U.S. patent application number 12/021195 was filed with the patent office on 2008-05-29 for hemocompatible polymers on hydrophobic porous polymers.
This patent application is currently assigned to Advanced Cardiovascular Systems, Inc.. Invention is credited to Andre-Jean Lundkvist, Wouter E. Roorda, Niraj Shah.
Application Number | 20080125857 12/021195 |
Document ID | / |
Family ID | 39476595 |
Filed Date | 2008-05-29 |
United States Patent
Application |
20080125857 |
Kind Code |
A1 |
Roorda; Wouter E. ; et
al. |
May 29, 2008 |
HEMOCOMPATIBLE POLYMERS ON HYDROPHOBIC POROUS POLYMERS
Abstract
Various embodiments of the present invention provide a medical
device comprising at least one blood-contacting surface comprising
a porous hydrophobic polymer substrate, wherein at least a portion
of the at least one blood-contacting surface comprises a
hemocompatible polymer substrate. One embodiment of the present
invention relates to the providing of expanded
poly(tetrafluoroethylene) with one or more complexes of heparin,
typically containing heparin in combination with a hydrophobic
counter ion. The hemocompatible substance is dissolved in a mixture
of solvents in which a first solvent wets the polymer substrate to
be coated and the second solvent enhances the solubility of the
hemocompatible substance material in the solvent mixture. Typical
first solvents wetting a hydrophobic polymer substrate include
non-polar such as hydrocholorofluorocarbons. Typical second
solvents include polar solvents such as organic alcohols and
ketones. Azeotropic mixtures of the second solvent in the first
solvent are used in some embodiments of the present invention
although second solvents may be employed in a range of
concentration ranges from less than 0.1% up to saturation.
Inventors: |
Roorda; Wouter E.; (Palo
Alto, CA) ; Shah; Niraj; (West New York, NJ) ;
Lundkvist; Andre-Jean; (Santa Clara, CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA, SUITE 300
SAN FRANCISCO
CA
94111
US
|
Assignee: |
Advanced Cardiovascular Systems,
Inc.
|
Family ID: |
39476595 |
Appl. No.: |
12/021195 |
Filed: |
January 28, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10818927 |
Apr 5, 2004 |
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12021195 |
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09704212 |
Oct 31, 2000 |
6833153 |
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10818927 |
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Current U.S.
Class: |
623/1.39 |
Current CPC
Class: |
A61L 31/048 20130101;
A61L 31/08 20130101; A61L 2300/208 20130101; A61L 33/0011 20130101;
A61L 31/146 20130101; A61L 31/048 20130101; A61L 2300/42 20130101;
A61L 31/10 20130101; A61L 31/16 20130101; A61L 27/34 20130101; C08L
27/18 20130101; A61L 2300/236 20130101 |
Class at
Publication: |
623/1.39 |
International
Class: |
A61F 2/82 20060101
A61F002/82 |
Claims
1. A medical device, comprising at least one blood-contacting
surface comprising a porous hydrophobic polymer substrate, wherein
at least a portion of the at least one blood-contacting surface
comprises a hemocompatible polymer substrate produced by: a)
providing a hemocompatible substance, b) preparing a solution
comprising a mixture of: first solvent that wets the porous
hydrophobic polymer substrate; a second solvent that enhances the
solubility of the hemocompatible substance in the solution; and the
hemocompatible substance; and, c) contacting the surface of the
porous hydrophobic polymer substrate with the solution thereby
causing the hemocompatible substance to deposit onto the surface of
the porous hydrophobic polymer substrate, provided that the
hemocompatible substance is not subjected to a dialdehyde
cross-linking or dialdehyde stabilization step before in vivo
use.
2. The medical device of claim 1 wherein the medical device is a
stent.
3. The medical device of claim I wherein the porous hydrophobic
polymer substrate composes a blood-contacting component of a
medical device.
4. The medical device of claim I wherein the porous hydrophobic
polymer substrate includes at least one polymer material selected
from the group consisting of porous polyethylene materials, porous
polypropylene materials, porous polyurethane materials, porous
polyacrylate materials, porous polymethacrylate materials and
porous fluoropolymer materials.
5. The medical device of claim 4 wherein the porous fluoropolymer
material comprises an expanded poly(tetrafluoroethylene)
material.
6. The medical device of claim 1 wherein the hemocompatible
substance comprises ionic heparin and a hydrophobic counter
ion.
7. The medical device of claim 6 wherein the hydrophobic counter
ion is a hydrophobic quaternary ammonium ion.
9. The medical device of claim 6 wherein the hydrophobic counter
ion is one or more of benzylalkonium ion and
tridodecylmethylammonium ion.
10. The medical device of claim 1 wherein the hemocompatible
substance is deposited on the hydrophobic polymer substrate by
dipping.
11. The medical device of claim 10 wherein the second solvent
particularly enhances solubility of the hemocompatible
substance.
12. A medical device, comprising at least one blood-contacting
surface comprising a porous hydrophobic polymer substrate, wherein
at least a portion of the at least one blood-contacting surface
comprises a hemocompatible polymer substrate produced by: a)
providing a hemocompatible substance, b) preparing a solution
comprising a mixture of: a first solvent that wets the porous
hydrophobic polymer substrate; a second solvent that particularly
enhances the solubility of the hemocompatible substance in the
solution; and the hemocompatible substance; and c) contacting the
surface of the porous hydrophobic polymer substrate with the
solution thereby causing the hemocompatible substance to deposit
onto the surface of the porous hydrophobic polymer.
