U.S. patent application number 13/850605 was filed with the patent office on 2013-08-15 for implantable medical device with beneficial agent concentration gradient.
This patent application is currently assigned to Innovational Holdings LLC. The applicant listed for this patent is Innovational Holdings LLC. Invention is credited to Kinam Park, Theodore L. Parker, John F. Shanley.
Application Number | 20130209663 13/850605 |
Document ID | / |
Family ID | 33134802 |
Filed Date | 2013-08-15 |
United States Patent
Application |
20130209663 |
Kind Code |
A1 |
Shanley; John F. ; et
al. |
August 15, 2013 |
IMPLANTABLE MEDICAL DEVICE WITH BENEFICIAL AGENT CONCENTRATION
GRADIENT
Abstract
The implantable medical devices are configured to release at
least one therapeutic agent from a matrix affixed to the
implantable body with a release profile which is programmable to
the agent and treatment. The matrix is formed such that the
concentration of the therapeutic agent in the matrix varies as a
gradient relative to a surface of the implantable body. The change
in the concentration gradient of the agent in the matrix directly
controls the rate of elution of the agent from the matrix. The
therapeutic agent matrix can be disposed in the stent or on
surfaces of the stent in various configurations, including within
volumes defined by the stent, such as openings, holes, or concave
surfaces, as a reservoir of agent, and alternatively as a coating
on all or a portion of the surfaces of the stent structure.
Inventors: |
Shanley; John F.; (Emerald
Hills, CA) ; Parker; Theodore L.; (Danville, CA)
; Park; Kinam; (West Lafayette, IN) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Innovational Holdings LLC; |
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|
US |
|
|
Assignee: |
Innovational Holdings LLC
New Brunswick
NJ
|
Family ID: |
33134802 |
Appl. No.: |
13/850605 |
Filed: |
March 26, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11369592 |
Mar 7, 2006 |
8449901 |
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13850605 |
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10777283 |
Feb 11, 2004 |
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11369592 |
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10402893 |
Mar 28, 2003 |
7056338 |
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10777283 |
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Current U.S.
Class: |
427/2.25 ;
427/2.24 |
Current CPC
Class: |
A61L 31/08 20130101;
A61L 2300/60 20130101; A61L 31/16 20130101; A61L 2300/604 20130101;
A61L 31/041 20130101; A61L 31/10 20130101 |
Class at
Publication: |
427/2.25 ;
427/2.24 |
International
Class: |
A61L 31/08 20060101
A61L031/08 |
Claims
1. A method of forming an implantable medical device configured to
release at least one therapeutic agent therefrom, the method
comprising: providing an implantable medical device having a body,
a luminal surface, a mural surface and at least one recess in the
body; forming a first homogeneous solution comprising the at least
one therapeutic agent mixed with a polymeric binder; introducing
the first homogeneous solution into the at least one recess in the
body of the implantable medical device; solidifying the first
homogeneous solution, thereby forming a first portion of a matrix,
wherein a concentration of the at least one therapeutic agent in
the matrix varies as a continuous gradient relative to a surface of
the body of the implantable medical device; forming a second
homogeneous solution comprising the polymeric binder; applying the
second homogeneous solution to the first portion of the matrix,
thereby at least partially liquifying the first portion of the
matrix; and solidifying the second homogeneous solution, thereby
forming a second portion of the matrix, wherein the concentration
of the at least one therapeutic agent in the matrix is higher at
the luminal surface of the implantable body than at the mural
surface of the implantable body.
2. The method of claim 1, wherein the first and second homogenous
solutions include a solvent and the first and second homogenous
solutions are solidified by evaporation of the solvent.
3. The method of claim 2, wherein the solvent comprises a miscible
organic solvent.
4. The method of claim 3, wherein the miscible organic solvent is
selected from the group consisting of dimethyl sulfoxide, N-methyl
pyrrolidone, ethyl lactate, and simple alcohols.
5. The method of claim 2, wherein the solvent and the polymeric
binder are both non-water soluble.
6. The method of claim 5, wherein the non-water soluble solvent is
selected from the group consisting of a poly(lactide-co-glycolide)
polymer, N-methyl pyrrolidone, ethyl lactate, anisole, chloroform,
tetrahydrofuran, xylene, and methylene chloride.
7. The method of claim 1, further comprising: applying successive
homogeneous solutions to the matrix; and solidifying the successive
homogeneous solutions, thereby forming additional portions of the
matrix, wherein the concentration of the therapeutic agent in the
matrix is different in the successive portions of the matrix.
8. The method of claim 1, wherein said at least one recess extends
through the body of the implantable medical device.
9. The method of claim 1, wherein the polymeric binder of the first
homogeneous solution is water soluble.
10. The method of claim 1, wherein the therapeutic agent is
selected from the group consisting of antithrombotic agents,
antiproliferative agents, and antirestenotic agents.
11. The method of claim 1, wherein the matrix is selected from the
group consisting of poly(lactide-co-glycolide) (PLGA) and Poly
vinylpyrrolidone (PVP).
