (e.g., mycophenolic acid) diffuses or
elutes out of the nonporous rate-controlling element, the
therapeutic capable agent binds with the BSA, further delaying or
controlling the release of therapeutic capable agent. Other
examples of another rate-controlling element capable of binding
with the therapeutic capable agent include quarternary ammonim
compounds such as polyethylene imine. In one embodiment a hydrogel
compound is disposed under either or both the therapeutic capable
agent and the rate-controlling element or in the matrix. As body
fluids come in contact with the hydrogel compound, the hydrogel
compound swells causing a change in the flow or diffusion
properties of the therapeutic capable agent through the
rate-controlling element, as for example by causing disruptions in
the rate-controlling element layer.
[0147] The expandable structure may incorporate the therapeutic
capable agent and/or the optional another compound, by coating,
spraying, dipping, deposition, or painting the therapeutic capable
agent onto the prosthesis. Usually, the therapeutic capable agent
is dissolved in a solvent prior to its application. Suitable
solvents include aqueous solvents (e.g., water with pH buffers, pH
adjusters, organic salts, and inorganic salts), alcohols (e.g.,
methanol, ethanol, propanol, isopropanol, hexanol, and glycols),
nitrites (e.g., acetonitrile, benzonitrile, and butyronitrile),
amides (e.g., formamide and N-dimethylformamide), ketones, esters,
ethers, DMSO, gases (e.g., CO.sub.2), and the like. The therapeutic
capable agent-structure is then allowed to dry. Alternatively, the
therapeutic capable agent may first be prepared into a matrix by
mixing or dissolving the therapeutic capable agent and matrix
material, alone or in combination with a solvent, prior to its
incorporation to the structure.
[0148] In an exemplary method of making the devices of the present
invention, a bare or uncoated stent is first fabricated and/or
processed (e.g., descaled, electropolished, passivated using
conventional methods prior to the incorporation of the therapeutic
capable agent. By way of example, the bare stent is optionally
treated with coupling agents such as silane, plasma deposited
coating, plasma treatment, coronary discharge, and/or other means
to promote and/or enhance the adhesion of the rate-controlling
element to the bare stent in subsequent steps.
[0149] A bare structure (e.g., prosthesis) or a coated therapeutic
capable agent-structure may be placed in vapor deposition chamber
or plasma deposited coating chamber. A therapeutic capable agent in
solid or liquid form can be placed directly under the structure in
a container or dish in the same chamber. The container may be
heated to a desired temperature (i.e., the boiling point or
sublimation temperature of the therapeutic capable agent),
simultaneously or periodically while the rate-controlling element
(e.g., parylene) or plasma deposition occurs. Since the chamber is
in vacuum, the gaseous therapeutic capable agent will, by line of
sight, coat the structure. The dish configuration (round, square,
rectangular, depth, cover with holes), the therapeutic capable
agent amounts/distribution, presence of a perforated shield/fence,
and other factors will control the thickness, distribution, and
uniformity of the therapeutic capable agent dispersed or deposited
directly or indirectly onto the stent. Alternatively, nano-size
deposition techniques may be used to selectively apply the
therapeutic capable agent and/or rate-controlling element to or
onto the structure.
[0150] By way of example, herein is described a more detail process
for applying rate-controlling element and/or therapeutic capable
agent on or within a structure. A small diameter mandrel 112 or
other means is inserted into the stent. The mandrel-stent structure
is then placed in the deposition chamber. Preferably, the
mandrel-stent structure may be removably affixed on a rotating
device inside the chamber to get more consistent coating, as for
example shown in FIG. 12. The deposition chamber is sealed. The
rate-controlling element material or its precursor (e.g., parylene
C, in its dimer form) is loaded into the ambient temperature
vaporizer zone through a load door. The door is then sealed. The
amount of rate-controlling element or its precursor loaded depends
on the desired or required coating thickness, total surface area of
the substrate, deposition chamber size, and type of the
rate-controlling element (e.g. parylene N, C, D or F). In an
exemplary embodiment, the amount of rate-controlling element
precursor (e.g., parylene C dimmer) loaded was about 3 grams. The
sealed system is then pumped down by a vacuum pump to a steady
state base pressure of for example about -4 to about 100 mTorr,
usually from about 4 to about 15 mTorr.
[0151] Once the system base pressure has been reached, the
vaporizer zone is then heated to an appropriate temperature, as for
example from about 70 to about 200.degree. C. (e.g., 80.degree.
C.). The vaporizer heater is cycled on/off by the chamber pressure
controller in order to maintain the pressure in the chamber. As the
pressure reaches the chamber-pressure set point, the power to the
vaporizer heater is reduced to prevent the chamber pressure from
overshooting. The vaporizer heater is then maintained at a
temperature where the chamber pressure is at the pressure set point
to aid in the gradual vaporization and/or sublimation of the solid
rate-controlling element or its precursor (e.g., parylene
dimer).