13. The medical device of claim 12 wherein the medical device is a
stent.
14. The medical device of claim 12 wherein the porous hydrophobic
polymer substrate composes a blood-contacting component of a
medical device.
16. The medical device of claim 12 wherein the porous hydrophobic
polymer substrate includes at least one polymer material selected
from the group consisting of porous polyethylene materials, porous
polypropylene materials, porous polyurethane materials, porous
polyacrylate materials, porous polymethacrylate materials and
porous fluoropolymer materials.
17. The medical device of claim 16 wherein the porous fluoropolymer
material comprises an expanded poly(tetrafluoroethylene)
material.
18. The medical device of claim 12 wherein the hemocompatible
substance comprises ionic heparin and a hydrophobic counter
ion.
19. The medical device of claim 18 wherein the hydrophobic counter
ion is a hydrophobic quaternary ammonium ion.
20. The medical device of claim 18 wherein the hydrophobic counter
ion is one or more of benzylalkonium ion and
tridodecylmethylammonium ion.
21. The medical device of claim 12 wherein the hemocompatible
substance is deposited on the hydrophobic polymer substrate by
dipping.
22. A medical device, comprising at least one blood-contacting
surface comprising a porous hydrophobic polymer substrate, wherein
at least a portion of the at least one blood-contacting surface
comprises a hemocompatible polymer substrate produced by: a)
providing a hemocompatible substance, b) preparing a solution
comprising a mixture of: a first solvent that wets the porous
hydrophobic polymer substrate; a second solvent that enhances the
solubility of the hemocompatible substance in the solution; and the
hemocompatible substance; and, c) contacting the surface of the
porous hydrophobic polymer substrate with the solution thereby
causing the hemocompatible substance to deposit onto the surface of
the porous hydrophobic polymer substrate, provided that the amount
of a mixture of trichloro trifluoro ethanes is 10 wt % or less.
23. The medical device of claim 22 wherein the medical device is a
stent.
24. The medical device of claim 22 wherein the porous hydrophobic
polymer substrate composes a blood-contacting component of a
medical device.
25. The medical device of claim 22 wherein the porous hydrophobic
polymer substrate includes at least one polymer material selected
from the group consisting of porous polyethylene materials, porous
polypropylene materials, porous polyurethane materials, porous
polyacrylate materials, porous polymethacrylate materials and
porous fluoropolymer materials.
26. The medical device of claim 25 wherein the porous fluoropolymer
material comprises an expanded poly(tetrafluoroethylene)
material.
27. The medical device of claim 22 wherein the hemocompatible
substance comprises ionic heparin and a hydrophobic counter
ion.
28. The medical device of claim 27 wherein the hydrophobic counter
ion is a hydrophobic quaternary ammonium ion.
29. The medical device of claim 27 wherein the hydrophobic counter
ion is one or more of benzylalkonium ion and
tridodecylmethylammonium ion.
30. The medical device of claim 22 wherein the hemocompatible
substance is deposited on the hydrophobic polymer substrate by
dipping.
31. The medical device of claim 30 wherein the second solvent
particularly enhances solubility of the hemocompatible
substance.
32. A medical device, comprising at least one blood-contacting
surface comprising a porous hydrophobic polymer substrate, wherein
at least a portion of the at least one blood-contacting surface
comprises a hemocompatible polymer substrate produced by: a)
providing a hemocompatible substance, b) preparing a solution
comprising a mixture of: a first solvent that wets the porous
hydrophobic polymer substrate; a second solvent that enhances the
solubility of the hemocompatible substance in the solution; and the
hemocompatible substance; and c) contacting the surface of the
porous hydrophobic polymer substrate with the solution thereby
causing the hemocompatible substance to deposit onto the surface of
the porous hydrophobic polymer substrate, provided that the
solution has a maximum ethanol content of 10 wt %.
33. The medical device of claim 32 wherein the medical device is a
stent.
34. The medical device of claim 32 wherein the porous hydrophobic
polymer substrate composes a blood-contacting component of a
medical device.
35. The medical device of claim 32 wherein the porous hydrophobic
polymer substrate includes at least one polymer material selected
from the group consisting of porous polyethylene materials, porous
polypropylene materials, porous polyurethane materials, porous
polyacrylate materials, porous polymethacrylate materials and
porous fluoropolymer materials.
36. The medical device of claim 35 wherein the porous fluoropolymer
material comprises an expanded poly(tetrafluoroethylene)
material.
37. The medical device of claim 32 wherein the hemocompatible
substance comprises ionic heparin and a hydrophobic counter
ion.
38. The medical device of claim 37 wherein the hydrophobic counter
ion is a hydrophobic quaternary ammonium ion.
39. The medical device of claim 37 wherein the hydrophobic counter
ion is one or more of benzylalkonium ion and
tridodecylmethylammonium ion.
40. The medical device of claim 32 wherein the hemocompatible
substance is deposited on the hydrophobic polymer substrate by
dipping.
41. The medical device of claim 40 wherein the second solvent
particularly enhances solubility of the hemocompatible substance.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 10/818,927, filed Apr. 5, 2004, which is a
Continuing-in-Part application from U.S. application Ser. No.
09/704,212, filed 31 Oct. 2000, issued as U.S. Pat. No. 6,833,153,
the teachings of which are incorporated herein by reference in
their entirety.
