U.S. patent application number 15/797218 was filed with the patent office on 2018-06-07 for morphology profiles for control of agent release rates from polymer matrices.
The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Yung-Ming Chen, Thierry Glauser, Syed F.A. Hossainy, Lothar W. Kleiner, Andrew F. McNiven, Sean A. McNiven, Stephen D. Pacetti, Wouter E. Roorda, Fuh-Wei Tang, Yiwen Tang, Brandon J. Yoe, Gina Zhang.
Application Number | 20180154051 15/797218 |
Document ID | / |
Family ID | 38599766 |
Filed Date | 2018-06-07 |
United States Patent
Application |
20180154051 |
Kind Code |
A1 |
Hossainy; Syed F.A. ; et
al. |
June 7, 2018 |
Morphology Profiles For Control Of Agent Release Rates From Polymer
Matrices
Abstract
The present disclosure teaches methods of controlling the
release rate of agents from a polymeric matrix that include
designing and creating a predetermined initial morphology (IM)
profile in a polymeric matrix. The teachings indicate, inter alia,
that control over the release rate of agents can provide for an
improved control over the administration of agents as well as have
an effect upon the mechanical integrity and absorption rate of the
polymeric matrix.
Inventors: |
Hossainy; Syed F.A.;
(Hayward, CA) ; Tang; Fuh-Wei; (Temecula, CA)
; Kleiner; Lothar W.; (Los Altos, CA) ; Glauser;
Thierry; (Redwood City, CA) ; Tang; Yiwen;
(San Jose, CA) ; Roorda; Wouter E.; (Palo Alto,
CA) ; Pacetti; Stephen D.; (San Jose, CA) ;
Zhang; Gina; (Calabasas, CA) ; Chen; Yung-Ming;
(San Jose, CA) ; McNiven; Andrew F.; (Temecula,
CA) ; McNiven; Sean A.; (San Francisco, CA) ;
Yoe; Brandon J.; (Temecula, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Family ID: |
38599766 |
Appl. No.: |
15/797218 |
Filed: |
October 30, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13953656 |
Jul 29, 2013 |
9821091 |
|
|
15797218 |
|
|
|
|
11448956 |
Jun 6, 2006 |
|
|
|
13953656 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 27/40 20130101;
A61L 27/54 20130101; A61L 31/12 20130101; A61L 27/50 20130101; A61L
31/16 20130101; A61P 9/00 20180101; A61L 2300/00 20130101; A61L
27/44 20130101; A61L 31/14 20130101; A61L 31/10 20130101 |
International
Class: |
A61L 31/10 20060101
A61L031/10; A61L 27/54 20060101 A61L027/54; A61L 31/16 20060101
A61L031/16; A61L 27/40 20060101 A61L027/40; A61L 27/44 20060101
A61L027/44; A61L 27/50 20060101 A61L027/50; A61L 31/12 20060101
A61L031/12; A61L 31/14 20060101 A61L031/14 |
Claims
1. A method for coating an implantable medical device comprising:
(a) applying a polymer composition onto the device, the polymer
composition comprising one or more polymers, one or more bioactive
agents, and one or more solvents; and (b) drying the polymer
composition for a period of time at room temperature in an
environment having relative humidity about 20% or lower than 20%;
wherein at least one of the one or more polymers is a polymer
formed from one or more constituent monomers, the constituent
monomer(s) comprising D-lactide, D,L-lactide, L-lactide, L-lactic
acid, D-lactic acid, D,L-lactic acid, or a combination thereof.
2. The method of claim 1, wherein at least one of the one or more
bioactive agents is rapamycin, methyl rapamycin, zotarolimus,
everolimus, tacrolimus, pimecrolimus,
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or a combination
thereof.
3. The method of claim 1, wherein at least one of the one or more
solvents is DMAC, DMF, THF, cyclohexanone, xylene, toluene,
acetone, i-propanol, methyl ethyl ketone, propylene glycol
monomethyl ether, methyl butyl ketone, ethyl acetate, n-butyl
acetate, dioxane, or a mixture thereof.
4. The method of claim 1, wherein the medical device is a
stent.
5. The method of claim 2, wherein the medical device is a
stent.
6. The method of claim 3, wherein the medical device is a
stent.
7. The method of claim 3, wherein the thickness of the coating
formed is in the range of 0.1 nm to 100 .mu.m.
8. The method of claim 3, wherein the thickness of the coating
formed is in the range of 10 .mu.m to 50 .mu.m.
9. The method of claim 6, wherein the thickness of the coating
formed is in the range of 0.1 nm to 100 .mu.m.
10. The method of claim 6, wherein the thickness of the coating
formed is in the range of 10 .mu.m to 50 .mu.m.
11. The method of claim 4, wherein at least one of the one or more
polymers is poly(lactide-co-glycolide), poly(D,L-lactic acid),
poly(D,L-lactide), poly(glycolic acid-co-trimethylene carbonate),
or a combination thereof.
12. The method of claim 5, wherein at least one of the one or more
polymers is poly(lactide-co-glycolide), poly(D,L-lactic acid),
poly(D,L-lactide), poly(glycolic acid-co-trimethylene carbonate),
or a combination thereof.
13. The method of claim 6, wherein at least one of the one or more
polymers is poly(lactide-co-glycolide), poly(D,L-lactic acid),
poly(D,L-lactide), poly(glycolic acid-co-trimethylene carbonate),
or a combination thereof.
14. The method of claim 2, wherein at least one of the one or more
bioactive agents is rapamycin, zotarolimus, everolimus, tacrolimus,
pimecrolimus, or a combination thereof.
15. The method of claim 5, wherein at least one of the one or more
bioactive agents is rapamycin, zotarolimus, everolimus, tacrolimus,
pimecrolimus, or a combination thereof.
16. The method of claim 6, wherein at least one of the one or more
bioactive agents is rapamycin, zotarolimus, everolimus, tacrolimus,
pimecrolimus, or a combination thereof.
17. The method of claim 3, wherein at least one of the one or more
solvents is acetone, i-propanol, methyl ethyl ketone, propylene
glycol monomethyl ether, methyl butyl ketone, or a mixture
thereof.
18. The method of claim 6, wherein at least one of the one or more
solvents is acetone, i-propanol, methyl ethyl ketone, propylene
glycol monomethyl ether, methyl butyl ketone, or a mixture
thereof.
19. The method of claim 10, wherein at least one of the one or more
solvents is acetone, i-propanol, methyl ethyl ketone, propylene
glycol monomethyl ether, methyl butyl ketone, or a mixture
thereof.
20. The method of claim 19, wherein the one or more solvents
comprise acetone, and the at least one of the one or more bioactive
agents is rapamycin, zotarolimus, everolimus, tacrolimus,
pimecrolimus, or a combination thereof, and the one or more
polymers is poly(D,L-lactide) or a combination of poly(D,L-lactide)
and one or more other polymers.
Description
RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 13/953,656, filed on Jul. 29, 2013, and published as United
States Patent Application Publication number US 2014-0004250 A1 on
Jan. 2, 2014, which is a divisional application of U.S. application
Ser. No. 11/448,956, filed on Jun. 6, 2006, and published as United
States Patent Application Publication number US 2008-0124372 A1, on
May 29, 2008, both of which are hereby incorporated by reference
herein for all purposes, and which are incorporated by reference
herein in their entirety, including any drawings.
BACKGROUND
Field of the Invention
[0002] This invention is directed to the control of the
morphologies within polymer matrices in facilitating the design of
release rate profiles of agents from within these matrices.
Description of the State of the Art
[0003] Biomaterials research is continuously striving to improve
the compositions from which medical articles, such as medical
devices and coatings for medical devices, are produced. An example
of a medical article is an implantable medical device.
[0004] A stent is an example of an implantable medical device that
can benefit from improvements, such as a coating that can be used
as a vehicle for delivering pharmaceutically active agents in a
predictable manner. Stents can act as a mechanical intervention to
physically hold open and, if desired, expand a passageway within a
subject. Typically, a stent may be compressed, inserted into a
small vessel through a catheter, and then expanded to a larger
diameter once placed in a proper location. Examples of patents
disclosing stents include U.S. Pat. Nos. 4,733,665, 4,800,882 and
4,886,062.
[0005] Stents play an important role in a variety of medical
procedures such as, for example, percutaneous transluminal coronary
angioplasty (PTCA), which is a procedure used to treat heart
disease. In PTCA, a balloon catheter is inserted through a brachial
or femoral artery, positioned across a coronary artery occlusion,
inflated to compress atherosclerotic plaque and open the lumen of
the coronary artery, deflated and withdrawn. Problems with PTCA
include formation of intimal flaps or torn arterial linings, both
of which can create another occlusion in the lumen of the coronary
artery. Moreover, thrombosis and restenosis may occur several
months after the procedure and create a need for additional
angioplasty or a surgical by-pass operation. Stents are generally
implanted to reduce occlusions, inhibit thrombosis and restenosis,
and maintain patency within vascular lumens, such as the lumen of a
coronary artery.
[0006] Stents are also being developed to provide a local delivery
of agents. Local delivery of agents is often preferred over
systemic delivery of agents, particularly where high systemic doses
are necessary to achieve an effect at a particular site within a
subject--high systemic doses of agents can often create adverse
effects within the subject. One proposed method of local delivery
includes coating the surface of a medical article with a polymeric
carrier and attaching an agent to, or blending it with, the
polymeric carrier.
[0007] Agent-coated stents have demonstrated dramatic reductions in
the rates of stent restenosis by inhibiting tissue growth
associated with the restenosis. Restenosis is a very complicated
process and, agents have been applied, alone and in combination, in
an attempt to circumvent the process. The process of restenosis in
coronary artery disease is derived from a complex interplay of
several implant-centered biological parameters. These are thought
to be the combination of elastic recoil, vascular remodeling, and
neointimal hyperplasia. Since restenosis is a multifactorial
phenomenon, the local delivery of agents from a stent can be
improved through the design of a release rate profile that would
deliver agents as needed from the stent in a controlled and
predictable manner. For example, one method of applying multiple
agents involves blending the agents together in one formulation and
applying the blend to the surface of a stent in a polymer matrix. A
disadvantage of this method is that the agents are released from
the matrix through a somewhat variable polymeric matrix morphology
and, as such, compete with one another for release in an
unpredictable manner. Other methods suffer from a sudden initial
release of agents in high amounts, known as a burst release, which
can prevent a prolonged release of agents in sufficient
concentrations.
[0008] In some cases, polymeric matrices that are otherwise
desirable are unable to meet particular performance characteristics
that are required by some medical articles. Often, the inability to
meet particular performance characteristics results from combining
components that are desirable independently but form undesirable
morphologies that cannot meet the required performance
characteristics when formed into a polymeric matrix.
[0009] In other cases, polymeric matrices that are desirable upon
manufacture can be unpredictable in performance at the time of use.
Morphological changes are known to happen to medical articles
during processing and storage, as well as after application in
vivo. Unfortunately, the predictability of a medical article can
rely on the ability to control these changes.
[0010] Those skilled in the art will appreciate a reliable way of
controlling the performance of medical articles which includes
controlling the release of agents, since a controlled release of
agents can be critical to preventing, inhibiting, treating or
mitigating a disease process. The ability to select and design the
morphology of a polymeric matrix can not only provide for control
over the release rate of agents but can also can assist in
designing and maintaining the physical and mechanical properties of
medical devices and coatings. Accordingly, control over the
morphology of a polymeric matrix is an important design
consideration and one of the next hallmarks in the development of
novel medical articles.
SUMMARY
[0011] The present invention describes a method for creating a
medical article. The article comprises a polymeric matrix having a
predetermined initial morphology (IM) profile and an agent. The
method includes selecting a desired IM profile; forming a polymeric
layer comprising the agent on a surface of the medical article; and
subjecting the polymeric layer to a terminal process step
comprising:
[0012] exposing the polymeric layer to a fluid while forming the
layer, wherein the composition of the fluid is preselected to be
miscible or immiscible with a component in the polymeric layer;
[0013] applying a pressure to the polymeric layer;
[0014] applying a combination of heat and pressure to the polymeric
layer; or
[0015] a combination thereof; wherein, the subjecting transforms
the polymeric layer into a polymeric matrix having a predetermined
IM profile.
