U.S. patent application number 09/070192 was filed with the patent office on 2002-05-09 for medical device for delivering a therapeutic agent and method of preparation.
Invention is credited to TUCH, RONALD J..
Application Number | 20020055710 09/070192 |
Document ID | / |
Family ID | 22093731 |
Filed Date | 2002-05-09 |
United States Patent
Application |
20020055710 |
Kind Code |
A1 |
TUCH, RONALD J. |
May 9, 2002 |
MEDICAL DEVICE FOR DELIVERING A THERAPEUTIC AGENT AND METHOD OF
PREPARATION
Abstract
A device useful for localized delivery of a therapeutic agent is
provided. The device includes a structure including a porous
polymeric material and an elutable therapeutic agent in the form of
a solid, gel, or neat liquid, which is dispersed in at least a
portion of the porous polymeric material. Methods for making a
medical device having a blood-contacting surface is also provided.
One method involves: providing a structure comprising a porous
material; contacting the structure comprising a porous material
with a concentrating agent to disperse the concentrating agent
throughout at least a portion of the porous material; contacting
the structure comprising a porous material and the concentrating
agent with a solution of a therapeutic agent; and removing the
therapeutic agent from solution within the porous material at the
locations of the concentrating agent. Another method involves
multiple immersion steps without the use of a concentrating
agent.
Inventors: |
TUCH, RONALD J.; (PLYMOUTH,
MN) |
Correspondence
Address: |
MEDTRONIC AVE, INC.
3576 UNOCAL PLACE
SANTA ROSA
CA
95403
US
|
Family ID: |
22093731 |
Appl. No.: |
09/070192 |
Filed: |
April 30, 1998 |
Current U.S.
Class: |
604/103.02 ;
427/2.1 |
Current CPC
Class: |
A61L 31/16 20130101;
A61L 2300/42 20130101; A61F 2210/0004 20130101; A61L 29/146
20130101; A61L 29/16 20130101; A61L 31/043 20130101; A61F 2/82
20130101; A61L 31/146 20130101; A61L 31/042 20130101; A61L 31/10
20130101; A61L 29/145 20130101; A61L 2300/432 20130101; A61F
2240/001 20130101; A61L 2300/236 20130101; A61L 29/044 20130101;
A61L 29/06 20130101; A61L 31/145 20130101; A61L 29/041 20130101;
A61L 31/048 20130101; A61F 2/88 20130101; A61F 2/958 20130101; A61L
31/06 20130101; A61F 2250/0067 20130101 |
Class at
Publication: |
604/103.02 ;
427/2.1 |
International
Class: |
A61M 029/00; A61M
031/00; A61M 037/00 |
Claims
We claim:
1. A medical device having at least one blood-contacting surface
comprising: a porous polymeric material comprising a nonswellable
biostable polymer; and an elutable therapeutic agent in the form of
a solid, gel, or neat liquid, which is dispersed in at least a
portion of the porous polymeric material.
2. The medical device of claim 1 wherein the porous polymeric
material comprises a film.
3. The medical device of claim 1 wherein the nonswellable biostable
polymer is selected from the group consisting of silicone,
polyurethane, polysulfone, cellulose, polyethylene, polypropylene,
polyamide, polyester, polytetrafluoroethylene, and a combination of
two or more of these materials.
4. The medical device of claim 3 wherein the porous polymeric
material comprises an integral portion of the device.
5. The medical device of claim 1 wherein the therapeutic agent
comprises an antithrombotic material.
6. The medical device of claim 5 wherein the antithrombotic
material is heparin.
7. The medical device of claim 1 wherein the therapeutic agent is a
peptic drug.
8. The medical device of claim 1 wherein the device has a generally
cylindrical shape.
9. The device of claim 8 wherein the device is selected from the
group consisting of a catheter, a stent, and a guide wire.
10. The device of claim 1 wherein the device has a generally
sheet-like shape.
11. The medical device of claim 1 wherein the device is an
intralumenal stent.
12. An intralumenal stent comprising: a generally cylindrical stent
body; and and an adherent layer on the stent body comprising a
porous polymeric material and an elutable therapeutic agent in the
form of a solid, gel, or neat liquid, which is dispersed in at
least a portion of the porous polymeric material.
13. A method for making a medical device comprising: (a) providing
a structure comprising a porous material; (b) contacting the
structure comprising a porous material with a concentrating agent
to disperse the concentrating agent throughout at least a portion
of the porous material; (c) contacting the structure comprising a
porous material and the concentrating agent with a solution of a
therapeutic agent; and (d) removing the therapeutic agent from
solution within the porous material at the locations of the
concentrating agent.
14. The method of claim 13 wherein precipitating agent is selected
from the group of a binding agent, sequestering agent, a nucleating
agent, a seed crystal, or combinations thereof.
15. The method of claim 13 wherein the porous material is selected
from the group consisting of a natural hydrogel, a synthetic
hydrogel, silicone, polyurethane, polysulfone, cellulose,
polyethylene, polypropylene, polyamide, polyester,
polytetrafluoroethylene, and a combination of two or more of these
materials.