BACKGROUND
[0002] 1. Field of the Invention
[0003] The present invention relates to the field of hemocompatible
polymers on hydrophobic porous polymeric materials and, in
particular, to hemocompatible substances based upon complexes of
heparin deposited upon porous hydrophobic polymers, typically
expanded PTFE.
[0004] 2. Description of Related Art
[0005] Continuing advances in medical technology have led to the
development and use of numerous medical devices that come into
contact with blood or other bodily fluids. To be concrete in our
discussion, we focus herein on the particular example of medical
devices coming into contact with mammalian blood, particularly
human blood, not intending thereby to limit the scope of the
present invention to medical devices used exclusively on human
patients. In using such devices, it is important that contact of
the blood or other bodily fluid with the various components of the
medical device not cause therapeutically detrimental alterations to
the fluid. In many cases, it is desirable to coat such devices with
materials to enhance the biocompatiblity of the devices, including
coatings that contain bioactive agents, anticoagulants,
antimicrobial agents or a variety of other drugs.
[0006] It is convenient to consider blood-contacting medical
devices as invasive or extra-corporal, although some devices span
both classes. Invasive devices are used internally in the treatment
of the patient, implanted into the patient for an indefinite or
extended period of time or inserted into the patient for relatively
brief periods. In many cases, the materials comprising the
blood-contacting portions of the invasive device lack
sufficient-biocompatibility and/or hemocompatibility. This tends to
cause changes harmful to the patient in the blood or other fluid
coming into contact with the surface (or surfaces) of the device.
In such cases it is desirable to coat the surfaces of these devices
with materials to enhance the biocompatibility and/or
hemocompatibility. Invasive devices that are typically coated with
biocompatible or therapeutic substances include implantable
artificial orthopedic devices, dental implants, intravascular
catheters, emboli capturing systems, epicardial immobilization
devices, grafts, stents, intraluminal prosthetic devices and
artificial heart valves, among others.
[0007] There are also many examples of extra-corporal medical
devices that come into contact with blood in which blood is
transported and/or processed external to the patient. A few
representative examples include cardiopulmonary bypass devices,
kidney dialysis equipment, blood oxygenators, separators and
defoaming devices, among others. Following such extra-corporal
processing, the blood or other bodily fluid may be reintroduced
into the patient, transported for storage and/or introduced into
another patient. In using such extra-corporal devices, it is
important that contact of the blood or other bodily fluid with the
various components of the device not cause therapeutically
detrimental alterations to the fluid.
[0008] It is important in some cases that the surface or the
surfaces of the invasive or extra-corporal medical device be coated
with substances having therapeutic functions, wherein the coatings
may serve several functions in addition to increasing the
biocompatibility/hemocompatibility of the surface. Examples of such
additional functions include the release of one or more therapeutic
agents into the blood in appropriate dosages with appropriate
timed-released characteristics and at the proper location within
the patient. Thus, the medical device may serve as a convenient
delivery platform for the delivery of therapeutically beneficial
drugs in addition to its other functions.
[0009] One important application related to implantable devices
arises in connection with endoluminal stents, particularly as
occurring in connection with percutaneous transluminal angioplasty
("PCTA"). Following balloon angioplasty, the lumen of the
just-expanded vessel may contract due to several causes. An initial
rebound of the walls of the vessel may occur following removal of
the balloon. Further thrombosis or restenosis of the blood vessel
may occur over time following the angioplasty procedure. The result
is often the necessity for another angioplasty procedure or
surgical by-pass. Endoluminal stents have been in use for several
years in conjunction with a surgical procedure inserting a tube or
stent into the vessel following the PCTA procedure to assist in
retaining the desired intraluminal opening. A review of the
procedure may be found in Endoluminal Stenting by Ulrich Sigwart,
Ed. (W. B. Saunders, 1996). A compendium of coronary stents is
given in Handbook of Coronary Stents, 3.sup.rd Ed. by P. W. Serruys
and M. JB Kutryk, Eds. (Martin Dunitz Ltd., 2000). However, even
with stenting, occlusions frequently recur within the stent
requiring further PCTA or by-pass surgery. Such restenosis
following PCTA and the insertion of a stent is sought to be
prevented by the use of coated stents. Coatings on stents are often
used for the delivery of anticoagulants or other medication that
assist in preventing thrombosis and restenosis.
[0010] Heparin is an anticoagulant drug composed of a highly
sulfated polysaccharide, the principle constituent of which is a
glycosaminoglycan. In combination with a protein cofactor, heparin
acts as an antithrombin (among other medical effects as described,
for example, in Heparin-Binding Proteins, by H. B. Conrad (Academic
Press, 1998)). Heparin is an attractive additive to coat on the
surface(s) of blood-contacting devices in order to increase the
hemocompatibility of the material and/or to release heparin or
heparin complexes into the blood to combat thrombosis and
restenosis.
[0011] The heparin molecule contains numerous hydrophilic groups
including hydroxyl, carboxyl, sulfate and sulfamino making
underivatized heparin difficult to coat onto hydrophobic polymers.