[0152] As the vacuum pump operates, the precursor gas flows
downstream through the pyrolysis zone. The high temperature
pyrolysis furnace cleaves the dimer gas to form the
rate-controlling element (e.g., parylene monomer) gas. As the
reactive monomer gas exits the pyrolysis zone and enters the
deposition chamber containing the structure (e.g., the prosthesis
structure) deposition takes place. The monomer will deposit and
polymerize on all or substantially all of the ambient temperature
surface within the deposition chamber which are available for
coating.
[0153] As the monomer gas flows into the deposition chamber, the
additional gas causes the pressure in the chamber to rise.
Typically, the desired rise ranges from about 10 to about 40 mTorr
above the base pressure for Parylene C. The growth rate of the
rate-controlling element (e.g., nonporous parylene film) in the
deposition chamber is proportional to the partial pressure of the
monomer gas. A feedback control system may be used to maintain the
desired pressure within the deposition chamber by controlling the
rate at which dimer is vaporized.
[0154] Concurrently and/or sequentially with the rate-controlling
element monomer gas (e.g., parylene C monomer gas) depositing onto
the structure surface, the dish containing the therapeutic capable
agent is heated to above the boiling point or sublimation
temperature of the therapeutic capable agent causing the gaseous
therapeutic capable agent to flow upward in the vacuum chamber.
Since the structure is in the line of sight with the therapeutic
capable agent gas, the structure is also coated with the
therapeutic capable agent. The therapeutic capable agent, thus, may
be coated on the structure as part of a matrix (e.g., therapeutic
capable agent with rate-controlling element) or as a separate
layer. It should be appreciated that in the latter case, the
therapeutic capable agent may be coated onto the structure first
followed by a coating of the rate-controlling element or vice
versa. The separate layers, may of course, form a matrix interface
therebetween.
[0155] Because of the gas flow dynamics associated with the vacuum
pump, any rate-controlling element monomer gas and therapeutic
capable agent gas that flows into the deposition chamber and which
does not deposit onto the structure, will tend to flow through the
cold trap and toward the vacuum pump.
[0156] When the dimer and/or therapeutic capable agent have been
completely vaporized, the pressure in the deposition chamber will
decrease and approach the base pressure. At this point, the
deposition cycle has completed, the system can be brought back to
atmospheric pressure and the coated stent removed.
[0157] The process parameters for applying parylene (e.g., parylene
C) onto a structure, in an exemplary embodiment, were as follows.
The parylene process parameters were: vaporization (sublimation)
temperature of about 80.degree. C., pyrolysis temperature of about
650.degree. C., base pressure (vacuum) of about 15 mTorr or less,
pressure (vacuum) set point of about 20 mTorr above base pressure.
The therapeutic capable agent evaporation parameters were: dish
temperature before evaporation being below boiling point or
sublimation temperature, dish temperature during evaporation at or
above boiling point or sublimation temperature, base pressure
(vacuum) of about 15 mTorr or less, and pressure (Vacuum) set point
of about 20 mTorr above base pressure.
[0158] In an exemplary embodiment of a method of making the devices
of the invention, as shown in FIG. 13A, a mandrel 112 having an
outer diameter, preferably, similar to that of the inner diameter
of the stent is positioned within the frame of the stent. To better
maintain the stent onto the mandrel, the stent may be sufficiently
crimped onto the mandrel so as to prevent the stent from slipping
off the mandrel. The mandrel, when formed of a solid material or
one having a closed exterior surface may optionally serve as a mask
to shield the inner surface of the cylindrical frame (i.e., the
luminal surface of the stent) during subsequent coating steps.
[0159] Optionally, a mandrel having an outer diameter sufficiently
smaller than the inner diameter of the stent and/or one being
formed of a sufficiently open lattice structure (the pattern
preferably designed to prepare the desired coating pattern on the
stent) may be used to allow for the coating of the luminal surface
of the stent during the coating process.
[0160] Optionally, an expansible balloon 115 having a generally
cylindrical expanded shape and formed, preferably, from a material
such as silicone rubber, polyurethane, nylon, or the like, may be
used as the mandrel. The balloon in its expanded configuration,
preferably, has an outer diameter, similar to that of the inner
diameter of the stent. Use of the balloon as the mandrel allows for
easier removal from the stent after the completion of the
coating.
[0161] As shown in FIG. 13B, the balloon may be formed so as to
include a series of longitudinally spaced apart areas of larger
diameter (such as a centipede shape). The larger diameter areas are
sufficiently spaced apart so as to come in contact with the luminal
surface of the stent being of relatively higher mechanical profile,
thus masking the relatively higher stress areas during the coating
process.
[0162] In yet another optional embodiment, the balloon comprises an
exterior tubing formed from a soft material such as soft rubber
such that the balloon can be positioned in the spaces between the
struts and links to mask the edges of the same, thus, allowing
coating only on the tissue facing surface of the stent while
masking the edges (e.g., thickness) of the rings.