16. The method of claim 13 wherein the therapeutic agent is an
antithrombotic material.
17. The method of claim 13 wherein the step of removing the
therapeutic agent from solution comprises reducing the temperature
of the solution of the therapeutic agent.
18. The method of claim 13 wherein the step of removing the
therapeutic agent from solution comprises changing the pH of the
solution of the therapeutic agent.
19. The method of claim 13 wherein the step of removing the
therapeutic agent from solution comprises changing the ionic
strength of the solution of the therapeutic agent.
20. A method for making a medical device comprising: (a) providing
a structure comprising a porous material; (b) immersing the
structure comprising a porous material in a saturated solution of a
therapeutic agent for a sufficient period of time to allow the
solution to fill the porous material; (c) removing the medical
device from the solution; (d) drying the medical device; and (e)
repeating steps (b) through (d) to provide a therapeutic agent
dispersed within the porous material.
21. The method of claim 20 further comprising a step of removing
air bubbles from the porous material while being immersed in the
solution of the therapeutic agent.
22. The method of claim 21 wherein the step of removing air bubbles
from the porous material comprises applying ultrasonics, reduced
pressure, elevated pressure, or a combination thereof, to the
solution.
23. The method of claim 20 wherein the medical device is a
stent.
24. The method of claim 23 wherein the stent has a porous polymeric
film thereon.
25. The method of claim 23 further comprising a step of applying an
overlayer of a polymer.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to a medical device employing a
therapeutic agent as a component thereof. For example, in an
arterial site treated with percutaneous transluminal coronary
angioplasty therapy for obstructive coronary artery disease a
therapeutic antithrombogenic substance such as heparin may be
included with a device and delivered locally in the coronary
artery. Also provided is a method for making a medical device
capable of localized application of therapeutic agents.
[0002] Medical devices which serve as substitute blood vessels,
synthetic and intraocular lenses, electrodes, catheters, and the
like, in and on the body, or as extracorporeal devices intended to
be connected to the body to assist in surgery or dialysis are well
known. For example, intravascular procedures can bring medical
devices into contact with the patient's vasculature. In treating a
narrowing or constriction of a duct or canal percutaneous
transluminal coronary angioplasty (PTCA) is often used with the
insertion and inflation of a balloon catheter into a stenotic
vessel. Other intravascular invasive therapies include atherectomy
(mechanical systems to remove plaque residing inside an artery),
laser ablative therapy, and the like. However, this use of
mechanical repairs can have adverse consequences for the patient.
For example, restenosis at the site of a prior invasive coronary
artery disease therapy can occur. Restenosis, defined
angiographically, is the recurrence of a 50% or greater narrowing
of a luminal diameter at the site of a prior coronary artery
disease therapy, such as a balloon dilatation in the case of PTCA
therapy. In particular, an intra-luminal component of restenosis
develops near the end of the healing process initiated by vascular
injury, which then contributes to the narrowing of the luminal
diameter. This phenomenon is sometimes referred to as "intimal
hyperplasia." It is believed that a variety of biologic factors are
involved in restenosis, such as the extent of the injury,
platelets, inflammatory cells, growth factors, cytokines,
endothelial cells, smooth muscle cells, and extracellular matrix
production, to name a few.
[0003] Attempts to inhibit or diminish restenosis often include
additional interventions such as the use of intravascular stents
and the intravascular administration of pharmacological therapeutic
agents. Examples of stents which have been successfully applied
over a PTCA balloon and radially expanded at the same time as the
balloon expansion of an affected artery include the stents
disclosed in U.S. Pat. Nos. 4,733,665 (Palmaz), 4,800,882
(Gianturco), and 4,886,062 (Wiktor).
[0004] Also, such stents employing therapeutic agents such as
glucocorticoids (e.g. dexamethasone, beclamethasone), heparin,
hirudin, tocopherol, angiopeptin, aspirin, ACE inhibitors, growth
factors, oligonucleotides, and, more generally, antiplatelet
agents, anticoagulant agents, antimitotic agents, antioxidants,
antimetabolite agents, and anti-inflammatory agents have been
considered for their potential to solve the problem of restenosis.
Such substances have been incorporated into (or onto) stents by a
variety of mechanisms. These mechanisms involve incorporating the
therapeutic agents into polymeric coatings and films, including
hydrogels, as well as covalently binding the therapeutic agents to
the surface of the stent.
[0005] For example, therapeutic agents have been dissolved or
dispersed in a solution of polymer in an organic solvent. This is
then sprayed onto the stent and allowed to dry. Alternatively,
therapeutic agents have been incorporated into a solid composite
with a polymer in an adherent layer on a stent body with fibrin in
a separate adherent layer on the composite to form a two layer
system. The fibrin is optionally incorporated into a porous polymer
layer in this two layer system. The therapeutic agent, however, is
incorporated into the underlying solid polymer. The overlying
porous polymer layer provides a porous barrier through which the
therapeutic agent is transferred.