[0016] In some embodiments, the present invention provides a method
of creating a medical article having a desired rate of release of
an agent, wherein the method comprises:
[0017] selecting a rate of release of an agent from a medical
article having a polymeric matrix comprising the agent;
[0018] obtaining the agent in a desired form, or a combination of
forms, that provides the selected rate of release through
dissolution, diffusion, or a combination thereof; wherein, the
form, or combination of forms, comprises a component selected from
a group consisting of a polymorph, a solvate, a hydrate, and an
amorphous form of the agent;
[0019] preparing a composition comprising a polymer and the
agent;
[0020] applying the composition on the medical article to form a
polymeric layer comprising the agent; and
[0021] forming the polymeric matrix from the polymeric layer,
wherein the polymeric matrix has the selected rate of release of
the agent.
[0022] In some embodiments, the present invention provides a
medical article comprising a polymeric matrix having a first
component and a second component; wherein, the first component
comprises a first polymer, the second component comprises an agent,
and the polymeric matrix has a predetermined initial morphology
(IM) profile. Some exemplary agents include, but are not limited
to, paclitaxel, docetaxel, estradiol, nitric oxide donors, super
oxide dismutases, super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
biolimus, tacrolimus, dexamethasone, rapamycin, rapamycin
derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),
40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)
ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,
40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), clobetasol,
pimecrolimus, imatinib mesylate, midostaurin, prodrugs thereof,
co-drugs thereof, or a combination thereof.
[0023] The coating can be formed on an implantable device such as a
stent, which can be implanted in a patient to treat, prevent,
mitigate, or reduce a vascular medical condition, or to provide a
pro-healing effect. Examples of these conditions include
atherosclerosis, thrombosis, restenosis, hemorrhage, vascular
dissection or perforation, vascular aneurysm, vulnerable plaque,
chronic total occlusion, claudication, anastomotic proliferation
(for vein and artificial grafts), bile duct obstruction, ureter
obstruction, tumor obstruction, or combinations of these.
BRIEF DESCRIPTION OF THE FIGURES
[0024] FIG. 1 is a diagram used to illustrate the local
pharmacokinetics of agent release from a stent and its subsequent
uptake in the coronary vasculature according to some embodiments of
the present invention.
[0025] FIG. 2 illustrates a cross-section of a coating on a stent
strut within a vascular organ according to some embodiments of the
present invention.
[0026] FIGS. 3a and 3b illustrate a section of a polymeric matrix
having a morphology containing an agent-enriched phase at a
concentration that is below about 30% by volume, and above about
30% by volume, respectively, according to some embodiments of the
present invention.
[0027] FIG. 4 illustrates an example of a three-dimensional view of
a stent according to some embodiments of the present invention.
[0028] FIGS. 5a and 5b illustrate a sandwiched-coating design
according to some embodiments of the present invention.
[0029] FIG. 6 illustrates an SEM of an IM profile at high
magnification that was produced using a low humidity gas phase
boundary condition according to some embodiments of the present
invention.
[0030] FIGS. 7a and 7b illustrate SEMs of an IM profile at high and
low magnification that were produced using a high humidity gas
phase boundary condition according to some embodiments of the
present invention.
[0031] FIG. 8 illustrates an SEM of an IM profile at high
magnification that was produced after exposing a coating produced
using low humidity to a blood flow simulation using distilled water
according to some embodiments of the present invention.
[0032] FIGS. 9a and 9b illustrate SEMs of an IM profile at high and
low magnification, respectively, that were produced after exposing
a coating produced using high humidity to a blood flow simulation
using distilled water according to some embodiments of the present
invention.
[0033] FIGS. 10a and 10b illustrate SEM photos of IM profiles that
were produced after exposing coatings produced using low humidity
conditions and high humidity conditions, respectively, to porcine
serum for one day according to some embodiments of the present
invention.
[0034] FIGS. 11a and 11b illustrate the agent release in a PBS/PEG
solution and a porcine serum, respectively, from coatings produced
using low humidity conditions and high humidity conditions,
according to some embodiments of the present invention.
[0035] FIGS. 12a and 12b illustrate the effect of pressure and
mechanical deformation on agent release according to some
embodiments of the present invention.
[0036] FIGS. 13a and 13b illustrate the effect of pressure and
temperature on the release rate of an agent according to some
embodiments of the present invention.
DETAILED DESCRIPTION
[0037] As discussed in more detail below, the embodiments of the
present invention generally encompass controlling the morphology of
polymeric matrices to control their performance characteristics.
More particularly, the present invention provides a method of
forming a medical article having such a polymeric matrix to provide
a controlled release of an agent from the medical article. A
"medical article" can include, but is not limited to, a medical
device or a coating for a medical device.
[0038] Examples of medical devices include, but are not limited to,
stents, stent-grafts, vascular grafts, artificial heart valves,
foramen ovale closure devices, cerebrospinal fluid shunts,
pacemaker electrodes, guidewires, ventricular assist devices,
cardiopulmonary bypass circuits, blood oxygenators, coronary shunts
(AXIUS.TM., Guidant Corp.), vena cava filters, and endocardial
leads (FINELINE.RTM. and ENDOTAK.RTM., Guidant Corp.). In some
embodiments, the stents include, but are not limited to, tubular
stents, self-expanding stents, coil stents, ring stents,
multi-design stents, and the like. In other embodiments, the stents
are metallic; low-ferromagnetic; non-ferromagnetic; biostable
polymeric; biodegradable polymeric or biodegradable metallic. In
some embodiments, the stents include, but are not limited to,
vascular stents, renal stents, biliary stents, pulmonary stents and
gastrointestinal stents.
[0039] The medical devices can be comprised of a metal or an alloy,
including, but not limited to, ELASTINITE.RTM. (Guidant Corp.),
NITINOL.RTM. (Nitinol Devices and Components), stainless steel,
tantalum, tantalum-based alloys, nickel-titanium alloy, platinum,
platinum-based alloys such as, for example, platinum-iridium
alloys, iridium, gold, magnesium, titanium, titanium-based alloys,
zirconium-based alloys, alloys comprising cobalt and chromium
(ELGILOY.RTM., Elgiloy Specialty Metals, Inc.; MP35N and MP20N, SPS
Technologies) or combinations thereof. The tradenames "MP35N" and
"MP20N" describe alloys of cobalt, nickel, chromium and molybdenum.
The MP35N consists of 35% cobalt, 35% nickel, 20% chromium, and 10%
molybdenum. The MP20N consists of 50% cobalt, 20% nickel, 20%
chromium, and 10% molybdenum. Medical devices with structural
components that are comprised of bioabsorbable polymers or
biostable polymers are also included within the scope of the
present invention.
[0040] The control over the release of agents provides for control
over, inter alia, the therapeutic, prophylactic, diagnostic, and
ameliorative effects that are realized by a patient in need of such
treatment. The terms "subject" and "patient" can be used
interchangeably and refer to an animal such as a mammal including,
but not limited to, non-primates such as, for example, a cow, pig,
horse, cat, dog, rat, and mouse; and primates such as, for example,
a monkey or a human.
[0041] FIG. 1 is a diagram used to illustrate the local
pharmacokinetics of agent release from a stent and its subsequent
uptake in the coronary vasculature according to some embodiments of
the present invention. In region 101, the agent that will be
released from the stent is a drug. The agent can be released and
passed through tissue cells within adjoining tissue 102, blood 103,
or the agent can remain as residual agent ("R") 104 on the stent.
The agent can also be metabolized ("M") 105 after its delivery to
adjoining tissue 102, blood 103, other vascular organs 106, or
vital organs 107. In addition, the control of the release rate of
agents also has an effect upon the mechanical integrity of the
polymeric matrix, as well as a relationship to a subject's
absorption rate of the absorbable polymers.
[0042] FIG. 2 illustrates a cross-section of a coating on a stent
strut within a vascular organ according to some embodiments of the
present invention. The cross-section of the coated stent strut 201
includes a stent 202, an optional primer layer 203, a polymer
matrix 204 that includes at least one agent 205, and an optional
top-coat layer 206 that can further control the diffusion of the
agent 205 out of the polymer matrix 204. The coated stent strut 201
is adjoining vascular tissue 207 and blood 208. The agent 205 is
released from the polymer reservoir 204 into the blood 208 and the
vascular tissue 207. This release of the agent 205 includes a
diffusion parameter, so design of the polymeric matrix 204 can
include diffusion considerations in order to further obtain control
over the release of the agent 205.
[0043] In some embodiments, the invention is a method for creating
a medical article, wherein the medical article includes a polymeric
matrix having a predetermined initial morphology profile and an
agent. The medical article can include a polymeric matrix having a
predetermined initial morphology profile ("IM profile"), i.e. a
predetermined arrangement of the components within the matrix,
wherein at least one of these components includes an agent. It has
been discovered that these predetermined IM profiles can be
designed to provide a controllable release rate of agents from the
polymeric matrix. The term "initial morphology" refers to the
morphology of the polymeric matrix in its initial state after the
medical article has been manufactured but before implantation.
[0044] The morphology of a polymeric matrix refers the way that the
components of the matrix are arranged. In some embodiments, the
morphology can include, for example, by the presence and
characteristics of phase separations between components within the
polymeric matrix, where the phase separation can exist between
polymers, an agent and a polymer, between agents, or between other
components in the polymeric matrix.
[0045] FIGS. 3a and 3b illustrate a section of a polymeric matrix
having a morphology containing an agent-enriched phase at a
concentration that is below about 30% by volume, and above about
30% by volume, respectively, according to some embodiments of the
present invention. FIG. 3a illustrates a section of a polymeric
matrix containing an agent-enriched phase at a concentration that
is below about 30% by volume. The section 301 of the polymeric
matrix is below the percolation threshold, since the agent-enriched
phase 302 has not yet reached the concentration required to begin
forming an interconnected network within the bulk phase 303 of the
polymeric matrix. The "percolation threshold" is the point at which
the agent-enriched phase begins to connect with itself and form an
interconnected network of the agent-enriched phase within the
polymeric matrix. The percolation threshold is the point at which
the agent-enriched phase forms its own channel for diffusion.
[0046] FIG. 3b illustrates a section of a polymeric matrix
containing an agent-enriched phase at a concentration that is above
about 30% by volume. The section 304 of the polymeric matrix is
above the percolation threshold, since the agent-enriched phase 305
has reached the concentration required to begin forming an
interconnected network within the bulk phase 306 of the polymeric
matrix.
[0047] In some embodiments, the morphology design can include
control over the characteristics of the zone of phase separation
between phases in a polymeric matrix, where the zone of phase
separation can be thin, thick, continuous, non-continuous,
hydrophobic, hydrophilic, porous, interconnected, dispersed, and
the like. In some embodiments, the morphology can include, for
example, other physical characteristics of a polymeric matrix
including, but not limited to, the presence of pores, crystalline
regions, amorphous regions, polymorphism of agents, the presence of
metals, the presence of ceramics, and the like. The variations
possible in the design of the morphology of a polymeric matrix can
be extraordinarily large in number. The invention includes any
polymeric matrix design that can be preselected and created to have
an arrangement of components that provides a predictable
performance characteristic.
[0048] The methods of the present invention include selecting a
desired IM profile; forming a polymeric layer comprising the agent
on a surface of the medical article; and subjecting the polymeric
layer to a terminal process step to create the desired polymeric
matrix. In most embodiments, the polymeric matrices may be selected
to have a predetermined IM profile having at least a first
component and a second component, where the first component can
comprise a first polymer, and the second component can comprise an
agent. In some embodiments, the second component can optionally
comprise a second polymer.
[0049] In many embodiments, the morphology of the polymeric matrix
can be selected to include a dispersed phase among the components
of the matrix, and the dispersed phase may contain an agent. In
some embodiments, the agent can be selected such that it dissolves
in a polymer phase without a phase separation, or it can form a
dispersed phase or a percolated phase. This dissolution can depend
on factors including, but not limited to, the thermodynamic
relationships between the agents and the polymers as well as the
concentration of the agent in the polymeric matrix. One of skill
will appreciate, for example, that the solubility parameters of the
polymeric components of the matrix, as well as the miscibility of
the combination of the polymers and agents, are design
considerations that can assist in controlling the formation of
phases in the polymeric matrix.