[0163] In yet another embodiment of a process of making the devices
of the present invention, to avoid or minimize the coating of the
stent at the relatively higher mechanical profile areas, one or
more washers shown in FIGS. 13C and 13D, such as silicone rubber
washers (or of other material in other shapes as may be desired),
are disposed over the relatively higher mechanical profile areas of
the tissue facing surface of the stent, thus masking the areas
during the coating process. After the application of the
rate-controlling element, the the washer, such as that depicted in
FIG. 13B, which may be torn across a tear 121 to allow for easy
removal from the device. The washers may have an inner diameter
substantially the same, slightly larger, or more preferably,
smaller than the inner diameter of the stent. Preferably, the
washers have a width greater than the width of the relatively
higher mechanical profile areas of the stent.
[0164] In yet another embodiment, the structure may be masked by
creating a negative image of the structure on another material such
as a plastic or metal tube. The tube can be slitted into two
halves. The slitted tube is then clamped onto the stent. Only the
outer surface of the stent is exposed. The sides and luminal
surface are not exposed. When the therapeutic capable agent is
sprayed onto the stent, therapeutic capable agent is only on the
outer surface of the stent. This would result in FIGS. 6B, 6D, or
similar embodiments.
[0165] To mask desired portions, such as structure areas having
relatively higher mechanical profile, the stent structure may be
masked, as shown in FIG. 14A, by a variety of ways such as a flat
plate, curve plate, a tube, or other surfaces 124 having exposed
apertures or slots, such as FIGS. 144B, such that the aperture
and/or slots expose the desired areas to coating (e.g., low
mechanical profile areas) while masking the other areas (e.g., high
mechanical profile areas). Alternatively, a flexible tape 127 as
shown in FIG. 14C may be used to cover the tissue facing surface of
the stent at the high stress areas.
[0166] In another embodiment, the stent is either not masked or is
minimally masked during the coating. If desired, unwanted areas of
coating may be removed by way of application of fine tip sand
blaster, high pressure air nozzle, high pressure spray nozzle with
an appropriate solvent (e.g., methanol, ethanol, isopropanol
acetone, water), low power laser, electron beam, or the like.
Alternatively, a very fine spray nozzle or nano-size deposition
tool may be used to selectively apply the therapeutic capable agent
and/or rate-controlling element to or onto the structure.
[0167] The stent is then exposed to a source of therapeutic capable
agent, as shown in FIGS. 15A through 15B. The therapeutic capable
agent 28 is preferably dissolved or mixed in an appropriate
solvent(s) and/or matrix, and applied by methods such as spraying.
Preferably, the stent is removably fixed to a rotating device so
that the stent may be evenly disposed with the source (therapeutic
capable agent as dissolved in a solvent and/or matrix material).
Preferably, the width of the source application device is
sufficiently long so as to apply the source onto the entire length
of the stent. The therapeutic capable agent is dissolved in
appropriate matrix material and is then, preferably, sprayed onto
the stent (masked or otherwise).
[0168] The thickness of the therapeutic capable agent and/or the
matrix coating may be controlled by the time period of spraying and
the speed of rotation of the mandrel. The thickness of the
therapeutic capable agent and/or matrix coating is typically in a
range from about 1 angstroms (A) to about 50 microns (.mu.m), from
about 100 angstroms to about 20 microns, usually from about 100
angstroms to about 10 microns, normally from about 5000 angstroms
to about 5 microns, and nominally from abut 7500 angstroms to about
2 microns. Once the stent has been coated with the therapeutic
capable agent and/or the matrix, the stent may be placed in a
vacuum, oven, or vacuum oven to complete the evaporation of the
solvent.
[0169] A nonporous parylene coating is clear, transparent, and has
film-like qualities. It is resistant to solvent and will not swell
more than about 3% in film thickness in organic solvents such as
alcohol (isopropanol, methanol, ethanol), ketones (acetones and
2,3-pentanedione), aliphatic hydrocarbons (iso-octane), aromatic
hydrocarbons (xylene, toluene), chlorinated olefins
(trichloroethylene), chlorinated aromatics (chlorobenzene and
O-dichlorobenzene), heterocyclic bases (pyridene), and fluorinated
solvents (trichlorotrifluoroethane). In addition, after swelling,
nonporous parylene swelling is completely reversible once the
solvents have been removed by vacuum drying.
[0170] In an embodiment of a process for making a partially
rate-controlling element coated device the process may comprise any
one or more of the process steps discussed above. By way of
example, the structure may be coated with nonporous polymers by
means other than vapor deposited coatings (i.e., nonporous
parylene) or other than nonporous plasma deposited or glow
discharge coating. Alternatively, a portion of the vapor deposited
coating or plasma deposited/glow discharge coating at the stressed
areas may be removed with a laser, electronic beam, or other means;
masking the areas where rate-controlling element is not desirable.
In another embodiment, after the therapeutic capable agent is
applied, the stressed areas (with little or no therapeutic capable
agent) may masked before the stent is coated with the
rate-controlling element. The mask is removed after coating.
[0171] The desired areas of the stent may be shielded with fences
(cold or heated) to prevent flow of parylene reactive intermediate,
mono(p-xylylene), during vacuum deposition of coating or the plasma
free radicals during plasma deposited/glow discharge coating to the
stressed area of the stent.