12. The method of claim 1, further comprising: applying a solution
of a barrier material prior to applying introducing the first
homogenous solution, the barrier material forming a barrier to the
passage of the therapeutic agent in the first homogenous solution
to one side of the body of the implantable medical device.
13. The method of claim 1, wherein the second homogenous solution
contains no therapeutic agent.
14. The method of claim 1, wherein the second homogeneous solution
comprises the at least one therapeutic agent, and wherein a
concentration of the at least one therapeutic agent in the second
homogeneous solution is different from a concentration of the at
least one therapeutic agent in the first homogeneous solution.
15. The method of claim 1, wherein the implantable medical device
is a stent.
16. The method of claim 14, further comprising: applying successive
homogeneous solutions to the matrix; and solidifying the successive
homogeneous solutions, thereby forming additional portions of the
matrix, wherein the concentration of the at least one therapeutic
agent in the matrix is different in the successive portions of the
matrix.
17. A method of forming an implantable medical device configured to
release at least one therapeutic agent therefrom, the method
comprising: providing an implantable medical device having a
substantially cylindrical body, a luminal surface, a mural surface
and a plurality of struts; forming a homogeneous solution
comprising a polymeric binder and a solvent; evaporating the
solvent in the homogeneous solution, thereby forming a matrix;
exposing the matrix to a solution comprising the therapeutic agent
for a time sufficient to produce a partial diffusion of the
therapeutic agent into the matrix wherein a concentration of the at
least one therapeutic agent in the matrix varies as a continuous
gradient; and affixing the matrix to the body of the implantable
medical device body such that the matrix is disposed in the
plurality of holes passing through at least some of the struts in
the implantable body; and coating the matrix with a barrier layer
at the luminal surface, wherein the therapeutic agent has a maximum
concentration substantially adjacent to the barrier layer and a
minimum concentration substantially adjacent to the mural surface
of the implantable body.
18. The method of claim 17, wherein the matrix is affixed to the
implantable medical device body by placing the matrix into the body
prior to immersing the matrix in the solution comprising the
therapeutic agent.
19. The method of claim 17, wherein the matrix is affixed to the
implantable medical device body by disposing the homogeneous
solution comprising a polymeric binder and a solvent into the
plurality of openings and then evaporating the solvent.
20. The method of claim 17, wherein the implantable medical device
is a stent.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/369,592 filed on Mar. 7, 2006, which is a
divisional of U.S. patent application Ser. No. 10/777,283, filed
Feb. 11, 2004, abandoned, which is a Continuation-in-Part of U.S.
patent application Ser. No. 10/402,893 filed on Mar. 28, 2003, now
U.S. Pat. No. 7,056,338, issued Jun. 6, 2006, all of which are
incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates to a therapeutic agent delivery device
which has a concentration gradient of the therapeutic agent
contained within a matrix to provide release kinetics which are
specifically programmable for the particular agent, administration
period, and release rate desired.
BACKGROUND
[0003] Implantable medical devices are sometimes used for delivery
of a therapeutic agent, such as a drug, to an organ or tissue in
the body. It is hoped that these devices may deliver agents to a
wide variety of bodily systems to provide a wide variety of
treatments.
[0004] One implantable medical device which has been used for local
delivery of therapeutic agents is the coronary stent. Coronary
stents are typically introduced percutaneously, and transported
transluminally until positioned at a desired location. These
devices are then expanded either mechanically, such as by the
expansion of a mandrel or balloon positioned inside the device, or
expand themselves by releasing stored energy upon actuation within
the body. Once expanded within the lumen, these devices, called
stents, become encapsulated within the body tissue and remain a
permanent implant.
[0005] Of the many problems that may be addressed through
stent-based local delivery of therapeutic agents, one of the most
important is restenosis. Restenosis is a major complication that
can arise following vascular interventions such as angioplasty and
the implantation of stents. Simply defined, restenosis is a wound
healing process that reduces the vessel lumen diameter by
extracellular matrix deposition, neointimal hyperplasia, and
vascular smooth muscle cell proliferation, and which may ultimately
result in renarrowing or even reocclusion of the lumen. Despite the
introduction of improved surgical techniques, devices, and
pharmaceutical agents, the overall restenosis rate is still
reported in the range of 25% to 50% within six to twelve months
after an angioplasty procedure. To treat this condition, additional
revascularization procedures are frequently required, thereby
increasing trauma and risk to the patient.
[0006] One of the techniques under development to address the
problem of restenosis is the use of surface coatings of various
therapeutic agents on stents. U.S. Pat. No. 5,716,981, for example,
discloses a stent that is surface-coated with a composition
comprising a polymer carrier and paclitaxel (a well-known compound
that is commonly used in the treatment of cancerous tumors). Known
surface coatings, however, can provide little actual control over
the release kinetics of therapeutic agents. These coatings are
generally very thin, typically 5 to 8 microns deep. The surface
area of the stent, by comparison is very large, so that the entire
volume of the therapeutic agent has a very short diffusion path to
discharge into the surrounding tissue. The ability to shape the
release profiles from such systems is severely limited.