[0050] The polymeric matrix can be selected to include a morphology
that includes a combination of polymers. In some embodiments, an
agent can be selected that is more thermodynamically stable in a
first polymer than in a second polymer, preferentially dissolve in
the first polymer, and create a first polymer/agent combination as
a dispersed phase that can be substantially or completely
immiscible with the second polymer. In these embodiments, the
second polymer can be referred to as a "bulk phase," and the first
polymer/agent combination can be referred to as an "agent-enriched
phase." The IM profile can refer to a morphology profile in any
direction or combination of directions, or in any region or
combination of regions, within a polymeric matrix. The emphasis of
the present invention is that virtually any IM profile or
combination of IM profiles can be preselected and created upon
demand. The predetermined IM profiles can be selected to provide a
desired physical, mechanical, chemical, or biological
characteristic of the polymeric matrix. Examples of physical
characteristics include an increased or decreased water uptake, a
dispersed-phase morphology, a percolated-phase morphology, a
solid-solution morphology, and a porous morphology within the
matrix. Examples of mechanical characteristics include an increased
or decreased toughness, an increased elasticity, an increased or
decreased Young's modulus, an increased tensile strength, and an
increased tear strength of the matrix. Examples of chemical
characteristics include an increased agent loading capacity, an
increased durability, and an increased hydrophilicity of the
matrix. Examples of biological characteristics include an increased
biocompatibility, a desired bioactivity, an increased
biobeneficiality, and a controllable rate of biodegradation and
elimination of the matrix from a subject. Biobeneficiality is the
attribute of a biobeneficial material which enhances the
biocompatibility of the particles or device by being non-fouling,
hemocompatible, actively non-thrombogenic, or antiinflammatory, all
without depending on the release of a pharmaceutically active
agent.
[0051] Water uptake by a polymeric matrix can be an important
characteristic in the design of the matrix. Water can act as a
plasticizer, diffusion medium, and can also hydrolyze chemical
bonds within the matrix. Accordingly, control of water uptake can
provide additional control over the mechanical properties of the
matrix as well as the degradation rate, absorption rate, and the
agent release rate of a medical article in vivo. In some
embodiments, an increase in hydrolysis can also increase the in
vivo release rate of an agent by creating channels within a medical
article that can serve as transport pathways for diffusion of the
agents from the composition within a subject. Moreover, water
uptake can affect the storage life of a medical device by causing
premature hydrolysis of the matrix, agent migration, and/or agent
release.
[0052] The ability of the medical article to withstand stresses in
vivo that can cause mechanical failure include, but are not limited
to, cracking, flaking, peeling, fracturing, and perhaps a change in
the modulus of the material that may affect, for example, the
rigidity and toughness of the medical article. An example of a
chemical property that can affect performance of a biodegradable
composition in vivo is the rate of absorption of the composition by
a subject. An example of a biological property that can affect
performance of a composition in vivo is the bioactive and/or
biobeneficial nature of the composition, both of which are
described below.
[0053] It should be appreciated that the polymeric matrix can
include other components, such as encapsulated agents that can be
liposomally-encapsulated or polymer-encapsulated agents as part of
the morphology; or a carrier, organic or inorganic, such as a
porous calcium phosphate microparticle, where the carrier assists
in obtaining a given loading of an agent needed for a localized
treatment of a disease. Moreover, a polymeric matrix can comprise
biodegradable components, and these components may be biodegradable
due to the labile nature of chemical functionalities, such as ester
groups between chemical moieties. Accordingly, the polymeric
matrices can be designed to be biodegradable, such that they can be
broken down, absorbed, resorbed and eliminated by a mammal.
[0054] In some embodiments, the polymeric matrix can release agents
without biodegradation of the matrix, where the agent-release is at
least partially independent of biodegradation. In other
embodiments, the agents release during biodegradation of the
matrix, such that the agent-release is at least partially dependent
on biodegradation. In other examples, the polymeric matrix releases
agents according to a combination of designs, wherein the
combination can include agent release rates that are at least
partially independent of, or at least partially dependent on,
biodegradation of the polymeric matrix.
[0055] For the purposes of the present invention, a material is
"biodegradable" when all or a portion of it is capable of being
completely or substantially degraded or eroded when exposed to an
in vivo environment or a representative in vitro environment. A
polymer or polymeric matrix, for example, is capable of being
degraded or eroded when it can be gradually broken-down, resorbed,
absorbed and/or eliminated by, for example, hydrolysis,
enzymolysis, oxidation, metabolic processes, bulk or surface
erosion, and the like within a subject. It should be appreciated
that traces or residue of polymer may remain on the device, near
the site of the device, or near the site of a biodegradable device,
following biodegradation. The terms "bioabsorbable" and
"biodegradable" are used interchangeably in this application.
[0056] The methods of the present invention include forming a
polymer layer comprising an agent on a surface of a medical
article. In each of the embodiments, the term "layer" describes a
thickness of a polymeric material within which an agent must pass
through to be released into a subject. This term can refer, for
example, to any individual polymeric material that may be used to
form a medical device or a coating for a medical device. A layer
can include, but is not limited to, polymeric material from a
single-pass application or multiple-pass application, where a
"pass" can be any single process step, or combination of steps,
used to apply a material such as, for example, a pass of a spray
coating device, a pass of an electrostatic coating device, a pass
of a controlled-volume ejector, a dipping, an extrusion, a mold, a
single dip in a layered manufacturing process, or a combination
thereof. In general, a pass includes any single process step known
to one of skill in the art that can be used to apply materials in
the formation of a medical device or coating using a composition
comprising a polymeric material. A layer can consist of a single
pass or multiple passes. In some embodiments, the coating can be
applied to an entire medical device or select regions of the
medical device.
[0057] The term "thickness" of a layer can refer to the distance
between opposite surfaces of a polymeric material that is used in
the production of a medical device or coating. The thickness can
refer to that of a single layer, a single layer within a
combination of layers, or a combination layers. In some
embodiments, the thickness of a polymeric material can be the
thickness of a component within the structure of a medical device,
such as, for example, the thickness of a strut within a stent. In
other embodiments, the thickness of a polymeric material can be the
thickness of a layer of coating applied to a medical device, such
as a stent. In other embodiments, the thickness of a polymeric
material can be the thickness of a combination of layers applied as
a coating for a medical device.
[0058] In many embodiments, the thickness of a polymeric material
can range from about 0.1 nm to about 1.0 cm, from about 0.1 nm to
about 1.0 mm, from about 0.1 nm to about 100 .mu.m, from about 0.1
nm to about 1 .mu.m, from about 0.1 nm to about 100 nm, from about
0.1 nm to about 10 nm, from about 10 nm to about 100 nm, from about
10 .mu.m to about 50 .mu.m, from about 50 .mu.m to about 100 .mu.m,
or any range therein. In other embodiments, the thickness of a
polymeric matrix can range from about 1 .mu.m to about 10 .mu.m,
which can be found, for example, in some of the current
drug-eluting stent (DES) systems. In other embodiments, the
thickness of the polymeric matrices can be regionally distributed
throughout a device to create a variation in thicknesses such as,
for example, the variation in thicknesses that can be found in an
abluminally-coated DES stent.
[0059] The methods of forming a polymeric layer include,
essentially, wet dispensing and dry dispensing, where the wet
dispensing methods are dispensing a liquid. Wet dispensing methods
can include, but are not limited to, spraying; dipping; constant
volume applications such as, for example, a syringe pump; and
constant pressure applications such as, for example, pneumatic
dispensers. In some embodiments, the spraying can include, for
example air atomization, ultrasound atomization, or a combination
thereof. In some embodiments, the spray deposition can include, for
example, direct deposition by acoustic ejection or piezoelectric
droplet generation. In some embodiments, dipping can include
lithographic techniques such as, for example, layered
manufacturing.
[0060] Dry dispensing methods can include, but are not limited to,
chemical vapor deposition (CVD) methods such as, for example,
plasma deposition, and physical vapor deposition (PVD) methods such
as, for example, ion-beam assisted deposition (MAD). Other methods
of dry deposition can include, for example, ink-jet type
depositions, which can include the deposition of charged
particles.
[0061] In many embodiments, each layer can be applied to an
implantable substrate by any method of dispensing a composition
from any dispenser including, but not limited to, dipping,
spraying, pouring, brushing, spin-coating, roller coating, meniscus
coating, powder coating, inkjet-type application, controlled-volume
application such as drop-on-demand, or a combination thereof. In
these embodiments, a dry coating containing a biodegradable polymer
may be formed on the stent when the solvent evaporates. In some
embodiments, at least one of the layers can be formed on a stent by
dissolving one or more biodegradable polymers, optionally with a
non-biodegradable polymer, in one or more solvents, and either (i)
spraying the solution on the stent or (ii) dipping the stent in the
solution.
[0062] In other embodiments, a coating can be applied to a medical
article, such as a stent, using methods that may include sputtering
and gas-phase polymerization. Sputtering is a method that includes
placing a polymeric material target in an environment that is
conducive to applying energy to the polymeric material and
sputtering the polymeric material from the target to the device to
form a coating of the polymeric material on the device. Similarly,
a gas-phase polymerization method includes applying energy to a
monomer in the gas phase within an environment that is conducive to
formation of a polymer from the monomer in the gas phase, and
wherein the polymer formed coats the device.
[0063] The dispensing of the polymer layers may require the
selection and use of solvents to assist in creating and using the
compositions of the present invention. Since many applications of
the present invention include "casting" of the compositions, the
solvents will be referred to as "casting solvents." The casting
solvent used to form polymer layers may be chosen based on several
criteria including, for example, its polarity, ability to hydrogen
bond, molecular size, volatility, biocompatibility, reactivity and
purity. It is recognized that process conditions can affect the
chemical structure of the underlying materials and, thus, affect
their solubility in a casting solvent. It is also recognized that
the kinetics of dissolution are a factor to consider when selecting
a casting solvent, because a slow dissolution of an underlying
material, for example, may not affect the performance
characteristics of a product where the product is produced
relatively quickly.
[0064] Exemplary casting solvents for use in the present invention
include, but are not limited to, DMAC, DMF, THF, cyclohexanone,
xylene, toluene, acetone, i-propanol, methyl ethyl ketone,
propylene glycol monomethyl ether, methyl butyl ketone, ethyl
acetate, n-butyl acetate, and dioxane. Solvent mixtures can be used
as well. Representative examples of the mixtures include, but are
not limited to, DMAC and methanol (50:50 w/w); water, i-propanol,
and DMAC (10:3:87 w/w); i-propanol and DMAC (80:20, 50:50, or 20:80
w/w); acetone and cyclohexanone (80:20, 50:50, or 20:80 w/w);
acetone and xylene (50:50 w/w); acetone, xylene and FLUX REMOVER
AMS.RTM. (93.7% 3,3-dichloro-1,1,1,2,2-pentafluoropropane and
1,3-dichloro-1,1,2,2,3-pentafluoropropane, and the balance is
methanol with trace amounts of nitromethane; Tech Spray, Inc.)
(10:40:50 w/w); and 1,1,2-trichloroethane and chloroform (80:20
w/w).
[0065] The polymeric layer that is formed is subjected to a
terminal process step to form the predetermined IM profiles of the
present invention. The application of a terminal step can be used
to change the arrangement of components within a polymeric matrix,
for example, by promoting or inhibiting the migration of agents
within a matrix; creating concentration profiles of agents within a
matrix, promoting or inhibiting structural changes such as pores
and channels within a matrix. A "terminal process step" is any step
added subsequent to applying a polymeric material to a surface of a
medical article, any step added subsequent to drying the polymeric
material, any step added concurrent to applying the polymeric
material to the surface of the medical article, any step added
concurrent to the drying of the medical article, or any combination
thereof. Examples of such steps are provided herein.