Thus, many types of complexes of heparin with hydrophobic counter
ions have been used in order to increase the ability of the
heparin-counter ion complex to bind to hydrophobic surfaces. Such
counter ions are typically cationic to facilitate binding with
anionic heparin, and contain a hydrophobic region to facilitate
bonding with the hydrophobic polymer. Typical heparin complexes
include, but are not limited to, heparin complex with typically
large quaternary ammonium species such as benzylalkonium groups
(typically introduced in the form of benzylalkonium chloride),
tridodecylmethylammonium chloride ("TDMEC"), and the commercial
heparin complex offered by Baxter International under the tradename
DURAFLO or DURAFLO II. Herein we denote as "heparin complex" any
complex of heparin with a hydrophobic counter ion, typically a
relatively large counter ion. Examples of heparin complexes are
described in the following U.S. Pat. Nos. (incorporated herein by
reference): 4,654,327; 4,871,357; 5,047,020; 5,069,899; 5,525,348;
5,541,167 and references cited therein.
[0012] Considerable work has been done in developing coatings for
application to various medical devices in which the coatings
contain at least one form of heparin or heparin complex.
Combinations of heparin and heparin complexes with other drugs, as
well as various techniques for tailoring the coating to provide
desired drug-release characteristics have been studied. Examples of
such work include that of Chen et. al. (incorporated herein by
reference), published in J. Vascular Surgery, Vol 22, No. 3 pp
237-247 (September 1995) and the following U.S. Pat. Nos.
(incorporated herein by reference): 4,118,485; 4,678,468;
4,745,105; 4,745,107; 4,895,566; 5,013,717; 5,061,738; 5,135,516;
5,322,659; 5,383,927; 5,417,969; 5,441,759; 5,865,814; 5,876,433;
5,879,697; 5,993,890 as well as references cited in the foregoing
patents and article, such cited references hereby incorporated a
reference into this document.
[0013] Implantable medical devices often require some degree of
porosity to enable blood to come into contact with underlying
tissues, to increase the surface area for delivery of therapeutic
substances, or for other purposes. Therefore, porous polymers are
widely used in medical devices. The advantages of porosity are not
limited to implantable devices, and porous materials are used in
extra-corporal devices as well as invasive medical devices.
However, the problem of coating with heparin is exacerbated if the
hydrophobic polymer is also porous. In addition to binding with the
hydrophobic surface, the heparin complex must also penetrate into
the interstices of the porous structure of the polymer and bind to
all or substantially all of the polymer surface that comes into
contact with blood.
[0014] Fluorinated polymers are typically chemically unreactive,
have low surface energy and are hydrophobic. Such properties are
generally favorable for use in medical devices as described, for
example by F. H. Silver and D. L. Christiansen in Biomaterials
Science and Biocompatibility, (Springer-Verlag, 1999) p. 19.
Poly(tetrafluoroethylene), PTFE, is a polymeric material with
repeating units of (--CF.sub.2CF.sub.2--) having numerous
commercial uses, including in blood-contacting devices, due in
large part to its chemical inertness and desirable physical
properties. PTFE in the form of a film or solid has low surface
energy and, therefore, is a relatively difficult surface to coat
(or "wet"). "Wetting" typically indicates the tendency of a liquid
to spread and coat the surface onto which it is placed. The
specific relationship between surface energy and the contact angle
at the interface between a drop and the surface (the "wetting") is
given in standard references including Physical Chemistry of
Surfaces 6.sup.th Ed. by A. W. Adams and A. P. Gast (John Wiley,
1997), p. 465 ff. A contact angle between the liquid and the
surface greater than approximately 90.degree. typically indicates a
non-wetting liquid on that particular surface.
[0015] In many medical and non-medical commercial uses, it is
desirable to have PTFE in the form of a porous film that retains
adequate physical strength for the particular application while not
substantially increasing the cost of the material. Expanded PTFE
(hereinafter "ePTFE") is a form of PTFE that has been physically
expanded along one or more directions to create a porous form of
PTFE having varying amounts of porosity depending on several
factors including the specific procedures for performing the
mechanical expansion. The porous ePTFE thus created is useful for
the manufacture of several commercial products as illustrated (for
example) by the work of Gore in U.S. Pat. Nos. 3,953,566 and
4,187,390 and the work of House et. al. in U.S. Pat. No.
6,048,484.Applications to stents include the work of Lewis et. al.
(U.S. Pat. No. 5,993,489) and Bley et. al. (U.S. Pat. Nos.
5,674,241 and 5,968,070). The chemical inactivity, and other
properties of fluorinated polymers including PTPE and ePTFE, have
made them attractive substances for use in many medical and
blood-contacting devices. Representative examples include dental
implant devices (Scantlebury et. al. U.S. Pat. No. 4,531,916),
grafts, stents and intraluminal prosthetic devices (Bley et. al.
U.S. Pat. Nos. 5,674,241 and 5,968,070; Goldfarb et. al. U.S. Pat.
No. 5,955,016; Lewis et. al. U.S. Pat. No. 5,993,489; Tu et. al.
U.S. Pat. No. 6,090,134).
[0016] Expanded PTFE is widely used in medical devices and is
perhaps one of the most widely used vascular graft materials. In
fact, ePTFE has a large range of application in blood-contacting
medical devices including, but not limited to, segmental venous
replacements, reconstructed veins in organ transplantation, polymer
catheters, in-dwelling catheters, urological and coronary stents,
covered stents, heart valves, dental implants, orthopedic devices,
vascular grafts, synthetic by-pass grafts and other invasive and
implantable medical devices. In addition, ePTFE can be used in
extra-corporal blood-contacting devices. Examples include, but are
not limited to, heart by-pass devices, kidney dialysis equipment,
blood oxygenators, defoaming machines, among others.