[0007] Accordingly, it would be desirable to provide a therapeutic
agent delivery device with the ability to program the release
kinetics to the particular agent, administration period, and
release rate desired.
SUMMARY OF THE INVENTION
[0008] The present invention relates to implantable medical devices
for programmable delivery of a therapeutic agent, methods of
forming implantable medical devices, and methods for delivering
therapeutic agents from implantable medical devices.
[0009] In accordance with one aspect of the invention, an
implantable medical device configured to release at least one
therapeutic agent therefrom is provided, wherein the device
includes an implantable body and a matrix affixed to the
implantable body. The matrix contains the at least one therapeutic
agent therein, and the matrix is formed such that the concentration
of the therapeutic agent in the matrix varies as a continuous
gradient relative to a surface of the implantable body.
[0010] In accordance with another aspect of the invention, a method
of forming an implantable medical device configured to release at
least one therapeutic agent therefrom is provided. The therapeutic
agent is disposed in a matrix affixed to the body of the
implantable medical device, and the concentration of the at least
one therapeutic agent in the matrix varies as a continuous gradient
relative to a surface of the body of the implantable medical
device. The method involves forming a first homogeneous solution
comprising the at least one therapeutic agent mixed with a
polymeric binder, applying the first homogeneous solution to the
body of the implantable medical device, solidifying the first
homogeneous solution, thereby forming a first portion of the
matrix, forming a second homogeneous solution comprising the
polymeric binder, applying the second homogeneous solution to the
first portion of the matrix, thereby at least partially liquifying
the first portion of the matrix, and solidifying the second
homogeneous solution, thereby forming a second portion of the
matrix, wherein the concentration of the at least one therapeutic
agent in the matrix is different in the first and second portions
of the matrix.
[0011] In accordance with an additional aspect of the invention, a
method of forming an implantable medical device configured to
release at least one therapeutic agent therefreom is provided. The
therapeutic agent is disposed in a matrix affixed to a body of the
implantable medical device, and a concentration of the at least one
therapeutic agent in the matrix varies as a continuous gradient
relative to a surface of the implantable medical device body. The
method involves forming a homogeneous solution comprising a
polymeric binder and a solvent, evaporating the solvent in the
homogeneous solution, thereby forming a matrix, exposing the matrix
to a solution comprising the therapeutic agent for a time
sufficient to produce a partial diffusion of the therapeutic agent
into the matrix such that the concentration of the therapeutic
agent varies in the matrix, and affixing the matrix to the
implantable medical device body.
[0012] In accordance with a further aspect of the invention, a
method for treating a patient by local delivery of at least one
therapeutic agent is provided. The method involves delivering an
implantable medical device into the body of a patient, the
implantable medical device having a matrix affixed to a body of the
implantable medical device with concentration of the at least one
therapeutic agent in the matrix varying as a continuous gradient
relative to a surface of the body of the implantable medical
device. The method further involves delivering the therapeutic
agent at a release rate and over an administration period
determined by the gradient of therapeutic agent in the matrix.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The invention will now be described in greater detail with
reference to the preferred embodiments illustrated in the
accompanying drawings, in which like elements bear like reference
numerals, and wherein:
[0014] FIG. 1 is a perspective view of one example of a stent
according to the present invention.
[0015] FIG. 2 is a side view of a portion of the stent of FIG.
1.
[0016] FIG. 3 is a side cross sectional view of an example of an
opening in a stent showing a matrix with one therapeutic agent
having a concentration gradient.
[0017] FIG. 4 is a graph of the therapeutic agent concentration
gradient of FIG. 3.
[0018] FIG. 5 is a graph of the release kinetics of the stent of
FIG. 3.
[0019] FIG. 6 is a side cross sectional view of another example of
an opening in a stent matrix with one therapeutic agent having a
concentration gradient.
[0020] FIG. 7 is a graph of the therapeutic agent concentration
gradient of FIG. 6.
[0021] FIG. 8 is a graph of the release kinetics of the stent of
FIG. 6.
[0022] FIG. 9 is a side cross sectional view of an example of an
opening in a stent showing a matrix with two therapeutic agents
having concentration gradients.
[0023] FIG. 10 is a graph of the therapeutic agent concentration
gradients of FIG. 9.
[0024] FIG. 11 is a graph of the release kinetics of the stent of
FIG. 9.
DETAILED DESCRIPTION
[0025] The invention relates to a medical device or stent having a
matrix containing a therapeutic agent therein such that the
concentration of agent in the matrix varies as a function of the
position relative to the matrix surfaces. The agent may be any
therapeutic agent that provides a beneficial effect after the
deployment of the medical device and release of the agent from the
matrix into the tissue of a mammal.
[0026] First, the following terms, as used herein, shall have the
following meanings:
[0027] The terms "drug" and "therapeutic agent" are used
interchangeably to refer to any therapeutically active substance
that is delivered to a living being to produce a desired, usually
beneficial, effect.