[0172] Heated films, wires, or the like may be brought in contact
with the desired areas of the stent such that the stent resists
condensation of the parylene reactive intermediate,
mono(p-xylylene), during vacuum deposition of the coating or the
plasma free radicals during plasma deposited/glow discharge coating
on the stressed area of the stent.
[0173] In yet another embodiment, one or more tubes carrying a
flowing heated fluid may be brought into contact with the desired
areas of the stent during vacuum deposition of the coating or
plasma deposited/glow discharge coating. These shielded areas of
the stent are heated and resist condensation of the parylene
reactive intermediate, mono(p-xylylene), during vacuum deposition
of the coating or the plasma free radicals during plasma
deposited/glow discharge coating on the stressed area of the
stent.
[0174] Non-contact sources (e.g., convection heat source, infrared,
ultra violet, or the like) and may be directed at desired areas of
the stent, or films, wires, tubes, and the like which are in
contact with desired areas of the stent.
[0175] Areas of the stent which are not coated with nonporous
parylene or plasma deposited/glow discharge coating
rate-controlling element can be coated with therapeutic capable
agent by masking the areas of the stent with the nonporous polymer
rate-controlling element and then applying the therapeutic capable
agent on the unmasked area as described above.
[0176] If desired, the nonporous rate-controlling element can be
infiltrated with therapeutic capable agent(s) or small non-active
molecules by placing the stent, the therapeutic capable agent, and
the rate-controlling element (e.g., nonporous rate-controlling
element) in one or more solvents that will swell or can transmit
into and through the nonporous rate-controlling element, for a
period of time, as for example ranging from about 1 second to about
1 week, usually from about 1 hour to about 72 hours, and often from
about 2 hours to about 24 hours. The solvent(s) may or may not
contain the therapeutic capable agent or non-bioactive molecules
that are dissolved in the solvent(s) depending on whether the
source of the therapeutic capable agent or non-bioactive molecule
is from the therapeutic capable agent reservoir or from an external
source or both. The temperature of the solvent(s) during swelling
can range from room temperature to elevated temperatures, up to and
including the boiling point of the solvent(s).
[0177] The stent with the therapeutic capable agent reservoir and
nonporous rate-controlling element are heated to a temperature
below which the nonporous rate-controlling element will not be
damaged or at temperatures below which the therapeutic capable
agent will not significantly degraded, for a period of time,
usually ranging from about 1 second to about 1 week, often from
about 1 hour to about 72 hours, and nominally from about 2 hours to
about 24 hours.
[0178] The stent with therapeutic capable agent reservoir and
nonporous rate-controlling element can come in contact with one or
more vaporized solvents, which are preferably organic, for a period
of time, usually ranging from about 1 second to about 1 week, often
from about 1 hour to about 72 hours, and nominally from about 2
hours to about 24 hours. The coated therapeutic capable agent stent
may then be crimped onto a balloon of a PTCA catheter and deployed
into the targeted intracorporeal site.
[0179] In another embodiment of a method of making, the expandable
structure is first pre-treated by silane treatment, such as
methacryloxypropyl-trimethoxysilane (A-174) or other silane
coupling agents, to minimize the formation of cracks and/or
pinholes during the expansion of the device. By way of example, in
a method of making the device, the expandable therapeutic capable
agent-coated structure is immersed into a solution of methanol:
water: silane having a ratio of about 100:100:2 for a period of
time, preferably, 15 minutes. The structure is then removed and let
dry for about 10 minutes and is then rinsed with IPA. The treated
structure is then processed as described above to further include
the rate-controlling element. The silane treatment helps promote
the adhesion of the rate-controlling element, such as the
non-porous parylene, to the structure material, such as stainless
steel. Alternatively, a nonporous plasma deposited/glow discharge
coating (e.g., methane, C.sub.2F.sub.2, xylene, silane dimmer) can
also be applied to the structure surface to help promote the
adhesion. The pre-treatment of the structure with adhesion
promoting agents helps enable the application of relatively thinner
thickness of rate-controlling element, at for example the high
stress areas of the structure. The pre-treatment may be provided in
any of the other embodiments. By way of example, the pre-treatment
may be applied over the therapeutic capable agent source (e.g.,
reservoir). However when rate-controlling element-structure
adhesion profiles of lesser strength are desirable, the
pretreatment may not be necessary.
[0180] It may, alternatively, be desirable to have a thicker
rate-controlling element coating adjacent the therapeutic capable
agent source while having a stable yet thinner coating thickness at
the stressed areas of the device. The thicker coating of the
rate-controlling element produces a deliberate decrease in the
release rate of the therapeutic capable agent to the targeted
intracorporeal site. In an embodiment, the coating of the
rate-controlling element at those device segments not including the
therapeutic capable agent, preferably the higher stress areas,
comprises a relatively higher thickness to help minimize formation
of cracks and/or pinholes.
[0181] To accomplish the variable or selective coating of the
rate-controlling element, processes similar to those described
earlier may be utilized. To effectuate the controlled coating,
factors such as the flow rate of the rate-controlling element
monomer gas (e.g., parylene) may be reduced and/or its location may
be controlled.