[0066] An agent that migrates with a solvent can be profiled by
controlling the rate of solvent migration. The rate of solvent
migration can be controlled, for example, by exposing the polymeric
layer to a fluid while forming the layer, and by altering the
pressure and/or temperature in the environment of a solvent removal
process such as, for example, drying. Such control of the pressure
and/or temperature can allow for indirect control of the initial
morphology relative to position in a polymeric matrix. The IM
profiles can then be designed to take on virtually any profile
desired such as, for example, a predetermined wave profile that can
provide a pulsed administration of a desired agent. Accordingly, in
some embodiments, the terminal process step includes exposing the
polymeric layer to a fluid while forming the layer, wherein the
composition of the fluid is preselected to be miscible or
immiscible with a component in the polymeric layer. The fluid phase
can be a liquid phase, a gas phase, a combination thereof, or a
phase consisting essentially of a gas phase.
[0067] In some embodiments, the gas phase contains water, where an
increase or decrease in water concentration is referred to as an
increase or decrease in humidity. In some embodiments, the gas
phase is preferentially adsorbed by the agent. In some embodiments,
the gas phase is preferentially adsorbed by one or more polymers in
the polymeric matrix, wherein the polymer may or may not contain
agent. In some embodiments, the solvents can be highly volatile
solvents that are poor solvents such as, for example, Freon or a
hydrocarbon. In some embodiments, the gas phase can selectively
hydrolyze the polymeric matrix and/or create an intentional surface
leaching or enrichment of an agent. In some embodiments, a liquid
phase can selectively hydrolyze the polymeric matrix and/or create
an intentional surface leaching or enrichment of an agent.
[0068] The surface energy relationship between the fluid phase and
polymer layer can be a design parameter. The fluids miscibility
with the polymer layer and its relative ability to wet or spread
the polymer layer can control the effect of the fluid on the
predetermined IM profile of the polymeric matrix. In some
embodiments, the fluid phase is miscible with the polymer layer. In
some embodiments, the fluid is polar, non-polar, or a combination
thereof. In some embodiments, the fluid is hydrophilic,
hydrophobic, amphiphilic, or a combination thereof. In some
embodiments, the fluid comprises water to provide a desired
humidity while forming the polymer layer. The fluid may also
include a solvent used in forming the polymer layer.
[0069] In some embodiments, the terminal process step includes
applying a pressure to the polymeric layer, or polymeric matrix
formed from the layer, wherein the pressure can create a mechanical
deformation in the polymer material. The pressure can be applied
using any source of pressure known to one of skill in the art. In
many embodiments, the pressure can be ambient pressure, a pressure
higher than ambient pressure, a pressure lower than ambient
pressure, or a variation in pressures that can include a pulsing of
pressures. In some embodiments, the pressure can be isotropic or
anisotropic. In these embodiments, the pressure can be a high
isotropic pressure. In many embodiments, pressure can be applied to
the polymer layer before the polymer layer is dried, after the
polymer layer is dried, or a combination thereof. The pressure can
be applied using any means known to one of skill in the art
including, but not limited to a pressure vessel, or a mechanical
pressure. Examples of a means for applying a mechanical pressure to
a stent can be found in U.S. Pat. Nos. 6,510,722; 6,481,262;
6,277,110; 6,240,615; 6,202,272; 6,141,855; 6,125,523; 6,092,273;
6,082,990; 6,051,002; 6,024,737; 5,974,652; 5,972,016; 5,920,975;
5,893,852; 5,810,873; each of which is hereby incorporated herein
by reference.
[0070] In some embodiments, the pressure can be a point source of
pressure for localizing a desired IM profile in select areas to
provide additional control over the rate of release of an agent
from these select areas. This method of localizing the point source
of pressure can also assist in providing a polymeric matrix having
desired physical, mechanical, and chemical characteristics.
[0071] In some embodiments, the pressure can be applied at any time
during the formation of a polymer layer as a negative pressure, and
this pressure may also be pulsed during formation of the polymer
layer to, for example, control the localization of agent across the
thickness of the polymer layer so as to create a concentration
profile. The concentration profile can be a constant, linear or
non-linear to provide a rate of release that is tailored to a
particular treatment design. Furthermore, the resulting polymeric
matrix can be composed of multiple layers, wherein each layer can
have any one or any combination of an independently formed
concentration profile, an independently formed morphology profile,
and an independently selected agent or agents to provide for a
customized agent delivery.
[0072] In some embodiments, the pressure can be applied radially
inward using a crimping device for collapsing an expandable stent
onto a balloon catheter, a pressing device for pressing a collapsed
stent onto a balloon catheter while heating the stent and the
balloon catheter, or a combination thereof. In some embodiments,
the pressure is applied only to an abluminal surface of a stent. In
some embodiments, the pressure comprises pressure from inflation of
the balloon on the balloon catheter. The pressure can range from
about 10 psi to about 1000 psi, from about 50 psi to about 500 psi,
from about 100 psi to about 300 psi, or any range therein.
[0073] In some embodiments, the pressure can be applied with an
accompanying source of energy such as, for example, heat. In many
embodiments, the energy can include, but is not limited to, heat,
electromagnetic radiation, electron beam, ion or charged particle
beam, neutral-atom beam, chemical energy, or a combination thereof.
In some embodiments, the application of energy can result in a
coating composition temperature that ranges from about 35.degree.
C. to about 100.degree. C., from about 35.degree. C. to about
80.degree. C., from about 35.degree. C. to about 55.degree. C., or
any range therein. In many embodiments, the temperature can be a
temperature higher than ambient temperature, a temperature lower
than ambient temperature, or a variation in temperatures that can
include a pulsing of temperatures. In some embodiments, the
pressure and temperature can be applied for a period of time
ranging from about 1 second to about 3 minutes, from about 10
seconds to about 2 minutes, from about 15 seconds to about 90
seconds, from about 30 seconds to about 90 seconds, or any range
therein.
[0074] Diffusion Coefficients
[0075] As described above, the release of the agent from a medical
article will most often include a diffusion parameter, such that
the design of a polymeric matrix can include diffusion
considerations in obtaining control over the release of the agent.
The process of diffusion of an agent from a polymeric matrix in the
form of a coating can be affected by the following four
controllable factors: (1) coating parameters, (2) coating process,
(3) polymer physicochemical properties, and (4) agent
physicochemical properties.
[0076] The coating parameters can include, but are not limited to,
the initial solid phase concentration distribution, which includes
the drug to polymer (D/P) ratio, the thickness of an agent-free
polymer top-coating, the total drug content, the dispersed phase
microstructure, and the like. The coating process can include, but
is not limited to, the selection of solvents, the thermal history
of processing, the thermodynamics of phase separation, the solution
thermodynamics, and kinetics, to name a few. Polymer
physicochemical properties can include, but are not limited to,
glass transition temperature (Tg), melting temperature (Tm), heat
of fusion (AHf), percent crystallinity, water absorption,
lipid-induced swelling, and the like. Agent physicochemical
properties include, but are not limited to, the degree and type of
dispersed phase parameters, the extent of solid solution, and the
polymorphism of the agent (e.g. different crystalline forms of a
drug).
[0077] The diffusion coefficient that is measured across a polymer
matrix having multiple components can be described as an
"effective-diffusion coefficient." This is because the
effective-diffusion coefficient depends, at least in part, on the
often complex morphology of the polymer matrix within which the
agent passes. Without intending to be bound by any theory or
mechanism of action, the effective-diffusion coefficient can be
divided into at least two modes that can be referred to as
"biphasic modes:"
[0078] (1) in a first mode, the effective diffusivity corresponds
to the transport of an agent dissolved in a polymeric matrix
without phase separation; or, an agent that primarily transports
out of a dispersed agent phase into a surrounding polymeric matrix
and then diffuses out of the surrounding polymeric matrix; and,
[0079] (2) in a second mode, the effective diffusivity corresponds
to the transport of an agent through a dispersed agent phase, for
example, a dispersed agent phase within a polymeric matrix that has
interconnected to create a closely connected network (i.e. a
"percolated" phase) by virtue of being densely distributed
throughout the polymeric matrix; accordingly, the effective
diffusivity can include an intrinsic diffusivity of the agent
through a water medium in the polymeric matrix in addition to the
tortuosity and porosity of a percolated-phase passage that has
formed throughout the polymeric matrix.
[0080] In some embodiments, the overall mass transport can be
considered as dependent on one or a combination of the biphasic
modes. Since the diffusion coefficient can be proportional to the
rate of release, it can be measured experimentally for each
polymeric matrix and used as a defining characteristic for the
release of a particular agent from that system. Using this
methodology, one of skill can characterize polymeric matrices and
design predetermined IM profiles that are known to provide an agent
release that, although may be variable in rate over the life of a
medical article, is relatively controllable and predictable.
[0081] The creation of an interconnected agent-enriched dispersed
phase morphology provides a means for controlling the diffusion
coefficient. In many embodiments, an agent-enriched phase will
reach a percolation threshold at a concentration of about 30% by
volume within the combined volume of the polymer matrix and agent.
In some embodiments, diffusion of an agent through an
interconnected, agent-rich dispersed phase can result in either a
faster or slower release of an agent, and the result depends on the
relationship between the agent and the agent-enriched phase. In
some embodiments, the agent exists in both the interconnected,
agent-enriched dispersed phase and the bulk phase, such that
release of the agent occurs through diffusion across both phases.
In some embodiments, the agent has to diffuse through the phase
boundary between the dispersed phase and the bulk phase, and the
amount and characteristics of the phase boundary can affect the
rate of release of the agent.
[0082] Effects of IM Profiles on Physical and Mechanical
Properties
[0083] Designing predetermined IM profiles of the agents within the
polymeric matrices can assist in obtaining and maintaining
desirable physical and mechanical properties and, thus, aid in
preventing structural failure within medical articles. Many medical
implants, such as stents, can undergo a great deal of strain and
stress during their manufacture and use which can result in
structural failure. Structural failure can occur, for example, as a
result of manipulating an implant in preparation for placing the
implant in a subject and while placing the implant in a desired
location in a subject. As a result, the ability to identify
desirable polymeric matrices with morphologies that can withstand
such stress and strain can be invaluable to the success of a
medical procedure.
[0084] A stent is an example of an implant that can undergo a great
deal of physical and mechanical stress. A stent may be compressed,
inserted into a small vessel through a catheter, and then expanded
to a larger diameter in a subject. FIG. 4 illustrates an example of
a three-dimensional view of a stent according to some embodiments
of the present invention. The stent 401 may be made up of a pattern
of a number of interconnecting structural elements or struts 402.
As described herein, the embodiments disclosed are not limited to
stents or to the stent pattern illustrated in FIG. 4 and are easily
applicable to other patterns and other devices. The variations in
the structure of patterns are virtually unlimited. Controlled
application of particular agents in low strain areas 403 and high
strain areas 404, 405, and 406 of a stent, for example, can help to
avoid problems, such as cracking and flaking, that can occur during
implantation of the stent. Controlled application of the agents can
also be obtained through control of the morphology of a polymeric
matrix that forms after the application.
[0085] The Polymers
[0086] The polymers used in the present invention may include, but
are not limited to, condensation polymers and copolymers, and
should be chosen according to a desired performance parameter of a
product that will be formed from the composition. Such performance
parameters may include, for example, the toughness of a medical
article, the capacity for the loading concentration of an agent,
and the rate of biodegradation and elimination of the composition
from a subject. If the other polymers in a composition are
non-biodegradable, they should be sized to produce polymer
fragments that can clear from the subject following biodegradation
of the composition.
[0087] In most embodiments, the polymers that can be used include
natural or synthetic polymers; homopolymers and copolymers, such
as, for example, copolymers that are random, alternating, block,
graft, and/or crosslinked; or any combination and/or blend thereof.
The copolymers include polymers with more than two different types
of repeating units such as, for example, terpolymers. In some
embodiments, the polymers can be considered more hydrophobic in
character such as, for example, poly(D,L-lactide),
poly(caprolactone), and poly(vinylidene
fluoride-co-hexafluoropropylene) (Solef.RTM.). In some embodiments,
the polymers can be considered more hydrophilic in character such
as, for example, copolymers containing poly(ethylene glycol) (PEG).