[0028] The term "matrix" or "biocompatible matrix" are used
interchangeably to refer to a medium or material that, upon
implantation in a subject, does not elicit a detrimental response
sufficient to result in the rejection of the matrix. The matrix
typically does not provide any therapeutic responses itself, though
the matrix may contain or surround a therapeutic agent, and/or
modulate the release of the therapeutic agent into the body. A
matrix is also a medium that may simply provide support, structural
integrity or structural barriers. The matrix may be polymeric,
non-polymeric, hydrophobic, hydrophilic, lipophilic, amphiphilic,
and the like. The matrix may be bioresorbable or
non-bioresorbable.
[0029] The term "bioresorbable" refers to a matrix, as defined
herein, that can be broken down by either chemical or physical
process, upon interaction with a physiological environment. The
matrix can erode or dissolve. A bioresorbable matrix serves a
temporary function in the body, such as drug delivery, and is then
degraded or broken into components that are metabolizable or
excretable, over a period of time from minutes to years, preferably
less than one year, while maintaining any requisite structural
integrity in that same time period.
[0030] The term "openings" includes both through openings and
recesses.
[0031] The term "pharmaceutically acceptable" refers to the
characteristic of being non-toxic to a host or patient and suitable
for maintaining the stability of a therapeutic agent and allowing
the delivery of the therapeutic agent to target cells or
tissue.
[0032] 100311 The term "polymer" refers to molecules formed from
the chemical union of two or more repeating units, called monomers.
Accordingly, included within the term "polymer" may be, for
example, dimers, trimers and oligomers. The polymer may be
synthetic, naturally-occurring or semisynthetic. In preferred form,
the term "polymer" refers to molecules which typically have a
M.sub.w greater than about 3000 and preferably greater than about
10,000 and a M.sub.w that is less than about 10 million, preferably
less than about a million and more preferably less than about
200,000. Examples of polymers include but are not limited to,
poly-.alpha.-hydroxy acid esters such as, polylactic acid (PLLA or
DLPLA), polyglycolic acid, polylactic-co-glycolic acid (PLGA),
polylactic acid-co-caprolactone; poly (block-ethylene
oxide-block-lactide-co-glycolide) polymers (PEO-block-PLGA and
PEO-block-PLGA-block-PEO); polyethylene glycol and polyethylene
oxide, poly (block-ethylene oxide-block-propylene
oxide-block-ethylene oxide); polyvinyl pyrrolidone;
polyorthoesters; polysaccharides and polysaccharide derivatives
such as polyhyaluronic acid, poly (glucose), polyalginic acid,
chitin, chitosan, chitosan derivatives, cellulose, methyl
cellulose, hydroxyethylcellulose, hydroxypropylcellulose,
carboxymethylcellulose, cyclodextrins and substituted
cyclodextrins, such as beta-cyclodextrin sulfobutyl ethers;
polypeptides and proteins, such as polylysine, polyglutamic acid,
albumin; polyanhydrides; polyhydroxy alkonoates such as polyhydroxy
valerate, polyhydroxy butyrate, and the like.
[0033] The term "primarily" with respect to directional delivery,
refers to an amount greater than about 50% of the total amount of
therapeutic agent provided to a blood vessel.
[0034] The term "restenosis" refers to the renarrowing of an artery
following an angioplasty procedure which may include stenosis
following stent implantation.
[0035] The term "liquefied" is used herein to define a component
which is put in a liquid state either by heating the component to a
temperature higher than its melting point, or glass transition
temperature, or by dissolving the component in a solvent. The
typical liquefied materials of the present invention will have a
viscosity of less than about 10,000 centipoise, and preferably less
than about 1,000 centipoise, and more preferably less than about
100 centipoise.
[0036] The term "homogeneously disposed" refers to a mixture in
which each of the components are uniformly dispersed within the
matrix.
[0037] The term "heterogeneously disposed" refers to a mixture in
which the components are not mixed uniformly into a matrix.
[0038] FIG. 1 illustrates one example of an implantable medical
device in the form of a stent 10. Although the present invention
will be described with reference to a stent, the invention can also
be useful as other types of drug delivery implants including
subcutaneous implants, embolization devices, and implants for
delivery of chemotherapeutic agents.
[0039] FIG. 2 is an enlarged flattened view of a portion of the
stent of FIG. 1 illustrating one example of a stent structure
including struts 12 interconnected by ductile hinges 20. The struts
12 include openings 14 which can be non-deforming openings
containing the therapeutic agent and matrix. One example of a stent
structure having non-deforming openings is shown in U.S. Pat. No.
6,562,065 which is incorporated herein by reference in its
entirety.