[0182] In an embodiment, a removable physical fence (e.g., wires,
bars, tube having the same width as the therapeutic capable agent
reservoir, slotted plate), may be positioned adjacent the areas
desired to have a smaller thickness of the rate-controlling element
deposited thereon (e.g., the stent therapeutic capable agent
reservoir) to controllably limit the deposition of the
rate-controlling element.
[0183] Alternatively, low temperature heat (e.g., above room
temperature) may be aimed at the desired thin area to minimize
and/or reduce the reaction between the rate-controlling element
monomer gas and the material at the desired thin area. Examples of
such heat sources include infrared, ultra violet, heating coils,
heating elements, or any small source of lighting that can be aimed
at the desire area and generate differential amount of heat.
[0184] In yet another embodiment, a deliberate smaller quantity of
rate-controlling element may be applied when using the appropriate
processes such as spray coating.
[0185] By way of example, porous rate-controlling element may be
obtained, such as a porous parylene C layer, using any of the
following exemplary methods.
[0186] In an embodiment for creating a device having a porous
rate-controlling element, such as porous parylene or plasma
deposited/glow discharge film, the temperature of deposition may be
substantially below the glass transitional temperature of the
rate-controlling element material. By way of example, for parylene
C as the rate-controlling element, the glass transitional
temperature, Tg, is approximately 80 to 100.degree. C. As the
deposition temperature increases, the crystallinity of the film
increases. Higher temperatures allow rearrangements and molecular
motion possible after the coating is deposited on the surface of
the substrate. The polymeric chain becomes more conformationally
ordered. As the deposition temperature decreases, the crystallinity
of the film decreases, becoming more amorphous. When the
temperature is decrease further, from for example, -40.degree. C.
to near liquid nitrogen temperatures (-196.degree. C.), the
rate-controlling element film becomes increasingly amorphous and
porous. It should be noted that the porous films may be changed to
a targeted percentage, or usually change to a nonporous morphology
by annealing the thin films at suitable temperatures for a length
of time such as 205.degree. C. in Nitrogen gas for about two
hours.
[0187] In another embodiment for creating a device having a porous
rate-controlling element, porous parylene C layer, any one or more
combinations of the following parameters may be used: vaporization
(sublimation) temperature of about 20.degree. C. to about
200.degree. C., preferably about 40.degree. C. to about 60.degree.
C.; pyrolysis temperature of about 400.degree. C. to about
900.degree. C., preferably about 500.degree. C. to about
650.degree. C., and about or greater than 750.degree. C. for porous
parylene C; base pressure (vacuum) of about -4 to about 200 mTorr,
preferably about 100 mTorr or greater; pressure (vacuum) set point
of about 0 to about 200 mTorr above base pressure; stent
temperature of about -196.degree. C. to about 0.degree. C.,
preferably about -50.degree. C. or lower, more preferably at about
-100.degree. C. By way of example, in an exemplary embodiment for
making the porous parylene C rate-controlling element layer at
higher base pressure and or pressure set point, the parameters were
set as follows: vaporization temperature of 140.degree. C.,
pyrolysis temperature of 690.degree. C., base pressure of 120
mTorr, pressure set point of 135 mTorr, stent temperature at room
temperature. By way of example, in an exemplary embodiment for
making the porous parylene C rate-controlling element layer at
lower pyrolysis temperature and or vaporization temperature, the
parameters were set as follows: vaporization temperature of
60.degree. C., pyrolysis temperature of 650.degree. C., base
pressure at 15 mTorr, pressure set point at 20 mTorr, and stent
temperature at room temperature.
[0188] In another exemplary embodiment, porous rate-controlling
element may also be obtained by using the methods described above
for making a nonporous coating but changing the parameters to those
described with respect to the parameters for making a porous
rate-controlling element, and furthermore modifying one or more of
the process steps as follows: reducing the flow of gaseous parylene
or plasma deposited/glow discharge reactive monomers into the stent
loaded chamber by blocking inlet port to coating chamber; placing
fences around the stent to decrease the rate of deposition; adding
impurity to parylene dimmer; introducing gases into the chamber
during coating; concurrently plasma depositing of coating during
parylene coating; having plasma coating having heat labile groups;
releasing gas above a post-treatment temperature; concurrently
plasma depositing of coating during parylene coating; having plasma
coating with groups which are susceptible to degradation when
exposed to solvents or enzymes found in the body.
[0189] Referring now to FIG. 16, a graphical representation of an
exemplary embodiment of therapeutic capable agent release over a
predetermined time period is shown. The predetermined rate pattern
shown in FIG. 16 of the present invention improves the efficacy of
the delivery of the therapeutic capable agent to the susceptible
tissue site by making the therapeutic capable agent available at
none to some lower delivery rate during an initial phase. Once a
subsequent phase is reached, the delivery rate of the therapeutic
capable agent may be substantially higher. Thus, time delayed
therapeutic capable agent release can be programmed to impact
restenosis (or other targeted conditions as the case may be) at at
least a partial formation of the initial cellular deposition or
proliferation (hyperplasia). The present invention can further
reduce the washout of the therapeutic capable agent by timing the
release of the therapeutic capable agent to occur after at least
initial cellularization. Moreover, the predetermined rate pattern
may reduce the loading and/or concentration of the therapeutic
capable agent. The predetermined rate pattern may further provide
limited or reduced to no hindrance to endothelialization of the
vessel wall due to the minimization of washout of the therapeutic
capable agent and the increased efficiency of its release.