[0006] Conventional methods of loading the therapeutic agent into a
polymer, such as spray coating, do not provide high concentrations
of therapeutic agents. Typically, upon spray coating a therapeutic
agent onto a stent body, only about 2 percent of the spray is
captured by the stent. This can be prohibitively expensive for
therapeutic agents that are extremely costly and scarce, such as
peptidic drugs.
[0007] Thus, what is needed is a medical device, preferably, a
stent, having a porous polymeric material, typically a polymer
layer in the form of a coating or film, with a therapeutic agent
incorporated therein at sufficiently high concentrations that the
therapeutic agent can be delivered over an extended period of time.
Improved methods by which the therapeutic agent can be incorporated
into the porous polymeric material with lower levels of waste are
also needed.
SUMMARY OF THE INVENTION
[0008] This invention relates to a medical device having a porous
polymeric material with a therapeutic agent therein. Preferably,
the device according to the invention is capable of applying a
highly localized therapeutic agent into a body lumen to treat or
prevent injury. The term "injury" means a trauma, that may be
incidental to surgery or other treatment methods including
deployment of a stent, or a biologic disease, such as an immune
response or cell proliferation caused by the administration of
growth factors. In addition, the methods of the invention may be
performed in anticipation of "injury" as a prophylactic. A
prophylactic treatment is one that is provided in advance of any
symptom of injury in order to prevent injury, prevent progression
of injury or attenuate any subsequent onset of a symptom of such
injury.
[0009] In accordance with the invention, a device for delivery of
localized therapeutic agent includes a structure including a porous
material and an elutable (i.e., capable of being dissolved under
physiological conditions) therapeutic agent in the form of a solid,
gel, or neat liquid, which is dispersed throughout at least a
portion, and preferably a substantial portion, of the porous
material. Preferably, the device is capable of being implanted in a
body so that the localized therapeutic agent can be delivered in
vivo, typically at a site of vascular injury or trauma. Preferably,
the porous material is biocompatible, sufficiently tear-resistant,
and nonthrombogenic.
[0010] The porous material may be a layer (e.g., a film, i.e., a
sheet material or a coating) on at least a portion of the
structure. Alternatively, the porous material may be an integral
portion of the structure. Preferably, the porous material is a
polymeric material selected from the group of a natural hydrogel, a
synthetic hydrogel, silicone, polyurethane, polysulfone, cellulose,
polyethylene, polypropylene, polyamide, polyester,
polytetrafluoroethylene, and a combination of two or more of these
materials. Examples of natural hydrogels include fibrin, collagen,
elastin, and the like. More preferably, the porous polymeric
material is a nonswelling biostable polymer selected from the group
of silicone, polyurethane, polysulfone, cellulose, polyethylene,
polypropylene, polyamide, polyester, polytetrafluoroethylene, and a
combination of two or more of these materials.
[0011] The therapeutic agent can be one or more of a wide variety
of therapeutic agents, including peptidic drugs. Preferably, the
therapeutic agent includes an antithrombotic material. More
preferably, the antithrombotic material is a heparin or heparin
derivative or analog. Such therapeutic agents are soluble in water
such that they elute from the porous polymeric material.
[0012] The structure of the device can be adapted for its intended
extracorporeal or intravascular purpose in an internal human body
site, such as an artery, vein, urethra, other body lumens,
cavities, and the like or in an extracorporeal blood pump, blood
filter, blood oxygenator or tubing. In one aspect of the invention,
the shape is preferably generally cylindrical, and more preferably,
the shape is that of a catheter, a stent, or a guide wire. In
particularly preferred embodiments, the medical device is an
intralumenal stent.
[0013] The invention also provides methods for making a medical
device which includes therapeutic agents. In one embodiment, a
method of the invention includes: providing a structure comprising
a porous material; contacting the structure comprising a porous
material with a concentrating agent to disperse the concentrating
agent throughout at least a portion of the porous material;
contacting the structure comprising a porous material and the
concentrating agent with a solution of a therapeutic agent; and
removing the therapeutic agent from solution within the porous
material at the locations of the concentrating agent.
[0014] The present invention also provides a method for making a
medical device that includes: providing a structure comprising a
porous material; immersing the structure comprising a porous
material in a saturated solution of a therapeutic agent for a
sufficient period of time to allow the solution to fill the porous
material; removing the medical device from the solution; drying the
medical device; and repeating the steps of immersing, removing, and
drying to provide a therapeutic agent dispersed within the porous
material. Preferably, the method further includes a step of
removing air bubbles from the porous material while being immersed
in the solution of the therapeutic agent. The step of removing air
bubbles from the porous material can include applying ultrasonics,
reduced pressure, elevated pressure, or a combination thereof, to
the solution. Preferably, the method involves loading a stent
having a porous polymeric film thereon, and subsequently applying
an overlayer of a polymer.