[0040] The implantable medical devices of the present invention are
configured to release at least one therapeutic agent from a matrix
affixed to the implantable body. The matrix is formed such that the
concentration of the therapeutic agent in the matrix varies as a
gradient relative to a surface of the matrix affixed to the
implantable body. The deposition of a coating on a surface, such as
by dipping or spraying may result in the phenomenon know as
blooming by which the drug migrates to the surface resulting in
increased concentration at the matrix surface. However, known
coating methods do not achieve configurations in which a
concentration in an area adjacent the matrix surface is less than a
concentration of the drug at another part of the matrix. The
present invention provides methods and devices by which an
implantable medical device can be designed to achieve a particular
release profile by providing a concentration gradient of drug in a
homogeneous polymer matrix in which the concentration gradient is
provided other than by the phenomenon of blooming.
[0041] In one embodiment, the matrix is a polymeric material which
acts as a binder or carrier to hold the agent in or on the stent
and/or modulate the release of the agent from the stent. The
polymeric material can be a bioresorbable or a non-bioresorbable
material.
[0042] The therapeutic agent containing matrix can be disposed in
the stent or on surfaces of the stent in various configurations,
including within volumes defined by the stent, such as openings,
holes, or concave surfaces, as a reservoir of agent, and
alternatively as a coating on all or a portion of surfaces of the
stent structure. When the therapeutic agent matrix is disposed
within openings in the strut structure of the stent to form a
reservoir, the openings may be partially or completely filled with
matrix containing the therapeutic agent.
[0043] The concentration of agent in a local region of the matrix
is the sum of the amount of agent dissolved in the matrix, in a
so-called solid solution morphology, and the amount dispersed in
that local region of the matrix, a so-called solid emulsion
morphology. The relative amount of dissolved and dispersed agent in
a region is controlled by the solubility of the agent in the matrix
material. When the limit of solubility of the agent in the matrix
material is reached, any additional agent will be in a dispersed
second phase particulate morphology.
[0044] FIG. 3 is a cross section of the stent 10 and blood vessel
100 illustrating one example of an opening 14 arranged adjacent the
vessel wall with a mural surface 26 abutting the vessel wall and a
luminal surface 24 opposite the mural surface. The opening 14 of
FIG. 3 contains a matrix 40 with a therapeutic agent illustrated by
Os in the matrix. As can be seen in the example of FIG. 3, the
concentration of the therapeutic agent (Os) is highest at the
luminal side of the matrix 40 and lowest at the mural side of the
matrix. The luminal side 24 of the stent 10 is also provided with a
barrier layer 30. The barrier layer 30 causes the therapeutic agent
to be delivered primarily to the mural side 26 of the stent.
[0045] FIG. 4 illustrates graphically a concentration gradient
similar to that depicted in FIG. 3 where the agent concentration in
the matrix is highest in the middle of the stent or adjacent the
luminally located barrier layer 30 and the agent concentration
decreases moving toward the mural side of the matrix. The
concentration gradient is described by the local concentration of
the agent in matrix regions along a theoretical line substantially
perpendicular to the surfaces of the matrix. A continuous agent
concentration gradient is where the agent concentration in a volume
of matrix varies in a blended fashion in moving between successive
positions along the line substantially perpendicular to the matrix
surface. Thus, if the matrix surface was substantially collinear
with the stent surface and the matrix was sliced into a plurality
of slices substantially parallel to the stent surface, the adjacent
slices will have different agent concentrations. Alternately, the
matrix surface may be contoured and the adjacent slices may be
similarly configured.
[0046] As illustrated in FIG. 3, the barrier layer 30 includes no
therapeutic agent and the concentration gradient of therapeutic
agent is provided in the matrix in the portion of the opening 14
not containing the barrier material. Alternatively, the barrier
layer 30 may include some therapeutic agent and the concentration
gradient may continue in part or all of the barrier layer.
[0047] As shown in FIG. 4, the change in agent concentration in the
matrix is a continuous function of the position relative to the
matrix surfaces. As shown in FIG. 5, the release kinetics of the
system of FIGS. 3 and 4 can be essentially linear (essentially
constant release rate over time) after an initial release. Such
substantially linear release profiles are described in further
detail in U.S. patent application Ser. No. 10/777,881 filed on Feb.
11, 2004 which is incorporated herein by reference in its
entirety.
[0048] FIG. 6 illustrates a configuration of a matrix 50 in an
opening 14 where the matrix and therapeutic agent concentration
gradient are designed for rapid initial release of agent to the
luminal side followed by a low level release for an extended time.
The agent concentration in FIG. 6 is high at the luminal surface 24
of the matrix 50 and the concentration gradient will decrease
steeply in the interior of the matrix. FIG. 7 illustrates the
concentration gradient of the FIG. 6 example graphically. FIG. 8
illustrates the agent release over time for the example of FIGS. 6
and 7. Using careful specification of the agent concentration
gradient in this example, substantially first order agent release
kinetics with directionally controlled delivery may be
obtained.
[0049] Since the matrix is created in a stepwise manner, as will be
described below, individual chemical compositions and
pharmacokinetic properties can be imparted to different areas of
the matrix. Numerous useful arrangements of such matrix areas can
be formed, some of which will be described herein. Each of the
areas of the matrix may include one or more agents in the same or
different proportions from one area to the next. The matrix may be
solid, porous, or filled with other drugs or excipients. The agents
may be homogeneously disposed or heterogeneously disposed in
different areas of the matrix.