In these embodiments, the copolymers can include, but are not
limited to, copolymers of poly(butylene terephthalate) and
poly(ethylene glycol) (PBT-PEG; PolyActive.RTM.), a
poly(hydroxyalkanoate) and PEG (PHA-PEG), a poly(ester amide) and
PEG (PEA-PEG), or poly(butyl methacrylate) and PEG (PBMA-PEG). One
of skill in the art will be familiar with the wide variety of
polymers that are considered as hydrophilic, such as the many
functionalized hydrophobic polymers that are known--the present
invention encompasses the entirety of these polymers.
[0088] Examples of other polymers that can be used in the present
invention include, but are not limited to, poly(acrylates) such as
poly(butyl methacrylate), poly(ethyl methacrylate),
poly(hydroxyethyl methacrylate), poly(ethyl methacrylate-co-butyl
methacrylate), copolymers of ethylene-methyl methacrylate; poly
(2-acrylamido-2-methylpropane sulfonic acid), and polymers and
copolymers of aminopropyl methacrylamide; poly(cyanoacrylates);
poly(carboxylic acids); poly(vinyl alcohols); poly(maleic
anhydride) and copolymers of maleic anhydride; fluorinated polymers
or copolymers such as poly(vinylidene fluoride), poly(vinylidene
fluoride-co-hexafluoro propene), poly(tetrafluoroethylene), and
expanded poly(tetrafluoroethylene); poly(sulfone); poly(N-vinyl
pyrrolidone); poly(aminocarbonates); poly(iminocarbonates);
poly(anhydride-co-imides), poly(hydroxyvalerate); poly(L-lactic
acid); poly(L-lactide); poly(caprolactones);
poly(lactide-co-glycolide); poly(hydroxybutyrates);
poly(hydroxybutyrate-co-valerate); poly(dioxanones);
poly(orthoesters); poly(anhydrides); poly(glycolic acid);
poly(glycolide); poly(D,L-lactic acid); poly(D,L-lactide);
poly(glycolic acid-co-trimethylene carbonate); poly(phosphoesters);
poly(phosphoester urethane); poly(trimethylene carbonate);
poly(iminocarbonate); poly(ethylene); poly(propylene)
co-poly(ether-esters) such as, for example, poly(dioxanone) and
poly(ethylene oxide)/poly(lactic acid); poly(anhydrides),
poly(alkylene oxalates); poly(phosphazenes); poly(urethanes);
silicones; poly(esters; poly(olefins); copolymers of
poly(isobutylene); copolymers of ethylene-alphaolefin; vinyl halide
polymers and copolymers such as poly(vinyl chloride); poly(vinyl
ethers) such as poly(vinyl methyl ether); poly(vinylidene halides)
such as, for example, poly(vinylidene chloride);
poly(acrylonitrile); poly(vinyl ketones); poly(vinyl aromatics)
such as poly(styrene); poly(vinyl esters) such as poly(vinyl
acetate); copolymers of vinyl monomers and olefins such as
poly(ethylene-co-vinyl alcohol) (EVAL), copolymers of
acrylonitrile-styrene, ABS resins, and copolymers of ethylene-vinyl
acetate; poly(amides) such as Nylon 66 and poly(caprolactam); alkyd
resins; poly(carbonates); poly(oxymethylenes); poly(imides);
poly(ester amides); poly(ethers) including poly(alkylene glycols)
such as, for example, poly(ethylene glycol) and poly(propylene
glycol); epoxy resins; polyurethanes; rayon; rayon-triacetate;
biomolecules such as, for example, fibrin, fibrinogen, starch,
poly(amino acids); peptides, proteins, gelatin, chondroitin
sulfate, dermatan sulfate (a copolymer of D-glucuronic acid or
L-iduronic acid and N-acetyl-D-galactosamine), collagen, hyaluronic
acid, and glycosaminoglycans; other polysaccharides such as, for
example, poly(N-acetylglucosamine), chitin, chitosan, cellulose,
cellulose acetate, cellulose butyrate, cellulose acetate butyrate,
cellophane, cellulose nitrate, cellulose propionate, cellulose
ethers, and carboxymethylcellulose; and derivatives, analogs,
homologues, congeners, salts, copolymers and combinations thereof.
In some embodiments, the polymers are selected such that they
specifically exclude any one or any combination of these
polymers.
[0089] Examples of biodegradable polymers include, but are not
limited to, polymers having repeating units such as, for example,
an .alpha.-hydroxycarboxylic acid, a cyclic diester of an
.alpha.-hydroxycarboxylic acid, a dioxanone, a lactone, a cyclic
carbonate, a cyclic oxalate, an epoxide, a glycol, an anhydride, a
lactic acid, a glycolic acid, a lactide, a glycolide, an ethylene
oxide, an ethylene glycol, or combinations thereof. In other
embodiments, the biodegradable polymers include, but are not
limited to, polyesters, poly(ester amides); poly(hydroxyalkanoates)
(PHA), amino acids; PEG and/or alcohol groups, polycaprolactones,
poly(D-lactide), poly(L-lactide), poly(D,L-lactide),
poly(meso-lactide), poly(L-lactide-co-meso-lactide),
poly(D-lactide-co-meso-lactide), poly(D,L-lactide-co-meso-lactide),
poly(D,L-lactide-co-PEG) block copolymers,
poly(D,L-lactide-co-trimethylene carbonate), polyglycolides,
poly(lactide-co-glycolide), polydioxanones, polyorthoesters,
polyanhydrides, poly(glycolic acid-co-trimethylene carbonate),
polyphosphoesters, polyphosphoester urethanes, poly(amino acids),
polycyanoacrylates, poly(trimethylene carbonate), poly(imino
carbonate), polycarbonates, polyurethanes, copoly(ether-esters)
(e.g. PEO/PLA), polyalkylene oxalates, polyphosphazenes, PHA-PEG,
and any derivatives, analogs, homologues, salts, copolymers and
combinations thereof.
[0090] In some embodiments, the polymers can be poly(glycerol
sebacate); tyrosine-derived polycarbonates containing
desaminotyrosyl-tyrosine alkyl esters such as, for example,
desaminotyrosyl-tyrosine ethyl ester (poly(DTE carbonate)); and any
derivatives, analogs, homologues, salts, copolymers and
combinations thereof. In some embodiments, the polymers are
selected such that they specifically exclude any one or any
combination of any of the polymers taught herein.
[0091] Polymers that degrade should be designed to form fragments
that can be absorbed by the subject undergoing treatment. In some
embodiments, the number average molecular weight of the polymer
fragments should be at or below about 40,000 Daltons, or any range
therein. In other embodiments, the molecular weight of the
fragments range from about 300 Daltons to about 40,000 Daltons,
from about 8,000 Daltons to about 30,000 Daltons, from about 10,000
Daltons to about 20,000 Daltons, or any range therein. The
molecular weights are taught herein as a number average molecular
weight.
[0092] The Agents
[0093] An "agent" can include any chemical moiety having a
characteristic that is bioactive, biobeneficial, diagnostic,
plasticizing, or a combination of these characteristics, when used
in the present invention. A "moiety" can include any chemical
entity composed of as little as a single atom, a small molecule, a
peptide, a protein, an oligonucleotide, a polynucleotide, a
functional group, a bonded residue in a macromolecule, an
individual unit in a copolymer, or an entire polymeric block, to
name a few. A "bioactive agent" is a moiety that can be combined
with a polymer and provides a therapeutic effect, a prophylactic
effect, both a therapeutic and a prophylactic effect, or other
biologically active effect within a subject. Moreover, the
bioactive agents of the present invention may remain linked to a
portion of the polymer or be released from the polymer. A
"biobeneficial agent" is an agent that can be combined with a
polymer and provide a biological benefit within a subject without
necessarily being released from the polymer.
[0094] A "diagnostic agent" is a type of bioactive agent that can
be used, for example, in diagnosing the presence, nature, or extent
of a disease or medical condition in a subject. In one embodiment,
a diagnostic agent can be any agent that may be used in connection
with methods for imaging an internal region of a patient and/or
diagnosing the presence or absence of a disease in a patient.
Diagnostic agents include, for example, contrast agents for use in
connection with ultrasound imaging, magnetic resonance imaging
(MRI), nuclear magnetic resonance (NMR), computed tomography (CT),
electron spin resonance (ESR), nuclear medical imaging, optical
imaging, elastography, and radiofrequency (RF) and microwave
lasers. Diagnostic agents may also include any other agents useful
in facilitating diagnosis of a disease or other condition in a
patient, whether or not imaging methodology is employed.
[0095] The terms "plasticizer" and "plasticizing agent" can be used
interchangeably in the present invention, and can refer to any
agent, including any agent described above, where the agent can be
used to modify the mechanical properties of the polymeric material.
Plasticizers can, for example, reduce crystallinity, lower the
glass-transition temperature (T.sub.g), or reduce the
intermolecular forces between polymers and enhance mobility between
polymers. The mechanical properties that are modified include, but
are not limited to, Young's modulus, impact resistance (toughness),
tensile strength, and tear strength.
[0096] The bioactive agents can be any moiety capable of
contributing to a therapeutic effect, a prophylactic effect, both a
therapeutic and prophylactic effect, or other biologically active
effect in a mammal. The agent can also have diagnostic properties.
The bioactive agents include, but are not limited to, small
molecules, nucleotides, oligonucleotides, polynucleotides, amino
acids, oligopeptides, polypeptides, and proteins. In one example,
the bioactive agent inhibits the activity of vascular smooth muscle
cells. In another example, the bioactive agent controls migration
or proliferation of smooth muscle cells to inhibit restenosis.
[0097] Bioactive agents include, but are not limited to,
antiproliferatives, antineoplastics, antimitotics,
anti-inflammatories, antiplatelets, anticoagulants, antifibrins,
antithrombins, antibiotics, antiallergics, antioxidants, and any
prodrugs, metabolites, analogs, homologues, congeners, derivatives,
salts and combinations thereof. It is to be appreciated that one
skilled in the art should recognize that some of the groups,
subgroups, and individual bioactive agents may not be used in some
embodiments of the present invention.
[0098] Antiproliferatives include, for example, actinomycin D,
actinomycin IV, actinomycin I.sub.1, actinomycin X.sub.1,
actinomycin C.sub.1, dactinomycin (COSMEGEN.RTM., Merck & Co.,
Inc.), imatinib mesylate, and any prodrugs, metabolites, analogs,
homologues, congeners, derivatives, salts and combinations thereof.
Antineoplastics or antimitotics include, for example, paclitaxel
(TAXOL.RTM., Bristol-Myers Squibb Co.), docetaxel (TAXOTERE.RTM.,
Aventis S. A.), midostaurin, methotrexate, azathioprine,
vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride
(ADRIAMYCIN.RTM., Pfizer, Inc.) and mitomycin (MUTAMYCIN.RTM.,
Bristol-Myers Squibb Co.), midostaurin, and any prodrugs,
metabolites, analogs, homologues, congeners, derivatives, salts and
combinations thereof.
[0099] Antiplatelets, anticoagulants, antifibrin, and antithrombins
include, for example, sodium heparin, low molecular weight
heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,
prostacyclin and prostacyclin analogues, dextran,
D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist antibody, recombinant hirudin, and thrombin inhibitors
(ANGIOMAX.RTM., Biogen, Inc.), and any prodrugs, metabolites,
analogs, homologues, congeners, derivatives, salts and combinations
thereof.