EXAMPLES
Example 1
[0190] A stainless steel Duraflex.TM. stent, having dimensions of
approximately 3.0 mm.times.14 mm was sprayed with a solution of 25
mg/ml therapeutic capable agent in a 100% ethanol or methanol
solvent. The stent was dried and the ethanol was evaporated leaving
the therapeutic capable agent on the stent surface. A 75:25
PLLA/PCL copolymer (sold commercially by Polysciences) was prepared
in 1,4 Dioxane (sold commercially by Aldrich Chemicals). The
therapeutic capable agent coated stent was loaded on a mandrel
rotating at 200 rpm and a spray gun (sold commercially by Binks
Manufacturing) used to dispense the copolymer solution in a fine
spray onto the coated stent, as the stent rotated for approximately
a 10-30 second time period. The stent was then placed in an oven at
25-35.degree. C. for up to 24 hours to complete the evaporation of
the solvent.
Example 2
[0191] A stainless steel Duraflex stent (3.0.times.18 mm) was laser
cut from a SS tube. The surface area of the stent for receiving the
therapeutic capable agent was increased by increasing the surface
roughness of the stent. The surface area and the volume of the
stent can be further increased by creating 10 nm wide by 5 nm deep
grooves along the links of the stent strut. The grooves were
created in those stent areas experiencing low stress during
expansion so as not to compromise the stent radial strength. The
drug was loaded onto the stent and in the stent grooves by dipping
or spraying the stent in the therapeutic capable agent solution
prepared in low surface tension solvent such as isopropyl alcohol,
ethanol, or methanol. The stent was then dried with the therapeutic
capable agent remaining on the stent surface, and in the grooves
which served as a reservoir for the therapeutic capable agent.
Parylene was then vacuum deposited on the stent to serve as a
rate-controlling barrier. The drug was eluted from the stent over a
period of time in the range from 1 day to 45 days.
Example 3
[0192] A therapeutic capable agent was dissolved in methanol, then
sprayed onto the stent. The stent was left to dry with the solvent
evaporating from the stent leaving the therapeutic capable agent on
the stent. A matrix or barrier (silicone, polyurethane,
polytetrafluorethylene, parylast, parylene) was sprayed or
deposited on the stent covering the therapeutic capable agent. The
amount of therapeutic capable agent varied from about 100
micrograms to 2 milligrams, with release rates from 1 day to 45
days.
Example 4
[0193] A matrix solution including the matrix polymer and a
therapeutic capable agent was coated onto a stent, as described in
Example 2. The stent was then coated or sprayed with a top coat of
a rate-controlling barrier (and/or a matrix material without a drug
so as to act as a rate-controlling barrier). Alternatively, the
therapeutic capable agent may be coated on a stent via a
rate-controlling barrier, and then covered with a top coat (another
barrier or matrix). Use of topcoats provides further control of
release rate, improved biocompatibility, and/or resistance to
scratching and cracking upon stent delivery or expansion.
Example 5
[0194] The therapeutic capable agent may be combined with a second
therapeutic capable agent (cytotoxic drugs, cytostatic drugs, or
psoriasis drugs). One agent is in or coupled to a first coat while
other agent is in or coupled to a second coat. The therapeutic
capable agent is released for the first 1-3 weeks after being
implanted within a vessel while the second therapeutic capable
agent is released or continues to be released for a longer
period.
Example 6
[0195] A combination of multiple therapeutic capable agents that
are individually included in different coats can be used as the
matrix. The coats may release the multiple agents simultaneously
and/or sequentially. The agents may be selected from a therapeutic
capable agent class of inhibitors of de novo nucleotide synthesis
or from classes of glucocorticosteroids, immunophilin-binding
drugs, deoxyspergualin, FTY720, protein drugs, or peptides. This
can also apply to any combination of agents from the above classes
that are coupled to a stent with the addition of other cytotoxic
drugs.
Example 7
[0196] A matrix including the therapeutic capable agent,
mycophenolic acid, and matrix polymer, CAB (cellulose acetate
butyrate); at a mycophenolic acid loading of 70% to 80% by weight
was prepared by dissolving the therapeutic capable agent in acetone
at 15 mg/ml concentration, dissolving CAB in acetone at 15 mg/ml
concentration, and thereafter mixing together the mycophenolic acid
and CAB solutions in 3:1 portion matrix solution. The amount of
therapeutic capable agent varied from about 0.1 microgram to about
2 mg, preferably, at 600 microgram. The matrix solution was then
coated onto two sets of stents (Sets A and B) by spraying them with
an atomizer sprayer (EFD manufacturer) while each stent was
rotated. Each stent was allowed to let dry. One matrix-coated stent
was then coated with parylene as the rate-controlling barrier
(about 1.1 .mu.m) using methods similar to those described in
Example 2. Orifices were created on the top surface (parylene
rate-controlling barrier) of the stent of Set B by subjecting the
surface to laser beams or needle. The orifice size can range from
about 0.1 .mu.m to about 100 .mu.m in diameter. The orifice in Set
B stent was about 10 .mu.m in diameter. An orifice can be about
0.003 to about 2 inches apart from the next orifice (measured as
the curvilinear distance as you trace along the stent strut
pattern).