[0050] FIG. 9 illustrates an example of another stent 10 having a
matrix 60 containing two agents with different concentration
gradients. In FIG. 9, a first agent (Drug A) represented by Os has
a concentration gradient with a maximum concentration at a luminal
side 24 of the stent. A second agent (Drug B) represented by s has
a concentration gradient with a maximum concentration at a mural
side of the matrix. This configuration results in the delivery of
two drugs in different primary delivery directions. For example, an
antithrombotic agent (Drug A) may be delivered primarily luminally
at a relatively quick initial release rate while an antirestenotic
agent (Drug B) is delivered primarily murally with a different
delivery profile having a more constant release rate and longer
administration period. FIG. 10 illustrates graphically the agent
concentration gradients of the first agent (Drug A) and the second
agent (Drug B). FIG. 11 illustrates the cumulative release of the
first and second agents (Drug A and Drug B) over time.
[0051] It is envisioned that the continuous agent concentration
gradient will take a variety of forms depending on the desired
administration period and rate of elution of the agent into the
tissue surrounding the stent, as well as the desired direction of
elution of agent from the stent, either mural or luminal. FIGS.
3-11 are merely illustrative of some of the concentration gradients
which are useful. Further combinations of two or more agents with
independent concentration gradients can provide a range of
controlled release kinetic profiles of the agents from the matrix
in or on the stent.
Therapeutic Agents
[0052] Some of the therapeutic agents for use with the present
invention which may be transmitted primarily luminally, primarily
morally, or both include, but are not limited to,
antiproliferatives including paclitaxel and rapamycin,
antithrombins, immunosuppressants including sirolimus, antilipid
agents, anti-inflammatory agents, antineoplastics, antiplatelets,
angiogenic agents, anti-angiogenic agents, vitamins, antimitotics,
metalloproteinase inhibitors, NO donors, estradiols,
anti-sclerosing agents and vasoactive agents, endothelial growth
factors, estrogen, beta blockers, AZ blockers, hormones, statins,
insulin growth factors, antioxidants, membrane stabilizing agents,
calcium antagonists, retinoid, bivalirudin, phenoxodiol, etoposide,
ticlopidine, dipyridamole, and trapidil alone or in combinations
with any therapeutic agent mentioned herein. Therapeutic agents
also include peptides, lipoproteins, polypeptides, polynucleotides
encoding peptides, lipids, protein-drugs, protein conjugate drugs,
enzymes, oligonucleotides and their derivatives, ribozymes, other
genetic material, cells, antisense, oligonucleotides, monoclonal
antibodies, platelets, prions, viruses, bacteria, and eukaryotic
cells such as endothelial cells, stem cells, ACE inhibitors,
monocyte/macrophages or vascular smooth muscle cells to name but a
few examples. The therapeutic agent may also be a pro-drug, which
metabolizes into the desired drug when administered to a host. In
addition, therapeutic agents may be pre-formulated as
microcapsules, microspheres, microbubbles, liposomes, niosomes,
emulsions, dispersions or the like before they are incorporated
into the therapeutic layer. Therapeutic agents may also be
radioactive isotopes or agents activated by some other form of
energy such as light or ultrasonic energy, or by other circulating
molecules that can be systemically administered. Therapeutic agents
may perform multiple functions including modulating angiogenesis,
restenosis, cell proliferation, thrombosis, platelet aggregation,
clotting, and vasodilation.
[0053] Anti-inflammatories include but are not limited to
non-steroidal inti-inflammatories (NSAID), such as aryl acetic acid
derivatives, e.g., Diclofenac; aryl propionic acid derivatives,
e.g., Naproxen; and salicylic acid derivatives, e.g., Diflusinal.
Anti-inflammatories also include glucocoriticoids (steroids) such
as dexamethasone, aspirin, prednisolone, triamcinolone,
pirfenidone, meclofenamic acid, tranilast, and nonsteroidal
anti-inflammatories. Anti-inflammatories may be used in combination
with antiproliferatives to mitigate the reaction of the tissue to
the antiproliferative.