[0015] A therapeutic agent may be loaded onto a structure including
a porous material at any number of points between, and including,
the point of manufacture and the point of use. For example, the
device can be stored and transported prior to incorporation of the
therapeutic agent. Thus, the end user can select the therapeutic
agent to be used from a wider range of therapeutic agents.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is an elevational view of one embodiment of a device
according to the invention with a balloon catheter as a mode of
delivery of the device; and
[0017] FIG. 2 is an elevational view of another embodiment of a
device according to the invention with a balloon catheter as a mode
of delivery of the device.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0018] One of the more preferred configurations for a device
according to the invention is a stent for use in artery/vascular
therapies. The term "stent" refers to any device capable of being
delivered by a catheter and which, when placed into contact with a
portion of a wall of a lumen to be treated, will also deliver
localized therapeutic agent at a luminal or blood-contacting
portion of the device. A stent typically includes a lumen
wall-contacting surface and a lumen-exposed surface. Where the
stent is shaped generally cylindrical or tube-like, including a
discontinuous tube or ring-like structure, the lumen-wall
contacting surface is the surface in close proximity to the lumen
wall whereas the lumen-exposed surface is the inner surface of the
cylindrical stent. The stent can include polymeric or metallic
elements, or combinations thereof, onto which a porous material is
applied. For example, a deformable metal wire stent is useful as a
stent framework of this invention, such as that described in U.S.
Pat. No. 4,886,062 (Wiktor), which discloses preferred methods for
making a wire stent. Other metallic stents useful in this invention
include those of U.S. Pat. Nos. 4,733,655 (Palmaz) and 4,800,882
(Gianturco).
[0019] Other medical devices, such as heart valves, vascular
grafts, pacing leads, etc., can also include the embodiments of the
present invention. As used herein, medical device refers to a
device that has surfaces that contact tissue, blood, or other
bodily fluids in the course of their operation, which fluids are
subsequently used in patients. This can include, for example,
extracorporeal devices for use in surgery such as blood
oxygenators, blood pumps, blood sensors, tubing used to carry blood
and the like which contact blood which is then returned to the
patient. This can also include endoprostheses implanted in blood
contact in a human or animal body such as vascular grafts, stents,
pacemaker leads, heart valves, and the like that are implanted in
blood vessels or in the heart. This can also include devices for
temporary intravascular use such as catheters, guide wires, and the
like which are placed into the blood vessels or the heart for
purposes of monitoring or repair.
[0020] Referring now to FIG. 1, the stent 20 comprises a stent
framework 22 and a porous material coating 24. The stent framework
22 is deformable and can be formed from a polymeric material, a
metal, or a combination thereof. A balloon 15 is positioned in FIG.
1 adjacent the lumen-exposed surface of the stent to facilitate
delivery of the stent. The stent 20 can be modified to increase or
to decrease the number of wires provided per centimeter in the
stent framework 22. Similarly, the number of wire turns per
centimeter can also be modified to produce a stiffer or a more
flexible stent framework.
[0021] Polymeric stents can also be used in this invention. The
polymers can be nonbioabsorbable or bioabsorbable in part, or
total. Stents of this invention can be completely nonbioabsorbable,
totally bioabsorbable or a composite of bioabsorbable polymer and
nonabsorbable metal or polymer. For example, another stent suitable
for this invention includes the self-expanding stent of resilient
polymeric material as disclosed in International Publication No. WO
91/12779 (Medtronic, Inc.).
[0022] Nonbioabsorbable polymers can be used as alternatives to
metallic stents. The stents of this invention should not
substantially induce inflammatory and neointimal responses.
Examples of biostable nonabsorbable polymers that have been used
for stent construction with or without metallic elements include
polyethylene terephthalate (PET), polyurethane urea, and silicone.
Although the porous material is shown as a coating 24, it is to be
understood that, for the purposes of this invention, the porous
material can be incorporated into the material of the stent.
[0023] Referring to FIG. 2, an alternative stent 30 is shown. The
stent framework 34 is affixed with a film of a porous material 32.
This can be accomplished by wrapping the film 32 around the stent
framework 34 and securing the film 32 to the framework 34 (i.e.,
the film is usually sufficiently tacky to adhere itself to the
framework but a medical grade adhesive could also be used if
needed) so that the film 32 will stay on the balloon 36 and
framework 34 until it is delivered to the site of treatment. The
film 32 is preferably wrapped over the framework with folds or
wrinkles that will allow the stent 30 to be readily expanded into
contact with the wall of the lumen to be treated. Alternatively,
the film 32 can be molded to the stent framework 34 such that the
framework 34 is embedded within the film 32. Preferably, the film
32 is located on a lumen-wall contacting surface 33 of the stent
framework 34 such that therapeutic material is substantially
locally delivered to a lumen wall, for example, an arterial wall
membrane (not shown).
[0024] Porous Material
[0025] As mentioned above, the device according to the invention is
generally a structure including a porous material. In one
embodiment, the porous material includes a polymeric film or
coating on at least a portion of the structure. In another
embodiment, the porous material is an integral portion of the
structure. Preferably, the porous material is a biocompatible
polymer and is sufficiently tear-resistant and nonthrombogenic.
Examples of suitable polymers are disclosed in U.S. Pat. No.