[0017] FIG. 1 is a scanning electron micrograph of porous ePTFE
from the work of House et. al. (U.S. Pat. No. 6,048,484). FIGS. 2A
and 2B are schematic depictions of two forms of ePTFE showing
biaxially oriented fibrils (FIG. 2A), and multiaxially oriented
fibrils (FIG. 2B). Both FIGS. 2A and 2B are from House et. al.
(supra). Low surface energy characteristic of fluoropolymers and
other hydrophobic polymers, in combination with the porosity of
ePTFE, make the application of a coating to ePTFE, including
coating of the interior surfaces of the pores, a significant
challenge. Providing such a coating for ePTFE is one objective of
the present invention.
[0018] However, when used in a blood-contacting environment, ePTFE
tends to be thrombogenic and its porosity may release entrapped
gases (which may itself be a source of thrombogenicity as
discussed, for example, by Vaun et. al. U.S. Pat. No. 5,181,903).
Therefore, considerable effort has gone into the coating of ePTFE
to reduce its thrombogenicity and/or provide other therapeutic
effects. Hemocompatibility can be achieved by a variety of means,
including coating with a hydrophilic, biologically passive,
polymer, or by coating with materials having a biologically active
component such as heparin or a complex of heparin including the
commercially available heparin complex DURAFLO or DURAFLO II
(Baxter Healthcare, Inc.). Improved procedures for coating ePTFE
with hemocompatible substances, typically substances containing
derivatives or complexes of heparin, and the improved
hemocompatible materials so produced are among the objects of the
present invention. We use the expressions "derivative of heparin"
and "complex of heparin" interchangeably herein without distinction
to indicate a chemical combination of heparin with a counter
ion.
[0019] Although fluoropolymers have been among the most commonly
used materials for blood-contacting devices, polyurethanes,
polyethylene terephthalates ("PETs") and numerous other fluorinated
and non-fluorinated polymers have also found considerable
application. Modifications of polyurethanes, PETs and other
plastics have included the introduction of coatings for
antithrombogenic and anticoagulant properties. PET is an example of
a non-fluorinated polymer that is highly hydrophobic and therefore
difficult to coat with polar, aqueous materials such as heparin.
PTFE is but one example of the general chemical class of
fluoropolymer that also includes FEP (fluorinated ethylene
propylene), PFA (perfluoroalkyl vinyl ether and tetrafluoroethylene
co-polymer), PVDF (polyvinylidenedifluoride), PVF
(polyvinylfluoride), PCTFE (polychlorotrifluoroethylene), ETFE
(ethylene and tetrafluoroethylene co-polymer) TFB (terpolymer of
vinylidenedifluoride, hexafluoropropylene and tetrafluoroethylene)
and other fluoropolymers as known in the art and described in many
references including, for example, W. Woebcken in Saechtling
International Plastics Handbook for the Technologist Engineer and
User, 3.sup.rd Ed., (Hanser Publishers, 1995) pp. 234-240,
incorporated herein by reference.
[0020] Coating the interior regions of highly porous materials such
as ePTFE with significant amounts of a hemocompatible substances
presents special challenges in addition to the hydrophobicity,
deriving in part from the relative inaccessibility of much of the
surface to be coated.
SUMMARY
[0021] According to an embodiment of the present invention, it is
provided a medical device comprising at least one blood-contacting
surface comprising a porous hydrophobic polymer substrate, wherein
at least a portion of the at least one blood-contacting surface
comprises a hemocompatible polymer substrate. The hemocompatible
polymer substrate is produced by a method comprising the following
acts: a) providing a hemocompatible substance, b) preparing a
solution comprising a mixture of: a first solvent that wets the
porous hydrophobic polymer substrate; a second solvent that
enhances the solubility of the hemocompatible substance in the
solution; and the hemocompatible substance; and, c)contacting the
surface of the porous hydrophobic polymer substrate with the
solution thereby causing the hemocompatible substance to deposit
onto the surface of the porous hydrophobic polymer substrate,
provided that the hemocompatible substance is not subjected to a
dialdehyde cross-linking or dialdehyde stabilization step before in
vivo use.
[0022] According to another embodiment of the present invention, it
is provided a medical device comprising at least one
blood-contacting surface comprising a porous hydrophobic polymer
substrate, wherein at least a portion of the at least one
blood-contacting surface comprises a hemocompatible polymer
substrate. The hemocompatible polymer substrate is produced by a
method comprising the following acts: a) providing a hemocompatible
substance, b) preparing a solution comprising a mixture of: a first
solvent that wets the porous hydrophobic polymer substrate; a
second solvent that particularly enhances the solubility of the
hemocompatible substance in the solution; and the hemocompatible
substance; and c) contacting the surface of the porous hydrophobic
polymer substrate with the solution thereby causing the
hemocompatible substance to deposit onto the surface of the porous
hydrophobic polymer substrate.
[0023] According to a further embodiment of the present invention,
it is provided a medical device comprising at least one
blood-contacting surface comprising a porous hydrophobic polymer
substrate, wherein at least a portion of the at least one
blood-contacting surface comprises a hemocompatible polymer
substrate. The hemocompatible polymer substrate is produced by a
method comprising the following acts: a) providing a hemocompatible
substance, b) preparing a solution comprising a mixture of: a first
solvent that wets the porous hydrophobic polymer substrate; a
second solvent that enhances the solubility of the hemocompatible
substance in the solution; and the hemocompatible substance; and c)
contacting the surface of the porous hydrophobic polymer substrate
with the solution thereby causing the hemocompatible substance to
deposit onto the surface of the porous hydrophobic polymer,
provided that the amount of a mixture of trichloro trifluoro
ethanes is 10 wt % or less.