[0197] The mycophenolic acid loaded stents were placed in an
elution solution of porcine serum and allowed to age for a period
of 1 to 7 days. Samples from the serum were taken at regular time
intervals and analyzed by HPLC. As can be seen from the data
represented in FIGS. 17A and 17B (corresponding to stent sets A and
B, respectively), Stent Set A showed a linear release rate for the
mycophenolic acid while stent Set B showed a relatively slow linear
release rate at the initial phase, followed by a relatively more
rapid release in the subsequent phase.
Example 8
[0198] Two sets of stents, Sets A and B, were coated with 250 and
300 .quadrature.g of mycophenolic acid, respectively, according to
Example 2. Set A was then coated with 1.7 micron of parylene as the
rate-controlling barrier. Set B was first coated with mycophenolic
acid followed by a subsequent coating of methylprednisolone as the
rate-limiting matrix material, and thereafter coated with 1.3
micron of parylene. The coated stents were then subjected to in
vitro elution test as described in Example 7, and the amount of
mycophenolic acid eluted was measured. As can be seen from the data
represented in FIGS. 18A and 18B (corresponding to stent Sets A and
B, respectively), both Sets showed a relatively fast linear release
of the mycophenolic acid in the initial phase followed by a
relatively slower release in the subsequent phase. This may suggest
that the more hydrophobic methylprednisolone may act as a
rate-controlling element for the more water soluble mycophenolic
acid, and can act to control the release rate of mycophenolic acid
along with the Parylene coating. This is useful when the diseased
area needs a large bolus of the drug initially and then a sustained
slower release.
Example 9
[0199] In order to assess the effect of therapeutic capable agents
of the present invention on cell cultures, samples of 5 sets of
therapeutic capable agents, as listed below, in varying
concentrations were prepared and added to different groups of
porcine smooth muscle cell cultures according to standard
procedures. Set A, B, C, D, and E corresponded to therapeutic
capable agent sets: Mycophenolic acid & Dexamethasone;
Mycophenolic acid & Triptolide; Wortmannin and Methotrexate;
Triptolide; Mycophenolate Mofetil; respectively. The amount of
incorporated thymidine for the different samples of varying
concentrations (0.003, 0.031, 0.31, 1.6, and 3.1 micromolar) was
measured. As can be seen from the data represented in FIGS. 19A-9E
(corresponding to Sets A-E, respectively) the IC50 (defined as the
concentration at which 50% of the cells are prevented from
proliferating) for the various sets occurred at different
concentrations. As can further be noted, Mycophenolate Mofetil
(reference E) may not be as effective in the absence of a
bio-condition (e.g., subject to bodily fluids such as blood).
Example 10
[0200] In another group of therapeutic capable agents, the amount
of incorporated thymidine for samples of varying concentrations
(0.003, 0.031, 0.31, 1.6, 3.1, 31, and 156 micromolar) was
measured. As can be seen from the data represented in FIGS.
20A-10B, and corresponding to Mycophenolic acid and
Methylprednisolone, respectively, the IC50 for these therapeutic
capable agent was 1.0 micromolar.
Example 11
[0201] In order to assess the effect of various therapeutic capable
agents, cell cultures were subjected to some therapeutic capable
agents, using methods similar to those described in Examples 9 and
10. As can be seen from data represented in FIGS. 21A-21B, and
corresponding, respectively, to Triptolide (T), Dexamethasone (D),
Methotrexate (M); and Mycophenolic Acid (MA); the therapeutic
capable agents did not lead to significant cell death. In addition,
it can be seen that at the IC50 concentrations, most of the cells
were alive yet 50% proliferating.
Example 12
[0202] A therapeutic capable agent, mycophenolic acid, was prepared
by dissolving the therapeutic capable agent in acetone at 15 mg/ml
concentration. The amount of therapeutic capable agent varied from
about 0.1 .mu.g to about 2 mg, preferably, at 600 .mu.g. The drug
solution was then coated onto or over a stent as described in
Example 8 by spraying them with an atomizer sprayer (EFD
manufacturer) while the stent was rotated. The stent was allowed to
let dry. The stent was then placed over the tri-fold balloon on a
PTCA catheter and crimped thereon. After crimping, the drug
remained intact and attached to the stent. Expansion of the stent
against a simulated Tecoflex vessel showed no cracking of the drug.
Exposure of fluid flow over the stent before stent deployment
against the simulated vessel did not result in drug detachment from
the stent.