5,679,400 (Tuch). More preferably, the porous material is selected
from the group of a natural hydrogel, a synthetic hydrogel,
silicone, polyurethane, polysulfone, cellulose, polyethylene,
polypropylene, polyamide, polyester, polytetrafluoroethylene, and a
combination of two or more of these materials. Examples of natural
hydrogels include fibrin, collagen, elastin, and the like. In
materials which do not include pores in their usual structural
configurations, pores of about 10 micrometers in diameter or as
large as 1000 micrometers in diameter can be introduced by
conventional means such as by introducing a solvent soluble
particulate material into the desired structure and dissolving the
particulate material with a solvent.
[0026] Typically, and preferably, the porous material is in the
form of a sheet material or coating of a nonswelling biostable
polymer. As used herein, a "nonswelling biostable" or "nonswellable
biostable" polymer is one that does not absorb a significant amount
of water (i.e., it absorbs less than about 10 weight percent water)
and it is not readily degraded in the body. Such nonswelling
biostable polymers include, for example, silicone, polyurethane,
polysulfone, cellulose, polyethylene, polypropylene, polyamide,
polyester, polytetrafluoroethylene, and combinations thereof. If
the polymer is biodegradable, the rate at which it degrades is
slower than the rate at which the therapeutic agent elutes.
[0027] If the porous material is in the form of a porous sheet
(i.e., film) or coating, it can be made by a variety of methods.
These methods can include, for example, using a solid particulate
material (also referred to herein as pore-forming material) that
can be substantially removed after the film or coating is formed,
thereby forming pores. By using a solid particulate material during
film or coating formation, the size of the pores can, to some
extent, be controlled by the size of the solid particulate material
being used. The particulate material can range from less than about
1 micrometer in diameter to about 1000 micrometers, preferably
about 1 micrometer to about 100 micrometers, more preferably about
5 micrometers to about 50 micrometers. For uniformity of pores, the
particulate material can be screened through successively finer
mesh sieves, e.g., through 100, 170, 270, 325, 400, and 500 mesh
analytical grade stainless steel mesh sieves, to produce a desired
range of particle sizes.
[0028] The particulate material may include inorganic and organic
particulate material, including, for example, sodium chloride,
lithium chloride, sucrose, glucose, sorbitol, sodium citrate,
sodium ascorbate, urea, citric acid, dextran, poly(ethylene
glycol), sodium nitroprusside, mannitol, sodium bicarbonate,
ascorbic acid, sodium salicylate, or combinations thereof. It will
be understood by one of skill in the art that a mixture of
different particulate materials can be used if desired. Also, it
will be understood by one of skill in the art that because a
portion of the particulate material may remain within the film, it
is preferred that the solid particulate material be
biocompatible.
[0029] Typically, the particulate material chosen is less soluble
than the polymer in the chosen solvent (e.g., water or an organic
solvent) used to deposit or form the polymer. The particulate
material may actually be soluble in the solvent; however, to form
pores, it only has to be less soluble than the polymer in the
solvent of choice. As the solvent is removed from the solution, the
pore-forming material will precipitate out of solution and form
particles surrounded by the polymer, which is still in solution.
The polymer then will come out of solution as more solvent is
removed and the particles will be dispersed within the polymer.
After the solvent is removed, the particulate material is removed
using a liquid in which the polymer is not soluble, thereby forming
pores.
[0030] In one method according to the present invention, a porous
sheet material (e.g., polyurethane sheet material) can be made by
dissolving a polymer (e.g., polyether urethane) in an organic
solvent (e.g., 1-methyl-2-pyrrolidone); mixing into the resulting
polymer solution a crystalline, particulate material (e.g., sodium
chloride, sucrose, etc.) that is not soluble in the solvent;
casting the solution with particulate material into a thin film;
and then applying a second solvent (e.g., water), to dissolve and
remove the particulate material, thereby leaving a porous sheet.
Such a method is disclosed in U.S. Pat. Nos. 5,591,227 (Dinh et
al.) and 5,599,352 (Dinh et al.).
[0031] Preferably, a combination of soluble and insoluble
particulate material may be used to create a broader range of pore
sizes. The use of a soluble particulate material, such as
poly(ethylene glycol), may create small (<2 .mu.m diameter)
interconnecting pores that create a solvent path for the removal of
the larger (e.g., 50 .mu.m) particles, which may not be in
particle-to-particle contact.
[0032] A suspension of particulate material may be created by first
dissolving the particulate in a solvent, then precipitating the
mixture in a solution of polymer in a second solvent in which the
particulate is insoluble. For example, an 8% solution of sodium
nitroprusside in ethanol can be added with rapid stirring to a 2%
solution of polyurethane in tetrahydrofuran. The sodium
nitroprusside precipitates to form a suspension of less than about
5 .mu.m particles.
[0033] The weight ratio of pore-forming material to polymer in a
coating composition may range from about 1:3 to about 9:1,
preferably, about 2:1 to about 9:1, although this is not
necessarily limiting. In theory, the porosity is limited by the
toughness of the polymer.
[0034] A smooth coating may be obtained by applying an atomized
spray to the stent. The spray should be applied at a rate such that
evaporation prevents the accumulation of sufficient liquid to form
drips along the stent. A macroscopically smooth surface may also be
obtained by keeping the particle size less than about 1/4 of the
coating or film thickness.