[0100] Cytostatic or antiproliferative agents include, for example,
angiopeptin, angiotensin converting enzyme inhibitors such as
captopril (CAPOTEN.RTM. and CAPOZIDE.RTM., Bristol-Myers Squibb
Co.), cilazapril or lisinopril (PRINIVIL.RTM. and PRINZIDE.RTM.,
Merck & Co., Inc.); calcium channel blockers such as
nifedipine; colchicines; fibroblast growth factor (FGF)
antagonists, fish oil (omega 3-fatty acid); histamine antagonists;
lovastatin (MEVACOR.RTM., Merck & Co., Inc.); monoclonal
antibodies including, but not limited to, antibodies specific for
Platelet-Derived Growth Factor (PDGF) receptors; nitroprusside;
phosphodiesterase inhibitors; prostaglandin inhibitors; suramin;
serotonin blockers; steroids; thioprotease inhibitors; PDGF
antagonists including, but not limited to, triazolopyrimidine; and
nitric oxide; imatinib mesylate; and any prodrugs, metabolites,
analogs, homologues, congeners, derivatives, salts and combinations
thereof. Antiallergic agents include, but are not limited to,
pemirolast potassium (ALAMAST.RTM., Santen, Inc.), and any
prodrugs, metabolites, analogs, homologues, congeners, derivatives,
salts and combinations thereof.
[0101] Other bioactive agents useful in the present invention
include, but are not limited to, free radical scavengers; nitric
oxide donors; rapamycin; methyl rapamycin; 42-Epi-(tetrazoylyl)
rapamycin (ABT-578); 40-O-(2-hydroxy)ethyl-rapamycin (everolimus);
tacrolimus; pimecrolimus; 40-O-(3-hydroxy)propyl-rapamycin;
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin; tetrazole containing
rapamycin analogs such as those described in U.S. Pat. No.
6,329,386; estradiol; clobetasol; idoxifen; tazarotene;
alpha-interferon; host cells such as epithelial cells; genetically
engineered epithelial cells; dexamethasone; and, any prodrugs,
metabolites, analogs, homologues, congeners, derivatives, salts and
combinations thereof.
[0102] Free radical scavengers include, but are not limited to,
2,2',6,6'-tetramethyl-1-piperinyloxy, free radical (TEMPO);
4-amino-2,2',6,6'-tetramethyl-1-piperinyloxy, free radical
(4-amino-TEMPO); 4-hydroxy-2,2',6,6'-tetramethyl-piperidene-1-oxy,
free radical (TEMPOL),
2,2',3,4,5,5'-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate,
free radical; 16-doxyl-stearic acid, free radical; superoxide
dismutase mimic (SODm) and any analogs, homologues, congeners,
derivatives, salts and combinations thereof. Nitric oxide donors
include, but are not limited to, S-nitrosothiols, nitrites,
N-oxo-N-nitrosamines, substrates of nitric oxide synthase,
diazenium diolates such as spermine diazenium diolate and any
analogs, homologues, congeners, derivatives, salts and combinations
thereof.
[0103] A biological benefit may be that the polymer or polymeric
matrix becomes non-thrombogenic, such that protein absorption is
inhibited or prevented to avoid formation of a thromboembolism;
promotes healing, such that endothelialization within a blood
vessel is not exuberant but rather forms a healthy and functional
endothelial layer; or is non-inflammatory, such that the
biobeneficial agent acts as a biomimic to passively avoid
attracting monocytes and neutrophils, which could lead to an event
or cascade of events that create inflammation.
[0104] Examples of biobeneficial agents include, but are not
limited to, carboxymethylcellulose; poly(alkylene glycols) such as,
for example, PEG; poly(N-vinyl pyrrolidone); poly(acrylamide methyl
propane sulfonic acid); poly(styrene sulfonate); sulfonated
polysaccharides such as, for example, sulfonated dextran; sulfated
polysaccharides such as, for example, sulfated dextran and dermatan
sulfate; and glycosaminoglycans such as, for example, hyaluronic
acid and heparin; and any derivatives, analogs, homologues,
congeners, salts, copolymers and combinations thereof. In some
embodiments, the biobeneficial agents can be prohealing such as,
for example, poly(ester amides), elastin, silk-elastin, collagen,
atrial natriuretic peptide (ANP); and peptide sequences such as,
for example, those comprising Arg-Gly-Asp (RGD). In other
embodiments, the biobeneficial agents can be non-thrombotics such
as, for example, thrombomodulin; and antimicrobials such as, for
example, the organosilanes. It is to be appreciated that one
skilled in the art should recognize that some of the groups,
subgroups, and individual biobeneficial agents may not be used in
some embodiments of the present invention.
[0105] Examples of heparin derivatives include, but are not limited
to, earth metal salts of heparin such as, for example, sodium
heparin, potassium heparin, lithium heparin, calcium heparin,
magnesium heparin, and low molecular weight heparin. Other examples
of heparin derivatives include, but are not limited to, heparin
sulfate, heparinoids, heparin-based compounds and heparin
derivatized with hydrophobic materials.
[0106] Examples of hyaluronic acid derivates include, but are not
limited to, sulfated hyaluronic acid such as, for example,
O-sulphated or N-sulphated derivatives; esters of hyaluronic acid
wherein the esters can be aliphatic, aromatic, arylaliphatic,
cycloaliphatic, heterocyclic or a combination thereof; crosslinked
esters of hyaluronic acid wherein the crosslinks can be formed with
hydroxyl groups of a polysaccharide chain; crosslinked esters of
hyaluronic acid wherein the crosslinks can be formed with
polyalcohols that are aliphatic, aromatic, arylaliphatic,
cycloaliphatic, heterocyclic, or a combination thereof; hemiesters
of succinic acid or heavy metal salts thereof; quaternary ammonium
salts of hyaluronic acid or derivatives such as, for example, the
O-sulphated or N-sulphated derivatives.
[0107] Examples of poly(alkylene glycols) include, but are not
limited to, PEG, mPEG, poly(ethylene oxide), poly(propylene
glycol)(PPG), poly(tetramethylene glycol), and any derivatives,
analogs, homologues, congeners, salts, copolymers and combinations
thereof. In some embodiments, the poly(alkylene glycol) is PEG. In
other embodiments, the poly(alkylene glycol) is mPEG. In some
embodiments, the poly(alkylene glycol) is poly(ethylene
glycol-co-hydroxybutyrate).
[0108] The copolymers that may be used as biobeneficial agents
include, but are not limited to, any derivatives, analogs,
homologues, congeners, salts, copolymers and combinations of the
foregoing examples of agents. Examples of copolymers that may be
used as biobeneficial agents in the present invention include, but
are not limited to, dermatan sulfate, which is a copolymer of
D-glucuronic acid or L-iduronic acid and N-acetyl-D-galactosamine;
poly(ethylene oxide-co-propylene oxide); copolymers of PEG and
hyaluronic acid; copolymers of PEG and heparin; copolymers of PEG
and hirudin; graft copolymers of poly(L-lysine) and PEG; copolymers
of PEG and a poly(hydroxyalkanoate) such as, for example,
poly(ethylene glycol-co-hydroxybutyrate); and, any derivatives,
analogs, congeners, salts, or combinations thereof. In some
embodiments, the copolymer that may be used as a biobeneficial
agent can be a copolymer of PEG and hyaluronic acid, a copolymer of
PEG and hirudin, and any derivative, analog, congener, salt,
copolymer or combination thereof. In some embodiments, the
copolymer that may be used as a biobeneficial agent is a copolymer
of PEG and a poly(hydroxyalkanoate) such as, for example,
poly(hydroxybutyrate); and any derivative, analog, congener, salt,
copolymer or combination thereof.
[0109] Examples of diagnostic agents include radioopaque materials
and include, but are not limited to, materials comprising iodine or
iodine-derivatives such as, for example, iohexal and iopamidol,
which are detectable by x-rays. Other diagnostic agents such as,
for example, radioisotopes, are detectable by tracing radioactive
emissions. Other diagnostic agents may include those that are
detectable by magnetic resonance imaging (MRI), ultrasound and
other imaging procedures such as, for example, fluorescence and
positron emission tomagraphy (PET). Examples of agents detectable
by MRI are paramagnetic agents, which include, but are not limited
to, gadolinium chelated compounds. Examples of agents detectable by
ultrasound include, but are not limited to, perflexane. Examples of
fluorescence agents include, but are not limited to, indocyanine
green. Examples of agents used in diagnostic PET include, but are
not limited to, fluorodeoxyglucose, sodium fluoride, methionine,
choline, deoxyglucose, butanol, raclopride, spiperone,
bromospiperone, carfentanil, and flumazenil.
[0110] In some embodiments, a combination of agents can be applied,
as taught herein, within a medical device, on a medical device, or
positioned within a controlled volume at a predetermined region on
the device or within a coating on the device. In some embodiments,
the agent combination includes everolimus and clobetasol. In other
embodiments, the agent combination includes tacrolimus and
rapamycin. In other embodiments, the agent combination includes
tacrolimus and everolimus. In other embodiments, the agent
combination can include rapamycin and paclitaxel. In other
embodiments, the agent combination can include an anti-inflammatory
such as, for example, a corticosteroid and an antiproliferative
such as, for example, everolimus. In some embodiments, the agent
combinations can provide synergistic effects for preventing or
inhibiting conditions such as, for example, restenosis,
atherosclerosis, vulnerable plaque, diffuse coronary artery
disease, and the like, that may be prevented, inhibited, mitigated,
or otherwise treated, using an agent-eluting stent.
[0111] Examples of plasticizing agents include, but are not limited
to, low molecular weight polymers such as, for example,
single-block polymers, multi-block copolymers, and other copolymers
such as graft copolymers; oligomers such as ethyl-terminated
oligomers of lactic acid; small organic molecules; hydrogen bond
forming organic compounds with and without hydroxyl groups; polyols
such as low molecular weight polyols having aliphatic hydroxyls;
alkanols such as butanols, pentanols and hexanols; sugar alcohols
and anhydrides of sugar alcohols; polyethers such as poly(alkylene
glycols); esters such as citrates, phthalates, sebacates and
adipates; polyesters; aliphatic acids; proteins such as animal
proteins and vegetable proteins; oils such as, for example, the
vegetable oils and animal oils; silicones; acetylated
monoglycerides; amides; acetamides; sulfoxides; sulfones;
pyrrolidones; oxa acids; diglycolic acids; and any analogs,
derivatives, copolymers and combinations thereof.
[0112] The amount of plasticizer used in the present invention, can
range from about 0.001% to about 70%; from about 0.01% to about
60%; from about 0.1% to about 50%; from about 0.1% to about 40%;
from about 0.1% to about 30%; from about 0.1% to about 25%; from
about 0.1% to about 20%; from about 0.1% to about 10%; from about
0.4% to about 40%; from about 0.6% to about 30%; from about 0.75%
to about 25%; from about 1.0% to about 20%; and any range therein,
as a weight percentage based on the total weight of the polymer and
agent or combination of agents. The plasticizers can be combined to
obtain the desired function. In some embodiments, a secondary
plasticizer is combined with a primary plasticizer in an amount
that ranges from about 0.001% to about 20%; from about 0.01% to
about 15%; from about 0.05% to about 10%; from about 0.75% to about
7.5%; from about 1.0% to about 5%, or any range therein, as a
weight percentage based on the total weight of the polymer any
agent or combination of agents.
[0113] It should be appreciated that classification of an agent as
a biobeneficial agent does not preclude the use of that agent as a
bioactive agent, diagnostic agent and/or plasticizing agent.
Likewise, classification of an agent as a bioactive agent does not
preclude the use of that agent as a diagnostic agent, biobeneficial
agent and/or plasticizing agent. Furthermore, classification of an
agent as a plasticizing agent does not preclude the use of that
agent as a biobeneficial agent, bioactive agent, and/or diagnostic
agent.
[0114] Agents that are released into the body of the subject being
treated should be sized such that the subject can absorb the agent.
In some embodiments, the molecular weight of an agent should be at
or below about 40,000 Daltons, or any range therein, to ensure
elimination of the agent from a mammal. In one embodiment, the
molecular weight of the agent ranges from about 300 Daltons to
about 40,000 Daltons, from about 8,000 Daltons to about 30,000
Daltons, from about 10,000 Daltons to about 20,000 Daltons, or any
range therein. If upon release, the biobeneficial agent is rapidly
broken down in the body, then the molecular weight of the agent
could be greater than about 40,000 Daltons without compromising
patient safety. The molecular weights as taught herein are a number
average molecular weight.