[0024] According to a further embodiment of the present invention,
it is provided a medical device, comprising at least one
blood-contacting surface comprising a porous hydrophobic polymer
substrate, wherein at least a portion of the at least one
blood-contacting surface comprises a hemocompatible polymer
substrate. The hemocompatible polymer substrate is produced by a
method comprising the following acts: a) providing a hemocompatible
substance, b) preparing a solution comprising a mixture of: a first
solvent that wets the porous hydrophobic polymer substrate; a
second solvent that enhances the solubility of the hemocompatible
substance in the solution; and the hemocompatible substance; and c)
contacting the surface of the porous hydrophobic polymer substrate
with the solution thereby causing the hemocompatible substance to
deposit onto the surface of the porous hydrophobic polymer
substrate, provided that the solution has a maximum ethanol content
of 10 wt %.
[0025] An example of the medican device of the above various
embodiments is a stent.
[0026] In the various embodiments above, the second solvent
particularly enhances solubility of the hemocompatible
substance.
[0027] In the various embodiments above, the porous hydrophobic
polymer substrate can compose a blood-contacting component of a
medical device. The porous hydrophobic polymer substrate can
include at least one polymer material such as porous polyethylene
materials, porous polypropylene materials, porous polyurethane
materials, porous polyacrylate materials, porous polymethacrylate
materials and porous fluoropolymer materials. In some embodiments,
the porous fluoropolymer material comprises an expanded
poly(tetrafluoroethylene) material.
[0028] In the various embodiments above, the hemocompatible
substance can comprise ionic heparin and a hydrophobic counter ion.
In some embodiments, the hydrophobic counter ion can be a
hydrophobic quaternary ammonium ion. In some embodiments, the
hydrophobic counter ion can one or more of benzylalkonium ion and
tridodecylmethylammonium ion. In some embodiments, the
hemocompatible substance can form a coating on the porous
hydrophobic polymer substrate.
[0029] In the various embodiments above, the hemocompatible
substance can be deposited on the porous hydrophobic polymer
substrate by dipping.
BRIEF DESCRIPTION OF THE FIGURES
[0030] FIG. 1: Scanning electron micrograph of ePTFE from U.S. Pat.
No. 6,048,484.
[0031] FIG. 2A: Schematic depiction of porous structure of ePTFE
from U.S. Pat. No. 6,048,484 depicting biaxially oriented
fibrils.
[0032] FIG. 2B: Schematic depiction of porous structure of ePTFE
from U.S. Pat. No. 6,048,484 depicting multiaxially oriented
fibrils.
[0033] FIG. 3: Cut-away depiction of a portion of a covered
stent.
DETAILED DESCRIPTION
[0034] The present invention relates to the coating of porous,
hydrophobic polymers, typically fluoropolymers such as expanded
poly(tetrafluoroethylene), ePTFE, with hemocompatible substances,
so as to perfuse and coat substantially all regions of the surface
that come into contact with blood, including the interior regions
of the porous structure that are difficult to access and difficult
to coat by conventional means. Complexes of heparin are the typical
hemocompatible substances employed in some embodiments of the
present invention.
[0035] We follow the conventional usage that "wetting" indicates
that the contact angle formed by the tangent to the surface of the
liquid and the surface of the solid at the point of contact is less
than 90.degree. (measured through the liquid phase) such that the
liquid tends to spread over the surface of the solid. Conversely,
nonwetting indicates that the liquid tends to ball up on the
surface of the solid and run off the surface easily. Contact angles
are known in the art and provide one criteria by which candidate
solvents of the present invention can be identified. For example,
contact angles of selected liquids with selected surfaces
(including fluoropolymers such as PTFE, FEP) are provided in
Physical Chemistry of Surfaces 6.sup.th Ed. (supra) pp.
365-366.
[0036] The present invention is not inherently limited to ePTFE or
to fluoropolymers as a class. Porous hydrophobic polymeric
materials, that are typically difficult to coat with hemocompatible
materials by procedures of the prior art are included within the
scope of the present invention. Examples of porous hydrophobic
polymers include the following: porous polyethylene, porous
polypropylene, porous polyurethanes, porous polyacrylates, porous
polymethacrylates, among others. Biocompatible polyurethanes, PETs
and other polymers have also been used as blood-contacting
substances in medical devices, subject to coating with heparin
complexes and/or other hemocompatible or therapeutic molecules
pursuant to the methods of the present invention. However, PTFE is
but one example of a class of commercially important
fluoropolymers. Other examples include those noted above; FEP, PFA,
PVDF, PVF, PCTFE, ETFE, TFB and other fluoropolymers as known in
the art. Blends containing ePTFE, other fluoropolymers and/or other
hydrophobic polymers are included within the scope of the present
invention. Such blends are coatable by means of the procedures
described herein and the resulting coated materials are useful in
blood-contacting medical devices.