[0035] Although films (i.e., sheet materials) for medical devices,
particularly stent bodies, according to the present invention can
be manufactured separately from the support structure of the
medical device and attached to the support structure after
formation, preferred methods include forming the films directly on
the support structure such that the support structure is at least
partially, preferably completely, encapsulated by the film (i.e.,
sheet material).
[0036] Alternatively, medical devices can include a coating of a
porous polymer made by spraying a solution of the polymer and
particulate material directly on the support. In this way, the
coating does not necessarily form a film that encapsulates the
device; rather it forms a coating around the structure (e.g., wire)
of the device. The geometry of the porous material (coated wires
vs. sheets or films) depends on the coating substrate and is
largely independent of the pore forming and application methods
used. A film can be made by spraying, dipping, or casting, as long
as the mandrel is a rod or a flat sheet. The stent wires can be
coated by any of these methods as well, although most preferably,
they are coated by spraying to prevent droplet formation.
[0037] In one such method, which is disclosed in International
Publication No. WO 97/07973 (Medtronic, Inc.), a stent is placed on
a mandrel. A particulate material is then applied to the mandrel
and stent such that it is lightly adhered to the mandrel. The
particulate material should be readily soluble in a solvent which
will not also dissolve the polymer chosen for the film. For
example, crystalline sodium bicarbonate is a water soluble material
that can be used as the particulate material. A nonaqueous liquid,
preferably a solvent for the polymer film material, can be applied
to the mandrel before applying the particulate material in order to
retain more of the particulate material on the mandrel. For
example, when a polyurethane is to be used for the film material,
the solvent 1-methyl-2-pyrrolidinone (NMP) can be used to wet the
surface of the mandrel before the application of particulate
material. Preferably, the mandrel is completely dusted with the
particulate in the portions of the mandrel to be coated with the
polymer film. This can be accomplished by dipping the mandrel in
NMP, allowing it to drain vertically for a few seconds and then
dusting the sodium bicarbonate onto the mandrel while rotating it
horizontally until no further bicarbonate particles adhere. Excess
particulate material can be removed by gently tapping the
mandrel.
[0038] Coating with polymer may proceed immediately following
application of the particulate material. A polymer is provided in a
dilute solution and is applied to the particle-coated stent and
mandrel. For example, polyurethane can be dissolved in NMP to make
a 10% solution. Gel particles and particulate impurities can be
removed from the solution by use of a clinical centrifuge. The
polymer solution can be applied by dipping the mandrel into the
solution and letting the solvent evaporate. With the solution of
polyurethane and NMP, a single dip in the solution can provide a
film of adequate thickness. To assist in the formation of
communicating passageways through the polymer between the
blood-contacting surface and the lumen-contacting surface,
additional sodium bicarbonate particles are preferably dusted onto
the polymer solution immediately after the dipping operation and
before the polymer solution has dried. Excess particulate material
can be removed by gently tapping the mandrel. To precipitate and
consolidate the polyurethane film on the stent, it can be dipped
briefly (about 5 minutes) in water and then rolled gently against a
wetted surface, such as a wet paper towel. The stent assembly can
then be placed into one or more water baths over an extended period
(e.g., 8 hours) to dissolve and remove the sodium bicarbonate.
After drying in air at temperatures from about 20.degree. C. to
about 50.degree. C., the film then can be trimmed to match the
contour of the wire.
[0039] In yet another method, a solvent in which the polymer is
soluble that is capable of phase separating from the polymer at a
reduced temperature can be used to prepare a porous polymer film.
In this method, the stent or other medical device is placed in a
cavity of a mold designed for forming a film around the stent,
similar to that disclosed in U.S. Pat. No. 5,510,077 (Dinh et al.).
A solution of the desired polymer, such as polyurethane, dissolved
in a solvent, such as dioxane, is added to the mold. The
temperature of the solution is then reduced to a temperature at
which the solvent freezes and phase separates from the polymer,
thereby forming particulate material (i.e., frozen solvent
particles) in situ. Typically, for polyurethane in dioxane, this is
a temperature of about -70.degree. C. to about 3.degree. C. The
composition is then immersed in an ice cold water bath (at about
3.degree. C.) for a few days to allow the dioxane to dissolve into
the ice cold water, thereby forming pores. The number and size of
the pores can be controlled by the concentration of the polymer and
the freezing temperature. A method similar to this is disclosed in
Liu et al., J. Biomed. Mater. Res., 26, 1489 (1992). This method
can be improved on by using a two-step freezing process as
disclosed in U.S. patent application Ser. No. ______, filed on Apr.
29, 1998 (Attorney Docket No. P4242).
[0040] In yet another embodiment, a porous material can be created
from a mixture of a low boiling good solvent and a higher boiling
poor solvent, in which the polymer is soluble. After application to
the target substrate, the lower boiling good solvent evaporates
preferentially until a point is reached where the polymer
precipitates from the remaining solvent mixture, which is
relatively richer in the poor solvent. The polymer precipitates in
and around pockets of the poor solvent, creating a porous
structure. The number and size of pores can be controlled by the
boiling points of the two solvents, the concentration of polymer
and the drying rate. An example is a 1% solution of poly(l-lactic
acid) (PLLA) in a 60:40 mixture of chloroform:iso-octane. As the
chloroform evaporates, the PLLA precipitates from the iso-octane to
create an opague PLLA coating containing 2-5 .mu.m pores. This
method is further described in U.S. Pat. No. 5,679,400 (Tuch).