[0054] The agents can also include anti-lymphocytes;
anti-macrophage substances; cyclooxygenase inhibitors;
immunomodulatory agents; anti-oxidants; cholesterol-lowering drugs;
statins and angiotens in converting enzyme (ACE); fibrinolytics;
inhibitors of the intrinsic coagulation cascade;
antihyperlipoproteinemics; and anti-platelet agents;
anti-metabolites, such as 2-chlorodeoxy adenosine (2-CdA or
cladribine); immuno-suppressants including sirolimus, everolimus,
tacrolimus, etoposide, and mitoxantrone; anti-leukocytes such as
2-CdA, IL-1 inhibitors, anti-CD116/CD18 monoclonal antibodies,
monoclonal antibodies to VCAM or ICAM, zinc protoporphyrin;
anti-macrophage substances such as drugs that elevate NO; cell
sensitizers to insulin including glitazones; high density
lipoproteins (HDL) and derivatives; and synthetic facsimile of HDL,
such as lipator, lovestatin, pranastatin, atorvastatin,
simvastatin, and statin derivatives; vasodilators, such as
adenosine, and dipyridamole; nitric oxide donors; prostaglandins
and their derivatives; anti-TNF compounds; hypertension drugs
including Beta blockers, ACE inhibitors, and calcium channel
blockers; vasoactive substances including vasoactive intestinal
polypeptides (VIP); insulin; cell sensitizers to insulin including
glitazones, P par agonists, and metformin; protein kinases;
antisense oligonucleotides including resten-NG; antiplatelet agents
including tirofiban, eptifibatide, and abciximab; cardio
protectants including, VIP, pituitary adenylate cyclase-activating
peptide (PACAP), apoA-I milano, amlodipine, nicorandil,
cilostaxone, and thienopyridine; cyclooxygenase inhibitors
including COX-1 and COX-2 inhibitors; and petidose inhibitors which
increase glycolitic metabolism including omnipatrilat. Other drugs
which may be used to treat inflammation include lipid lowering
agents, estrogen and Adiponectin.
[0055] Agents may also be delivered using a gene therapy-based
approach in combination with an expandable medical device. Gene
therapy refers to the delivery of exogenous genes to a cell or
tissue, thereby causing target cells to express the exogenous gene
product. Genes are typically delivered by either mechanical or
vector-mediated methods.
[0056] Some of the agents described herein may be combined with
additives which preserve their activity. For example additives
including surfactants, antacids, antioxidants, and detergents may
be used to minimize denaturation and aggregation of a protein drug.
Anionic, cationic, or nonionic detergents may be used. Examples of
nonionic additives include but are not limited to sugars including
sorbitol, sucrose, trehalose, dextrans including dextran,
carboxymethyl (CM) dextran, diethylamino etyl (DEAE) detran; sugar
derivatives including D-glucosaminic acid, and D-glucose diethyl
mercaptal, synthetic polyethers including polyethylene glycol (PEG
and PEO) and polyvinyl pyrrolidone (PVP); carboxylic acids
including D-lactic acid, glycolic acid, and propionic acid;
detergents with affinity for hydrophobic interfaces including
n-dodecyl-.beta.-D-maltoside, n-ocyl-.beta.-D-glucoside, PEO-fatty
acid esters (e.g. stearate (myrj 59) or oleate), PEO-sorbitan-fatty
acid esters (e.g. Tween 80, PEO-20 sorbitan monooleate),
sorbitan-fatty acid esters (e.g. SPAN 60, sorbitan monostearate),
PEO-glyceryl-fatty acid esters; glyceryl fatty acid esters (e.g.
glyceryl monostearate), PEO-hydrocarbon-esters (e.g., PEO-10 oleyl
ether; triton X-100; and Lubrol. Examples of ionic detergents
include but are not limited to fatty acid salts including calcium
stearate, magnesium stearate, and zinc stearate; phospholipids
including lecithin and phosphatidyl choline; CM-PEG; cholic acid;
sodium dodecyl sulfate (SDS); docusate (AOT); and taumocholic
acid.
Matrix Formation Methods
[0057] The agent matrix structure with the agent concentration
gradient can be formed by several methods. According to one method,
agent and polymer material are together converted into agent matrix
reservoirs with an agent concentration gradient structure by first
creating a homogeneous solution of agent and polymer carrier in a
liquid form, such as in a solvent. One example of a solvent is one
in which all agent and polymer are fully soluble at the respective
concentrations desired for processing such that all ingredients are
molecularly dissolved in the solvent.
[0058] Solvents may be water based, as when water soluble agents
and water soluble polymers are the components of the agent delivery
matrix. Alternatively, solvents can be mixtures of water with
miscible organic solvents, such as dimethyl sulfoxide (DMSO),
Nmethyl pyrrolidone (NMP), ethyl lactate (EL), dimethyl acetamide
(DMAc), or simple alcohols. Additionally, non-aqueous solvents,
predominantly organic solvents, can be suitable for non-water
soluble polymers, such as poly(lactide-co-glycolide) polymers
(PLGAs). Example organic solvents include DMSO, NMP, EL, anisole,
chloroform, tetrahydrofuran (THF), xylene, and methylene
chloride.
[0059] In the first method, steps (i) and (ii) are preformed
followed by steps (iii) and (iv) which are repeated until the
desired concentration gradient structure is obtained: [0060] i) a
solution comprised of suitable solvent and polymer material, and
optionally a therapeutic agent, is introduced into an opening on
the stent; [0061] ii) the solvent is evaporated from the solution
to form a first portion of matrix; [0062] iii) a second solution is
introduced which partially dissolves of otherwise liquifies the
precedent material from step (ii) and allows partial mixing of the
agent of precedent material and the components of the second
solution to create a new hybrid solution in the cavity or hole in
the stent; and [0063] iv) the solvent is evaporated from the newly
formed hybrid solution to provide a portion of matrix having a
concentration gradient of the agent therein. By changing the
composition of successive solutions there will result a final agent
containing matrix where the agent is present in a continuously
changing concentration relative to the depth of the matrix, termed
a concentration gradient.