[0037] To be concrete in our discussions we describe in detail the
particular embodiments in which expanded PTFE is coated with a
hemocompatible substance containing heparin as one component
thereof. Other embodiments making use of other porous hydrophobic
polymers and/or other hemocompatible substances consistent with the
procedures and conditions of the present invention represent
obvious modifications of the present invention and are included
within its scope. Some embodiments specifically exclude subjecting
the hemocompatible substance to a dialdehyde cross-linking or
dialdehyde stabilization step before in vivo use.
[0038] The present invention relates to coating ePTFE without
distinction as to the particular microstructure present in the
ePTFE prior to coating. Herein we use "ePTFE" to indicate any
porous structure of the PTFE polymer, irrespective of its specific
and detailed microstructure and irrespective of the detailed
procedure for its formation. Commercially available embodiments of
ePTFE such as GORE-TEX (W. L. Gore and Associates) are included. In
some embodiments of the present invention, mechanically expansion
of PTFE is the means by which porosity is obtained. However, as
described by Gore (U.S. Pat. Nos. 3,953,566 and 4,187,390,
incorporated herein by reference), mechanical expansion is not the
only way to obtain porous PTFE. The coating procedures of the
present invention can be used for coating porous polymeric
materials, including ePTFE, irrespective of the specific mechanism
by which the porosity is introduced into the material. However, for
economy of language, we use "ePTFE" to denote a porous form of
PTFE, however produced, recognizing that mechanically expanded PTFE
is but one means of obtaining the desired porosity.
[0039] Liquids having contact angles with PTFE less than 90.degree.
include non-polar organic solvents such as alkanes (pentane,
hexane, heptane and octane, among others) and cycloalkanes, freons
or related materials such as chlorofluorocarbons ("CFCs") and
hydrochlorofluorocarbons ("HCFCs"). Commercial solvents include
CFCs and HCFCs such as "Techspray AMS Flux Remover" (from
Techspray, Inc., of Amarillo, Tex.) and "Gensolv 2004" (from Micro
Care Corp. of Bristol, Conn.). Various ethers, tetrahydrofuran,
dioxane are among the solvents wetting PTFE. For some embodiments
of the present invention, a candidate solvent is any solvent that
is known to wet fluoropolymers (particularly ePTFE) or the
hydrophobic polymer of interest. Although pure solvents are
discussed herein, this is merely for economy of language. Mixtures
of solvents that retain the property of being able to wet the
hydrophobic surface, particularly ePTFE, are included within the
scope of the present invention.
[0040] Some invention embodiments specifically exclude solvent
mixtures that comprise more than 10 weight percent, more than 20
weight percent, more than 30 weight percent, or more than 40 weight
percent of a mixture of trifluoro trichloro ethanes.
[0041] A hydrophobic complex of heparin is dissolved in the
polymer-wetting primary solvent for penetration into the porous
structure and deposition onto ePTFE in some embodiments of the
present invention. Some (typically small) amount of heparin complex
dissolves in pure polymer-wetting solvent as described above, but
typically does not lead to biologically useful amounts of heparin
being deposited onto the hydrophobic surfaces. Therefore, in some
embodiments of the present invention, the solubility of heparin
complexes is enhanced by the addition of relatively small amounts
of a polar solvent to the non-polar primary solvent. The non-polar
primary solvent is chosen to provide adequate penetration into the
interior of the porous hydrophobic material, while the polar
solubility-enhancing component of the solvent is selected to
facilitate dissolution of heparin complexes in the solvent mixture.
Candidate polar solubility-enhancing additives included organic
alcohols (methanol, ethanol, among others), ketones (acetone,
methylethylketone, among others). Mixtures of one or more chemical
compounds can also be used as the solubility-enhancing solvent.
[0042] In some embodiments, the solubility-enhancing component is
limited to solvents or solvent mixtures that have at least the
following two characteristics. First, the hemocompatible substance
is more soluble in the solubility-enhancing component than the
substance is in the polymer-wetting primary solvent. Second, the
hemocompatible substance is more soluble in the
solubility-enhancing component than it is in a mixture of the
polymer-wetting primary solvent and the solubility-enhancing
component. Such solubility-enhancing components are said to be
particularly solubility enhancing.
[0043] Some invention embodiments specifically exclude solvent
mixtures that comprise more than 1 weight percent, more than 2
weight percent, more than 3 weight percent, more than 4 weight
percent, more than 5 weight percent, more than 10 weight percent,
more than 20 weight percent, more than 30 weight percent, or more
than 40 weight percent of ethanol.
[0044] It is desirable, but not inherently necessary in some
embodiments of the present invention, that the polar solvent be
added to the non-polar solvent in an amount so as to form an
azeotropic mixture. Azeotropic mixtures have the property of
evaporating such that the unevaporated liquid retains the same
composition to dryness. In contrast, non-azeotropic mixtures
typically become more concentrated in the less volatile solvent as
evaporation proceeds. A solute will thus experience a changing
solvent composition during evaporation for non-azeotropic mixtures.
This may lead to precipitation of the solute and tend to create
non-uniform coatings. Thus, while non-azeotropic mixtures may be
used with acceptable results, azeotropic mixtures typically give
better coatings.