[0041] Therapeutic Agent
[0042] The therapeutic agent used in the present invention could be
virtually any therapeutic agent which possesses desirable
therapeutic characteristics and which can be provided in a form
that can be solubilized, for example, by water or an organic
solvent, and are capable of being eluted from the porous polymeric
material in the body of a patient. Preferred therapeutic agents are
solids, gels, or neat liquids (i.e., materials not dissolved in a
solvent) at room temperature (i.e., about 20-25.degree. C.), and
preferably at body temperatures, that are capable of being eluted
from the porous polymeric material in the body of a patient. For
example, antithrombotics, antiplatelet agents, antimitotic agents,
antioxidants, antimetabolite agents, anti-inflammatory agents,
enzyme inhibitors, and anti-angiogenic factors as disclosed in U.S.
Pat. No. 5,716,981 (Hunter et al.) could be used. Anticoagulant
agents, such as heparin, heparin derivatives, and heparin analogs,
could also be used to prevent the formation of blood clots on the
device.
[0043] Methods of Making an Implantable Device
[0044] A structure having a porous material, preferably a porous
polymeric material, can be loaded with one or more therapeutic
agents using a wide variety of methods. For example, the porous
material can be immersed in a solution or dispersion of the
therapeutic agent in a solvent. The solution (preferably, a
supersaturated solution) or dispersion is allowed to fill the pores
and the solvent is allowed to evaporate leaving the therapeutic
agent dispersed within at least a portion of the pores. The solvent
can be water or an organic solvent that does not dissolve the
polymer. If the solvent does not dissolve the therapeutic agent,
the particles of the therapeutic agent are smaller than the pore
openings. Alternatively, in certain embodiments, the solvent can be
chosen such that it swells the polymer, thereby achieving a greater
level of incorporation of the therapeutic agent.
[0045] The following methods for loading one or more therapeutic
agents into porous material are improved over prior art methods,
such as spray coating methods. Although the same amount of
therapeutic agent can be loaded onto a medical device,
significantly less (e.g., about 100.times. less) waste of the
therapeutic agent occurs using the following methods. This is
particularly important for expensive therapeutic agents, such as
peptic drugs.
[0046] In one embodiment of the invention, filling of the pores can
be enhanced through the use of ultrasonics, vacuum, and/or
pressure. While the device is submerged in solution, ultrasonic
energy or vacuum can be used to accelerate the removal of air
bubbles from the pores allowing the pores to fill with the solution
containing the therapeutic agent. Hyperbaric pressure on the
solution may cause the air in the pores to be dissolved in the
solution, thereby allowing the pores to fill with liquid.
Furthermore, the level of incorporation can be increased by using
multiple dip-vacuum-dry cycles. If the therapeutic agent saturates
the solution by 10% by volume, for example, when the solvent
evaporates the pores will be 10% filled with the agent. Repeating
the cycle will fill the remaining 90% void space and fill an
additional 9% of the original pore volume. Further cycles continue
the trend. For this procedure to be effective, however, the
solution is saturated so that the previously deposited agent does
not dissolve in subsequent cycles.
[0047] Preferably, a method of the invention includes loading a
structure comprising a porous material with a concentrating agent,
which may be a precipitating agent (e.g., a binding agent,
sequestering agent, nucleating agent, etc.), a seed crystal, or the
like, dispersed throughout at least a portion, preferably, a
substantial portion, of the porous material, and subsequently
loading the structure comprising a porous material and the
concentrating agent with a solution of a therapeutic agent, wherein
the therapeutic agent is removed from solution (e.g., as by
crystallization and/or precipitation) within the porous material at
the locations of the concentrating agent. This is a significantly
improved method in that the concentrating agent provides a driving
force for localization of the drug within the pores of the polymer.
That is, it is believed that the concentrating agent provides a
thermodynamically favorable surface for crystallization or
precipitation.
[0048] The concentrating agent can be a precipitating agent or a
seed crystal, for example, or any substance that can cause the
therapeutic agent to fall out of solution. As used herein, a seed
crystal is a solid material that is the same as the therapeutic
agent being deposited. As used herein, a precipitating agent is a
solid material that is different from the therapeutic agent being
deposited. It can include, for example, materials that have a
particular affinity for the therapeutic agent of interest, such as
binding agents, sequestering agents, nucleating agents, and
mixtures thereof. Examples of sequestering agents include heparin
to sequester heparin binding growth factors such as bFGF and, for
example, cyclodextrins to trap appropriately sized therapeutic
agents to fit in their ring structures. Examples of binding agents
include polycations (e.g., protamine) and polyanions (e.g., heparin
sulfate) for binding anionic and cationic therapeutic agents,
respectively. The binding agent can also include a counterion of a
salt that is insoluble upon complexation with the therapeutic agent
in the solvent used in the solution of the therapeutic agent.