Example 13
[0203] In an embodiment when BSA is disposed adjacent an exterior
surface of the rate-controlling element, mycophenolic acid (MPA)
was bound to the BSA forming a MPA-BSA complex which is more stable
than mycophenolic acid alone, thus decreasing the metabolism of
mycophenolic acid to its glucuronide derivative (which is
biologically inactive). The MPA-BSA has an increases half time (as
measured by assaying methods such as liquid chromatography) as
compared to mycophenolic acid alone and as
1 Blood or Tissue BSA Half Life (T) Concentration (%) (minutes) 1
76 2 121 4 364 6 1924
Example 14
[0204] A series of stainless steel Duraflex.TM. stent, having
dimensions of approximately 3.5 mm.times.18 mm were sprayed with
about 600 .mu.g of therapeutic capable agent using a solution of 15
mg/ml therapeutic capable agent in a 100% methanol solvent. The
stents were dried and the solvent was evaporated leaving the
therapeutic capable agent on the stents surfaces. Parylene C was
then vacuum deposited on the stents to serve as a rate-controlling
barrier. The amount/thickness of the parylene was varied so as to
create stents having different rate-controlling element
thicknesses. The coated stents were place in porcine serum at
37.degree. C. The therapeutic capable agent was eluted from the
stents over a period of time and the amount eluted was measured
using HPLC. As can be seen from FIG. 22, the elution rate for the
stents decreased as the thickness of the rate-controlling element
increased.
Example 15
[0205] A number of stainless steel Duraflex.TM. stents, having
dimensions of approximately 3.5 mm.times.18 mm were sprayed with
about 700 mg of therapeutic capable agent using a solution of 15
mg/ml methylprednisolone in a 70% acetone:30% methanol solvent. The
stents were dried and the ethanol was evaporated leaving the
therapeutic capable agent on the stents surfaces. Parylene C was
then vacuum deposited on the stents to serve as a rate-controlling
element, at varying thicknesses. One series of the stents having a
rate-controlling element layer thickness of about 1.1 micron was
then further processed to include apertures, having nominal
diameter of about 0.0005 inch, in the rate-controlling element
layer similar to embodiment in FIG. 9B, in configurations of: one
aperture on every strut, one aperture on every other strut, 3
apertures on every strut, and a controlled disruption on every
strut (e.g., FIG. 9C). The coated stents were place in porcine
serum at 37.degree. C. The therapeutic capable agent was eluted
from the stents over a period of time and the amount eluted was
measured using HPLC. As can be seen from FIGS. 23A (with aperture
or disruptions) and 23B (without apertures or disruptions), the
amount of therapeutic capable agent eluted increased for both
series (with and without apertures) with increase in the elution
period, with the eluted amount increasing as the number of the
apertures increases.
Example 16
[0206] A series of stainless steel Duraflex.TM. stents, having
dimensions of approximately 3.5 mm.times.18 mm were first masked on
the higher stress areas of the stents, according to the embodiment
described with respect to FIG. 14C with a tape. The stents were
then sprayed with 600 .mu.g of therapeutic capable agent using a
solution of 15 mg/ml mycophenolic acid as the therapeutic capable
agent in a 100% methanol solvent. The stents were dried and the
solvent was evaporated leaving the therapeutic capable agent on the
lower stress areas of the stents. The mask was removed and Parylene
C was then vacuum deposited on the stents to serve as a
rate-controlling element with a nominal thickness of about 1.1
micron. The therapeutic capable agent was eluted from the stents
over a period of time. As can be seen from FIG. 24, the stent
having been coated with the therapeutic capable agent only on the
low stress areas (using masking) elutes at a lower amount than the
one coated with the therapeutic capable agent on both the high and
low stress areas, allowing for a more controlled release of the
therapeutic capable agent.
Example 17
[0207] A series of stainless steel Duraflex.TM. stents, having
dimensions of approximately 3.5 mm.times.18 mm were sprayed with
300 .mu.g of therapeutic capable agent using a solution of 15 mg/ml
mycophenolic acid as the therapeutic capable agent in a 100%
methanol solvent. The stents were dried and the solvent was
evaporated leaving the therapeutic capable agent on the lower
stress areas of the stents. Parylene C was then vacuum deposited on
the stents to serve as a rate-controlling element with a nominal
thickness of about 2 to 8 microns. The therapeutic capable
agent/rate-controlling element-coated stents were then divided in
two groups with the second group further being heated to about
145.degree. C. for about 1 hour. The therapeutic capable agent was
eluted from the stents over a period of time. As can be seen from
FIG. 25, the stent having been heated (Group B) after the final
coating of the device had a lower amount of therapeutic capable
agent released over the same period of time.
[0208] Although certain preferred embodiments and methods have been
disclosed herein, it will be apparent from the foregoing disclosure
to those skilled in the art that variations and modifications of
such embodiments and methods may be made without departing from the
true spirit and scope of the invention. Therefore, the above
description should not be taken as limiting the scope of the
invention which is defined by the appended claims.
* * * * *