[0115] The characteristics of the agents and the manner in which
they are incorporated into a polymeric matrix can affect the IM
profile and agent release. In some embodiments, the agents can be
chemically connected to a polymer by covalent bonds; chemically
connected to a polymer by non-covalent bonds such as, for example,
by ionic bonds or inter-molecular attractions; physically connected
to a polymer; or a combination thereof. In some embodiments, the
agents can be chemically and physically connected with a
polymer.
[0116] Examples of ionic bonding can include, but are not limited
to, ionic bonding of an anionic site to a cationic site between
polymers. In some embodiments, an anionic site can be bound to a
quaternary amine. Examples of inter-molecular attractions include,
but are not limited to, hydrogen bonding such as, for example, the
permanent dipole interactions between hydroxyl, amino, carboxyl,
amide, and sulfhydryl groups, and combinations thereof. Examples of
physical connections can include, but are not limited to,
interpenetrating networks and chain entanglement. The polymers can
also be blended or mixed with the agents.
[0117] In some embodiments, the agents have a reactive group that
can be used to link the agents to the polymer. Examples of reactive
groups include, but are not limited to, hydroxyl, acyl, amino,
amido, carbonyl, carboxyl, and sulfhydryl groups. In some
embodiments, the agents can be released or can separate from the
polymer composition. In some embodiments, the agents can be linked
to the medical article through linkages that are designed to
provide preselected release rates of the agent from the medical
article. In these embodiments, the agent may be linked to the
medical article through ether, amide, ester, orthoester, anhydride,
ketal, acetal, carbonate, and all-aromatic carbonate linkages to
provide, for example, a desired rate of hydrolysis of the agent
from the medical article.
[0118] The selection of a desired release rate of an agent can
depend on a variety of factors such as, for example, the
therapeutic, prophylactic, ameliorative or diagnostic needs of a
patient. In some embodiments, the agent can comprise an
antiproliferative and should have a sustained release ranging from
about 1 week to about 10 weeks, from about 2 weeks to about 8
weeks, from about 3 weeks to about 7 weeks, from about 4 weeks to
about 6 weeks, and any range therein. In some embodiments, the
agent can comprise an anti-inflammatory and should have a sustained
release ranging from about 6 hours to about 3 weeks, from about 12
hours to about 2 weeks, from about 18 hours to about 10 days, from
about 1 day to about 7 days, from about 2 days to about 6 days, or
any range therein. In general, any release rate can be desired and
can be a variable rate in some embodiments, however, the release
should range from about 4 hours to about 12 weeks; alternatively,
from about 6 hours to about 10 weeks; or from about 1 day to about
8 weeks. Since the agents of the present invention can be added in
combination to obtain desired effects, one of skill in the art can
tailor the compositions to release each agent of interest in the
desired amounts.
[0119] The amounts of the agents that compose the polymeric
compositions vary according to a variety of factors including, but
not limited to, the biological activity of the agent; the age, body
weight, response, or the past medical history of the subject; the
type of disease such as, for example, atherosclerotic disease; the
presence of systemic diseases such as, for example, diabetes; the
pharmacokinetic and pharmacodynamic effects of the agents or
combination of agents; and the design of the compositions for
sustained release of the agents. Factors such as these are
routinely considered by one of skill in the art when administering
an agent to a subject. Effective amounts, for example, may be
extrapolated from in vitro or animal model systems. In some
embodiments, the agent or combination of agents have a
concentration that ranges from about 0.001% to about 75%; from
about 0.01% to about 70%; from about 0.1% to about 60%; from about
0.25% to about 60%; from about 0.5% to about 50%; from about 0.75%
to about 40%; from about 1.0% to about 30%; from about 2% to about
20%; and, any range therein, where the percentage is based on the
total weight of the polymer and agent or combination of agents.
[0120] Other Components and Characteristics
[0121] The polymeric matrices can also include polymers combined
with ceramics and/or metals. Examples of ceramics include, but are
not limited to, hydroxyapatite, BIOGLASS.RTM., and absorbable
glass. Examples of metals include, but are not limited to
magnesium, copper, titanium, and tantalum. In some embodiments, a
polymeric matrix may be formed using a pore forming agent. The pore
forming agent can be dispersed or mixed within the composition used
to form the polymeric layer. One of skill will appreciate that
porous structure of the polymeric matrix may influence the
degradation rate. Such properties include, but are not limited to,
pore size distribution and porosity. Porosity may be defined as the
ratio of the void volume to the total volume of the polymeric
matrix. In some embodiments, the erosion profile may be controlled
by controlling the pore size distribution and porosity of the
polymeric matrix.
[0122] Potential Coating Configurations
[0123] There are many coating configurations within the scope of
the present invention, and each configuration can include any
number and combination of layers. In some embodiments, the coatings
of the present invention can comprise one or a combination of the
following four types of layers:
[0124] (a) an agent layer, which may comprise a polymer and an
agent or, alternatively, a polymer free agent;
[0125] (b) an optional primer layer, which may improve adhesion of
subsequent layers on the implantable substrate or on a previously
formed layer;
[0126] (c) an optional topcoat layer, which may serve as a way of
controlling the rate of release of an agent; and
[0127] (d) an optional biocompatible finishing layer, which may
improve the biocompatibility of the coating.
[0128] In some embodiments, a pure agent can be applied directly to
at least a part of an implantable substrate as a layer to serve as
a reservoir for at least one bioactive agent. In another
embodiment, the agent can be combined with a polymer. In another
embodiment, an optional primer layer can be applied between the
implantable substrate and the agent layer to improve adhesion of
the agent layer to the implantable substrate and can optionally
comprise an agent.
[0129] In other embodiments, a pure agent layer can be sandwiched
between layers comprising biodegradable polymer. In other
embodiments, the optional topcoat layer can be applied over at
least a portion of the agent layer to serve as a topcoat to assist
in the control the rate of release of agents and can optionally
comprise an agent. In another embodiment, a biocompatible finishing
layer can be applied to increase the biocompatibility of the
coating by, for example, increasing acute hemocompatibility, and
this layer can also comprise an agent.
[0130] In some embodiments, the topcoat layer and the biocompatible
finishing layer can be comprised of the same components, different
components, or share a combination of their components. In some
embodiments, the topcoat layer and the biocompatible finishing
layer can be the same layer, different layers, or can be combined.
In most embodiments, the finishing layer can be more biocompatible
than the topcoat layer.
[0131] In some embodiments, the methods of the present invention
can be used to coat a medical device with layers formed from
polymeric matrices having more than one coating configuration. In
some embodiments, the coating configurations can include a pure
agent as a layer within a combination of layers.
[0132] In some embodiments, the agent-containing compositions can
be applied selectively to an abluminal surface of a medical device
such as, for example, a stent. In most embodiments, the stent can
be a balloon-expandable stent or a self-expandable stent. The
"abluminal" surface refers to the surface of the device that is
directed away from the lumen of the organ in which the device has
been deployed. In one example, the lumen is an arterial lumen, and
the abluminal surface of the stent is the surface that is placed in
contact with the inner wall of the artery. Designing and applying
predetermined IM profiles of agents within polymeric matrices to
the abluminal surface of a medical device can provide a way for one
of skill in the art to control the delivery of the agents within a
subject and, thus, aid in preventing adverse effects and promoting
desirable effects obtained from the agents.
[0133] FIGS. 5a and 5b illustrate a sandwiched-coating design
according to some embodiments of the present invention. FIG. 5a
illustrates a cross-section of a stent strut 501 in which the
abluminal surface 502 includes a first layer 503 containing agent B
applied to the abluminal surface 502 and a second layer 504
containing agent A applied on the first layer 503 containing agent
B. Each of the layers can be formed by any method known to one of
skill in the art including, but not limited to, any one or any
combination of the methods described above, and the layers can be
applied to the entire stent or select regions of the stent.
[0134] In some embodiments, the first layer 503 can have an IM
profile that is different from an IM profile in the second layer
504, such that agents A and B are delivered at different release
rates, wherein the assumption can be that the difference between
diffusion coefficients of the first layer 503 and second layer 504
is negligible. FIG. 5b illustrates a cross-section of the stent
strut 501 in which the first layer 503 and the second layer 504 are
coated by a third layer 505. The third layer 505 can contain any
composition taught herein such as, for example, a topcoat to assist
in controlling the rate of release of the agents, act as a
biobeneficial layer, deliver one or more agents, or a combination
thereof.
[0135] In some embodiments, each layer within the combination of
layers can have a unique IM profile for each of the one or more
agents, such that the combination of layers provides a controlled
delivery of the one or more agents in a subject. In other
embodiments, the combination of layers provides a step-by-step
variation of IM profiles, the sum of which provides an overall IM
profile of one or more agents within a medical device, coating, or
a combination thereof.
[0136] Agent Morphology
[0137] The present invention also includes a method of obtaining an
agent in a desired form, or a combination of forms, to create a
medical article having a desired rate of release of the agent. The
form of the agent can provide the selected rate of release through
dissolution of the agent, diffusion of the agent, or a combination
thereof. The form, or combination of forms, of the agent includes a
component selected from a group consisting of a polymorph, a
solvate, a hydrate, and an amorphous form of the agent. As
described above, the medical article can include a stent or a
coating for a stent.
[0138] Polymorphism can be defined as the ability of the same
chemical substance to exist in different molecular packing
arrangements. These different structures represent different
thermodynamic stabilities and can be referred to as polymorphs,
polymorphic modifications, or forms that are in a different
polymorphic state. An example of polymorphs of the same substance
is that of graphite and diamond, which are both made of carbon.
Polymorphism is important in that each polymorph may provide a
unique physicochemical property that can be exploited to improve
the treatment of a subject by, for example, providing additional
control over the rate of release of an agent from a medical
article.
[0139] According to some embodiments, the method includes selecting
a desired rate of release of an agent from the medical article and
preparing a composition comprising a polymer and the agent. The
composition is then applied to a surface of the medical article to
form a polymeric layer comprising the agent; and a polymeric matrix
having the selected rate of agent release is then formed from the
polymeric layer, and any of the methods taught above can also be
used to control the rate of release of the agent from the medical
article.
[0140] The form of an agent can be chosen to provide varying
solubilities to control the rate of dissolution of an agent from a
medical article and into the bodily fluid or tissue of a subject.
In some embodiments, polymorphs can be chosen to provide varying
rates of diffusion through a bodily fluid by varying, for example,
the size, shape, or distribution of an agent throughout a medical
article. In some embodiments, polymorphs can be combined to provide
a combination of desired dissolution and diffusion
characteristics.
[0141] In some embodiments, the dissolution rate can be increased
to shorten the time it takes to achieve a maximum concentration of
an agent in a subject and/or to increase the maximum concentration
of an agent that is obtainable in a subject at a given point in
time, wherein a faster and more effective treatment with a
particular agent may be possible. Likewise, a slower dissolution
rate may be desired to lengthen the duration of the treatment and
perhaps to reduce the amount of agent obtainable in a subject at a
given point in time. In general, polymorphic forms of an agent can
have a range of solubilities that differ by a factor ranging from
above about 1 to above about 10 or above about 100 (e.g., a factor
of about 2 or 3).
[0142] In some embodiments, where desirable, the agent can comprise
any combination of forms, such as a combination of a polymorphic
form and an amorphous form of the agent, wherein the polymorphic
form is combined with the amorphous form in an amount that provides
a predetermined dissolution rate in a subject receiving treatment.
The ratios of the crystalline form verses the amorphous form can
vary from 100% of one component to 100% of the other.
[0143] The agent can comprise a polymorphic form that is
needle-shaped, rod-shaped, cubic, spherical, or a combination
thereof, to provide a predetermined diffusion rate of the agent
through the polymeric matrix. The size and shape of the agent,
whether a polymorphic crystal or an amorphous form, can affect the
movement of the agent through a polymeric matrix. For example, a
polymorph that is needle or rod-shaped have a higher aspect ratio
than a polymorph that is a cubic habit or irregular sphere and,
thus, can be slower at moving through a polymer matrix. Because
solubility of the agent is related to a polymorphic form of the
agent, different polymorphs of the agent have differing
solubilities.