[0049] The solution containing the therapeutic agent is preferably
a supersaturated solution, although this is not a necessary
requirement. This can be prepared at elevated temperatures taking
into consideration the limits of stability of the therapeutic
agents and the porous material. The porous polymeric material with
concentrating agent therein can be immersed in a solution of the
therapeutic agent in a solvent. The solution is allowed to fill the
pores and the therapeutic agent allowed to come out of solution
(e.g., as by the formation of crystals). The solvent can be water
or an organic solvent that does not dissolve the porous polymer,
although it may swell the polymer as described above. The choice of
solvent is one that is compatible with the therapeutic agent and
porous material of choice. Filling of the pores can be enhanced
through the use of ultrasonics, vacuum, and/or pressure, as well as
by using multiple dip-vacuum-dry cycles, as described above.
[0050] Crystal and/or precipitate formation can be initiated by a
variety of mechanisms. They may spontaneously form. Alternatively,
the solution of the therapeutic agent within the pores may need to
be cooled to initiate crystallization and/or precipitation. It may
be possible to initiate crystallization and/or precipitation by
changing the pH and/or ionic strength of the solution of the
therapeutic agent within the pores.
[0051] The initial concentrating agent, which may be a solid,
liquid, or a gel, can be placed in the pores of the porous material
by a variety of methods. For example, if the concentrating agent is
a seed crystal of the therapeutic agent of interest, immersing the
porous material in a solution or dispersion of the therapeutic
agent in a solvent, allowing it to fill the pores, and allowing the
solvent to evaporate, provides the therapeutic agent dispersed
within at least a portion of the pores, as described above.
Similarly, if the concentrating agent is a precipitating agent, the
porous material can be immersed in a solution of this agent.
[0052] The methods of the present invention are advantageous in
that the structure can be loaded with the therapeutic agent in
situ, i.e., at or near the point of therapeutic use, typically
before administration, preferably implantation, to a patient. This
is particularly useful because the device can be stored and
transported prior to incorporation of the therapeutic agent. This
feature has several advantages. For example, the relevant consumer
can select the therapeutic agent to be used from a wider range of
therapeutic agents. Thus, the therapeutic agent selected is not
limited to only those supplied with the device but can instead be
applied according to the therapy required.
[0053] In order to provide additional control over the elution of
the therapeutic agent, an overlayer may be applied to the medical
device, as is disclosed in U.S. Pat. Nos. 5,679,400 (Tuch),
5,624,411 (Tuch), and 5,624,411 (Tuch). The overlayer, typically in
the form of a porous polymer, is in intimate contact with the
therapeutic agent and allows it to be retained on the medical
device. It also controls the administration of the therapeutic
agent following implantation. For a stent, an overlayer is
particularly desirable to retain the therapeutic agent on the stent
during expansion of the stent.
[0054] The following nonlimiting examples will further illustrate
the invention. All parts, percentages, ratios, etc. are by weight
unless otherwise indicated.
EXAMPLE
[0055] Wiktor stents were coated as follows: 4 grams of a 5 wt %
solution of polyurethane as disclosed in U.S. Pat. No. 4,873,308
(Coury et al.) in tetrahydrofuran (THF) and 20 grams of a 5 wt %
solution of citric acid in THF were combined and sprayed onto
wiktor stents using an air brush, similar to the method disclosed
in U.S. Pat. No. 5,679,400 (Tuch). Citric acid was extracted with
deionized water for 10 minutes. The stent was then air dried at
ambient temperature and weighed. The porous polyurethane coating
weights were 0.5-0.7 mg.
[0056] Into a microcentrifuge tube was added 0.12 g tissue factor
pathway inhibitor (TFPI) and 1.0 ml sterile water. This was
agitated to dissolve the TFPI. The polyurethane coated stents were
immersed in the TFPI solution, which was subjected to reduced
pressure (28 inches of Hg) to evacuate the air from the pores. The
stents were air dried and the immersion/vacuum process was repeated
twice. After the last immersion process, stents were air dried at
ambient temperature for 20 minutes. Each stent was immersed for
less than two seconds in deionized water to remove TFPI on the
surface of the stents. The stents were then dried in ambient
temperature under vacuum for about 12 hours. The stents were
weighed to determine the amount of TFPI loaded into the pores,
which ranged from 0.15 mg to 0.33 mg.
[0057] Half the stents were overcoated with a 2 wt % solution of
polyurethane solution in THF using the spray coating method
described above, resulting in a coating weight of 0.6 mg. These
stents were tested for elution. The stents with the overcoating
eluted more slowly than the stents without the overcoating.
[0058] The complete disclosures of all patents, patent
applications, and publications referenced herein are incorporated
herein by reference as if individually incorporated. Various
modifications and alterations of this invention will become
apparent to those skilled in the art without departing from the
scope and spirit of this invention, and it should be understood
that this invention is not to be unduly limited to illustrative
embodiments set forth herein.
* * * * *