[0045] One example of a substantially azeotropic mixture described
in detail below includes a polymer-wetting solvent HCFC-225
containing about 6% methanol (by volume). This solvent mixture is
found to be adequate in the some embodiments of the present
invention. "HCFC-225" is a mixture of isomers of
dichloropentafluoropropane, typically HCFC-225ca is
CF.sub.3CF.sub.2CHCl.sub.2 and HCFC225cb is
CCIF.sub.2CF.sub.2CHFCl. However, azeotropic mixtures are not
necessary in the present invention and adequate results are
obtained with concentrations of polar solvent from approximately
0.00001% up to saturation of the polar solvent dissolved in the
non-polar solvent. In some embodiments of the present invention,
concentrations of polar solvent in the range from about 0.1% to
about 10% by volume are used. However, while the above ranges give
therapeutically useful amounts of hemocompatible substances, better
quality coatings are typically obtained with concentrations in the
range from approximately 0.1% to approximately 2%. A range from
approximately 0.5% to approximately 1% is particularly useful in
that 0.5% has enough hemocompatible material for therapeutically
effective coatings by 1% is dilute enough to avoid webbing.
[0046] Thus, the present invention includes adding relatively small
amounts of an organic alcohol (such as ethanol, methanol, among
others) or a similar solubility-enhancing polar solvent to a
polymer-wetting solvent. The solubility enhancing solvent is added
to the polymer-wetting solvent in such quantity (typically small)
that the mixed solvent provides adequate solubility for heparin
complexes without substantially hindering penetration of the pores
or wetting of the hydrophobic polymer. Thus, in one embodiment a
mixed solvent is created that both wets ePTFE and delivers heparin
to all surfaces of the porous structure.
[0047] Having dissolved a suitable heparin complex in a mixed
solvent as described herein, coating of the ePTFE with the heparin
complex may be performed by any convenient method that brings the
heparin-containing solution into intimate contact with all surface
regions of the ePTFE substrate including the interior regions of
the pores. Dip coating is one technique that can be used in some
embodiments of the present invention although other coating
techniques known in the art may also be used, including
spraying.
[0048] FIG. 3 depicts a portion of an endoluminal stent in cut-away
view, showing the interior region of the stent, 1, the struts, 2,
and a covering, 3. The covering material for the stent, 3, is
typically porous to allow blood flowing on the interior of the
stent, 1, to come into contact with the interior surfaces of the
lumen in which the stent is placed. Porous materials containing
hemocompatible substances thereon may be used in many medical
devices, one example of which is stent covering, 3. Expanded PTFE
is a typical stent covering material. Other materials for covering
stents are described elsewhere herein and in the references
cited.
[0049] Hemocompatible substances placed onto stent cover, 3,
include heparin and heparin complexes. One embodiment of the
present invention relates to coating a ePTFE stent covering
material with a heparin complex, typically DURAFLO or DURAFLO II.
Typical pore sizes of ePTFE are in the range of approximately 5
.mu.m (microns) to approximately 200 .mu.m, commonly in the range
from approximately 40 .mu.m to approximately 120 .mu.m.
EXAMPLES
[0050] DURAFLO II may be used herein in place of DURAFLO without
modification. [0051] 1) Prepare a solution consisting of the
hydrochlorofluorocarbon HCFC-225 and 6% by volume methanol whereby
the methanol enhances the solubility of the heparin complex in the
HCFC solvent. [0052] 2) Dissolve in the solution of step 1, a
heparin complex, DURAFLO. The concentration of DURAFLO in the
solution is selected to provide the desired coating of DURAFLO on
the stent cover. Too little drug on the stent cover may be
therapeutically ineffective. Too much may cause excess amounts of
drug to be released into the blood soon after the stent is
implanted, to the detriment of the patient. [0053] 3) Dip ePTFE
into the solution of step 2 allowing the solution to perfuse
throughout the ePTFE porosity and deposit the DURAFLO throughout.
[0054] 4) Repeat step 3 if additional coating of DURAFLO is
desired. Other solvents that may be used in step 1 above include
the following: [0055] 1-a) Techspray AMS Flux Remover containing
approximately 6% methanol. [0056] 1-b) Genesolv 2004,
dichlorofluoroethane containing approximately 4% methanol. [0057]
1-c) Cyclohexane including approximately 5% n-propanol. Other
solutes that may be used in step 2 above include the following:
[0058] 2-a) TDMEC heparin. [0059] 2-b) Benzalkonium heparin.
Concentrations of solute in solvent may be any convenient value
leading to the appropriate deposition of hemocompatible substance
onto the surface of the polymer. Typical concentrations in the
range of approximately 1%-3% are found to give adequate
coatings.
[0060] The material produced by the above procedure is a suitable
stent covering material containing DURAFLO (or other heparin
complex) coated on substantially all surfaces thereof that will be
exposed to blood during use. Dip or spray coating is conveniently
done on a porous, hydrophobic polymer already mounted on the
struts, forming thereby a stent covering. However, the hydrophobic,
porous material may be coated pursuant to the present invention
before, during or following the fabrication of the material into a
medical device. The timing of coating and device fabrication is
determined in part by manufacturing considerations including the
damage likely to result to the hemocompatible substance by
processing during device fabrication.
[0061] The properties of the coating can be tested in vitro by
standard testing methods including AT-III binding or anti-Factor Xa
Assay. Other biological assays include various ex vivo shunts.
[0062] This application hereby incorporated by reference the entire
specification and claims of parent application, U.S. application
Ser. No. 09/704,212.
[0063] Having described the invention in detail, those skilled in
the art will appreciate that, given the present disclosure,
modifications may be made to the invention without departing from
the spirit of the inventive concept described herein. Therefore, it
is not intended that the scope of the invention be limited to the
specific embodiments illustrated and described.
* * * * *