[0144] The size and shape of the polymorph can be controlled, to a
degree, through the method of particle formation. However, the size
can also be modified through methods, such as ball milling or wet
milling, both of which are methods well known to one of skill in
the art. Micronizing will improve dissolution kinetics. Particle
separations and fractionations can be performed using any method
known to one of skill. The particle fractions can then be combined
in any desired ratios to provide a polymer matrix having desired
dissolution and diffusion characteristics.
[0145] In some embodiments, the agent is melted to obtain a melted
form of the agent, and then the melted form is quenched to produce
the desired form, or combination of forms, of the agent that
provides the selected rate of release. In some embodiments, the
agent is dissolved in a solvent to produce a solution containing
the agent, and the solution is boiled to precipitate the agent into
the desired form, or combination of forms, that provides the
selected rate of release of the agent. In some embodiments, the
desired form, or a combination of forms, comprises a metastable
polymorphic form of the agent. Polymorphic forms can be
characterized, for example, using optical microscopy, x-ray
crystallography, infrared spectroscopy, differential scanning
calorimetry, thermogravimetric analysis, electron microscopy, and
atomic force microscopy.
EXAMPLES
[0146] The following examples are provided to further teach the
concepts and embodiments of the present invention.
Example 1
[0147] The release of hydrophilic and hydrophobic agents can be
controlled by combining particular agent and polymer
characteristics to control the surface chemistry relationship
between the components. Everolimus has a hydrophilic side chain and
is released slower from a hydrophobic polymeric material such as
poly(D,L-lactide) than a more hydrophilic polymeric material, such
as a block copolymer of poly(butyl methacrylate) (PBMA) and
poly(ethylene glycol) (PEG). Another hydrophilic polymer that is
useful in the present invention is copolymer of poly(butylene
terephthalate)(PBT) and PEG, otherwise known as PolyActive.RTM..
The effective diffusion coefficient of the PBMA-PEG can be changed,
and the release of the everolimus controlled, through the
application of a hydrophobic topcoat of poly(D,L-lactide)
(d,1-PLA).
[0148] A hydrophobic agent such as, for example, paclitaxel can be
encapsulated in a hydrophobic polymer or copolymer such as, for
example, a poly(styrene-co-isobutylene-co-styrene) triblock
copolymer and applied as a controlled volume. At a given loading of
agent, the release rate of agent from such a morphology can be
significantly lower using the hydrophobic encapsulating agent than
using an a hydrophilic encapsulating such as, for example,
poly(ethylene-co-vinyl alcohol).
Example 2
[0149] The path across which an agent must travel can be altered by
altering the morphological profile of the polymer matrix. A gas
phase boundary condition can be designed as a terminal step to
control the initial morphology profile of a polymeric matrix. In
this example, the gas phase composition contains water vapor and
shows that humidity control during the coating process affects the
final phase morphology of a hydrophobic polymer matrix that
includes PBMA, D,L-PLA, or PVDF-HFP. The formation of rapid phase
separation of the hydrophobic polymers by increasing the humidity
as a terminal process step provides a faster release rate of an
agent.
[0150] FIG. 6 illustrates an SEM of an IM profile at high
magnification that was produced using a low humidity gas phase
boundary condition according to some embodiments of the present
invention. In this example, the initial morphology (IM) profile of
a coating processed using a designed terminal step was observed
using scanning electron microscopy (SEM). A very thin coating of
D,L-PLA (MW 65K) was combined with everolimus at a drug-to-polymer
ratio (D/P) of 1:1 (w/w) in acetone. The composition was brush
coated with a needle onto a stent and dried at room temperature
under a boundary condition containing a low relative humidity of
20% to produce "the low humidity coating".
[0151] The IM profile shown in FIG. 6 is a cross-section of the
coating showing darker regions that are drug-enriched domains. The
smooth layer on right of the SEM is the zone of the phase
separation, sometimes referred to as "the skin". The domain
diameters are indicated by arrows--these domains are small domains
and are percolated. Note that each domain seems to be covered by a
thin layer, referred to as an "envelope" that can impede
diffusion.
[0152] FIGS. 7a and 7b illustrate SEMs of an IM profile at high and
low magnification that were produced using a high humidity gas
phase boundary condition according to some embodiments of the
present invention. In this example, the IM profile of the same
coating was observed after using the same conditions and
substituting only a high relative humidity for the low relative
humidity to produce "the high humidity coating". The composition
was brush coated with a needle onto a stent and dried at room
temperature under a boundary condition containing a high relative
humidity of 70%. In FIG. 7a, it becomes apparent that the
distinctive domains that form under low relative humidity
conditions are lost under high humidity conditions. In addition,
larger regions of drug-enriched area are formed under high humidity
conditions. Furthermore, although the domains remain percolated
under high humidity conditions, they are more heterogeneous in size
and have less envelope between domains that can impede diffusion.
FIG. 7b is an SEM with lower magnification to better illustrate the
increased heterogeneity in the sizes of the domains in the high
humidity coating.
Example 3
[0153] FIG. 8 illustrates an SEM of an IM profile at high
magnification that was produced after exposing a coating produced
using low humidity to a blood flow simulation using distilled water
according to some embodiments of the present invention. The low
humidity coating and high humidity coating of Example 2 were fluxed
in water for 1 hour to highlight the change in morphology that
occurs during agent release. Each coated stent was deployed in a
hollow catheter and distilled water was allowed to flow past the
stent for 1 hour at a flow rate of 50 ml/hr to simulate blood
flow.
[0154] FIG. 8 shows that the drug-enriched domains are nearly gone
after the hour of flux. The remaining material is the "envelope
material" responsible for impeding diffusion due to the change in
effective diffusion coefficient relative to the high humidity
coating. A large amount of envelope material is left over because
there were more small domains in the low humidity coating.
[0155] FIGS. 9a and 9b illustrate SEMs of an IM profile at high and
low magnification, respectively, that were produced after exposing
a coating produced using high humidity to a blood flow simulation
using distilled water according to some embodiments of the present
invention. The flux conditions used were the same as those used in
FIG. 8. The high humidity coating has a faster release than the low
humidity coating because there is less envelope material to impede
diffusion and impede the formation of pores and channels throughout
the coating. Note the homogeneity in the domain sizes--there are
still small domains, and the diffusion has dominated in the larger
domains.
Example 4
[0156] The rate of release of an agent from a polymeric matrix can
be measured in vitro in a release medium, such as a buffered
solution containing TRITON as a surfactant. FIGS. 10a and 10b
illustrate SEM photos of IM profiles that were produced after
exposing coatings produced using low humidity conditions and high
humidity conditions, respectively, to a blood flow simulation using
porcine serum according to some embodiments of the present
invention. The low humidity coating and high humidity coating of
Example 2 were fluxed in porcine serum at 37.degree. C. to for 1
hour to simulate in vivo conditions and highlight the change in
morphology that occurs during agent release. Each coated stent was
deployed in a hollow conduit and porcine serum was allowed to flow
past the stent for 1 hour at a flow rate of 50 ml/hr to simulate
blood flow.
[0157] The images provided in these figures provide excellent
illustrations of the differences in morphology between the low
humidity coating and the high humidity coating. Again, these photos
show that the coatings are percolated. Note also the homogeneity of
the domain sizes in the low humidity coating and the relative
heterogeneity of the domain sizes in the high humidity coating.
These differences in morphology relate to the increase in envelope
material in the low humidity coating that impedes diffusion and
creates different diffusion coefficients between coatings.
Example 5
[0158] FIGS. 11a and 11b illustrate the agent release in a PBS(pH
7.4)/10% PEG solution and a porcine serum, respectively, for
coatings produced using low humidity conditions and high humidity
conditions, according to some embodiments of the present invention.
The agent release rate was found to be higher initially in both
solutions for the high humidity coating, and this higher rate of
release continued for the first 3 days in the porcine serum. The
release rate was about the same as the low humidity coating
following 3 days in porcine serum.
Example 6
[0159] Release rate testing was performed on XIENCE V stents at 4
hours and 24 hours of oven-drying time. These procedures include
the series of oven-drying, crimping, pressing, split-molding, and
sterilizing. "Crimping" is the process of using mechanical force to
press the stent down onto a balloon. "Pressing" is the process of
using mechanical force to press a stent down onto a balloon, while
the stent and the balloon region are heated. "Split-molding" is the
process of using heat and pressure for a specified time during
which the diameter of the stent is radially constrained from
expanding. In this example, the pressing was done at 70 psi at a
temperature of 130.degree. F., and the split-molding was done at a
pressure of 300 psi, a temperature of 170.degree. F., for a
duration of 90 seconds.
[0160] The release rates were measured using the porcine serum
method of Example 4. For each of the drying time increments, the
release rates were measured between oven-drying and crimping,
between crimping and pressing, between pressing and split-molding,
between split-molding and sterilization, and after sterilization.
FIGS. 12a and 12b illustrate the effect of pressure and mechanical
deformation on agent release according to some embodiments of the
present invention. The results showed that processes that include
the application of pressure and mechanical deformation reduce the
release rate of the agent.
Example 7
[0161] Release rate testing was performed on CHAMPION DES stents
with respect to the effect of pressure and temperature, but with
particular attention to the added effect of temperature. The
CHAMPION DES system uses a PLA polymer for delivery of the agent.
In this example, the pressing was done at 70 psi at a temperature
of 130.degree. F., and the heat set was done at a pressure of 300
psi, a temperature of 55.degree. C., for a duration of 10
minutes.
[0162] FIGS. 13a and 13b illustrate the effect of pressure and
temperature on the release rate of an agent according to some
embodiments of the present invention. FIG. 13a illustrates that the
release rate doubled after crimping, showing that the use of a
mechanical pressure can increase the release rate. However, the
combined application of pressure and heat for a duration of time
increased the release rate to a much greater extent, highlighting
the dramatic effect of the addition of heat for a duration of time
on the rate of agent release from a stent. (Note that the term
"heat set" is used in FIG. 13a to indicate a process similar to the
split-molding process, in which the balloon is pressurized and
heated while the stent is radially constrained from expanding).
FIG. 13b illustrates that the temperature at which the heat set is
performed can have a dramatic effect on the amount of agent
released as well, showing that as the temperature is increased from
43.degree. C. to 55.degree. C., the release rate can increase by
about 500% due to these process conditions.
Example 8
[0163] Polymorphs of estradiol can be prepared and used to obtain
varying agent delivery rates. Estradiol hemihydrate can be obtained
from Sigma Chemical Co. Anhydrous forms of estradiol can be
prepared by melting the estradiol hemihydrate and slow cooling the
melt to obtain a first polymorph (P1). A second polymorph (P2) can
be prepared by melting the estradiol hemihydrate and rapidly
cooling the melt by quenching the melt in liquid nitrogen. The
second polymorph can also be prepared by boiling the estradiol
hemihydrate in an ethyl acetate solution and crystallizing P2 from
the solution. Both methods of producing P2 should produce a
polymorph with identical characteristics.
[0164] The polymorphic crystals can be combined into a polymeric
material, and each preparation can be distinguished from the
remainder of the substance (e.g. solvates, and not true polymorphs)
by viewing them as solid dispersions under crossed polarizers,
where the crystals will be brighter compared to the remainder of
the substance. The crystals of estradiol should include needle-like
crystals having dimensions ranging in size from 4-11 .mu.m. One
means of distinguishing between P1 and P2 is to use Raman
spectroscopy, where the two forms should be distinguishable by a
splitting of the C17-O peak at 1284 cm.sup.-1 and 1294 cm.sup.-1,
which is evidence of the presence and absence of hydrogen bonding
at the hydroxyl group of position 17.
[0165] While particular embodiments of the present invention have
been shown and described, those skilled in the art will note that
variations and modifications can be made to the present invention
without departing from the spirit and scope of the teachings. A
multitude of embodiments that include a variety of chemical
compositions, polymers, agents and methods have been taught herein.
One of skill in the art is to appreciate that such teachings are
provided by way of example only and are not intended to limit the
scope of the invention. The embodiments for the IM profiles that
are taught herein are not meant to be limiting, since the IM
profiles possible are virtually limitless in variety. The IM
profiles taught in the present invention can be incorporated into
any medical article.
* * * * *