[0064] Although the process has been described employing a solvent,
a similar process may use a solution without a solvent when the
polymer is heated to achieve a liquefied or flowable condition.
[0065] Two general sequences of solution compositions can provide
the concentration gradient structure of the invention. In a first
sequence, one or several iterations of the same agent and polymer
compositions are introduced as described followed by successive
iterations of solutions containing polymer only. In this manner a
first portion of matrix is fabricated with an agent containing
solution followed by introduction of a second portion of matrix
without agent. The second portion of matrix without the agent
introduced just after the first portion containing agent will
extract a portion of agent from the first portion into itself,
creating a concentration gradient of the agent in the combined
structure after the solvent has evaporated. Successive additions of
solutions with polymer and no agent will only be able to dissolve
the portion formed just before, which has successively smaller
amounts of agent, so as the depth of the matrix is increased by
successive additions the agent proportion will be successively
decreasing, continuing the formation of an agent concentration
gradient.
[0066] Although the first method has been described with reference
to depositing in a hole or cavity, the matrix may also be formed on
the stent or in the stent in other configurations including
coatings or partial coatings in substantially the same manner.
Coatings are generally less preferable than reservoirs, as the
depth of reservoirs permits more complex morphologies.
[0067] In a second sequence, a first series of iterations are done
with a solution containing matrix and an agent at a first agent
concentration, followed by a second series of iterations done with
a solution having matrix and the agent at a second agent
concentration. The resultant matrix will have a agent concentration
gradient where the absolute concentration is near the first
concentration at one side of the matrix, at an intermediate
concentration in the middle of the matrix, and near the second
agent concentration at the opposite side of the matrix.
[0068] In a second method an agent concentration gradient is formed
in the matrix by a process of diffusion. A matrix containing no
agent is first prepared from solutions containing polymer. The
formed matrix is then immersed in a solution containing an agent
for a time period to allow a partial diffusion of the agent from
the solution into the matrix, then the matrix is removed from the
solution. The resultant matrix will have a relatively higher agent
concentration near the surface(s) that contacted the solution and
lower concentration toward the opposite side, thus forming an agent
concentration gradient across the depth of the agent containing
matrix.
[0069] This second method can be performed with a matrix in the
form of a coating on a stent or a partial coating on a stent, with
a matrix within openings in a stent, a matrix prior to placing the
matrix on or in the stent, or another matrix configuration. When
the matrix is formed within openings in a stent a barrier layer may
be placed on one side of the opening to allow diffusion of the
agent into the matrix from primarily one side of the opening. The
barrier layer may subsequently be removed if delivery from the
barrier side is desired. Additional barrier layers may be added
after formation of the concentration gradient if desired. The
barrier layer can be a bioresorbable or non-bioresorbable.
EXAMPLE 1
Formulation Comprising a Gradient of a Therapeutic Agent
[0070] In the example below, the following abbreviations have the
following meanings. [0071] PLGA=poly(lactide-co-glycolide) [0072]
DMSO=Dimethyl sulfoxide [0073] NMP=N-methylpyrrolidone [0074]
DMAC=Dimethyl acetamide
[0075] A first mixture of high molecular weight PLGA and a suitable
organic solvent, such as DMSO, NMP, or DMAC 93% wt. is prepared.
The mixture is loaded dropwise into openings in the stent, then the
solvent is evaporated to begin formation of the barrier layer. A
one or more additional barrier layers are laid over the first by
the same method of filling polymer solution into the hole followed
by solvent evaporation.
[0076] A second mixture of paclitaxel and low molecular weight
PLGA, in a suitable organic solvent, such as DMSO, is introduced
into openings in the stent over the barrier layer. The solvent is
evaporated to form a drug filled therapeutic agent layer. The
filling and evaporation procedure is repeated until the hole is
filled to about 50% of its total volume with drug in therapeutic
agent layer layered on top of the barrier layer.
[0077] Multiple layers of a third solution, of low molecular weight
PLGA and a suitable organic solvent, such as DMSO, are then laid
down over the therapeutic agent layer to form the concentration
gradient. When each of the third solution layers is loaded into the
stent, a portion of the layer beneath is incorporated in the new
layer. In this way the matrix is formed containing a concentration
gradient of paclitaxel agent.
[0078] Following implantation of the filled stent in vivo, the
paclitaxel contained within the stent is delivered slowly over a
time period of about 5 to about 60 days, preferably about 10 to
about 30 days. The barrier layer prevents the therapeutic agent
from being delivered out the barrier layer side of openings in the
stent. The barrier layer completely degrades after the
administration of the paclitaxel.
[0079] While the invention has been described in detail with
reference to the preferred embodiments thereof, it will be apparent
to one skilled in the art that various changes and modifications
can be made and equivalents employed, without departing from the
present invention.
* * * * *