U.S. patent application number 12/492440 was filed with the patent office on 2009-12-31 for polyisobutylene urethane, urea and urethane/urea copolymers and medical devices containing the same.
This patent application is currently assigned to Cardiac Pacemakers, Inc.. Invention is credited to Mark Boden, Daniel J. Cooke, Shrojalkumar Desai, Mohan Krishnan, Marlene C. Schwarz, Michael C. Smith, Frederick H. Strickler.
Application Number | 20090326077 12/492440 |
Document ID | / |
Family ID | 41077669 |
Filed Date | 2009-12-31 |
United States Patent
Application |
20090326077 |
Kind Code |
A1 |
Desai; Shrojalkumar ; et
al. |
December 31, 2009 |
POLYISOBUTYLENE URETHANE, UREA AND URETHANE/UREA COPOLYMERS AND
MEDICAL DEVICES CONTAINING THE SAME
Abstract
The present invention pertains to polyisobutylene urethane, urea
and urethane/urea copolymers, to methods of making such copolymers
and to medical devices that contain such polymers. According to
certain aspects of the invention, polyisobutylene urethane, urea
and urethane/urea copolymers are provided, which comprise a
polyisobutylene segment, an additional polymeric segment that is
not a polyisobutylene segment, and a segment comprising a residue
of a diisocyanate. According to other aspects of the invention,
polyisobutylene urethane, urea and urethane/urea copolymers are
provided, which comprise a polyisobutylene segment and end groups
that comprise alkyl-, alkenyl- or alkynyl-chain-containing end
groups.
Inventors: |
Desai; Shrojalkumar; (Little
Canada, MN) ; Schwarz; Marlene C.; (Auburndale,
MA) ; Boden; Mark; (Harrisville, RI) ;
Krishnan; Mohan; (Shoreview, MN) ; Smith; Michael
C.; (Lino Lakes, MN) ; Strickler; Frederick H.;
(Natick, MA) ; Cooke; Daniel J.; (Roseville,
MN) |
Correspondence
Address: |
MAYER & WILLIAMS PC
251 NORTH AVENUE WEST, 2ND FLOOR
WESTFIELD
NJ
07090
US
|
Assignee: |
Cardiac Pacemakers, Inc.
St. Paul
MN
|
Family ID: |
41077669 |
Appl. No.: |
12/492440 |
Filed: |
June 26, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61076327 |
Jun 27, 2008 |
|
|
|
Current U.S.
Class: |
514/772.3 ;
523/105; 525/106; 525/123; 525/131; 607/116; 607/36; 607/5 |
Current CPC
Class: |
A61L 31/06 20130101;
C08G 18/10 20130101; C08G 18/10 20130101; A61L 31/06 20130101; C08G
18/7657 20130101; C08G 18/12 20130101; C08G 18/4063 20130101; C08G
18/6511 20130101; C08G 18/6204 20130101; A61L 27/18 20130101; C08G
18/12 20130101; A61L 27/18 20130101; C08G 18/4854 20130101; C08G
18/4858 20130101; C08G 18/3206 20130101; C08L 75/00 20130101; C08G
18/3206 20130101; C08L 75/00 20130101 |
Class at
Publication: |
514/772.3 ;
525/123; 525/106; 525/131; 523/105; 607/116; 607/5; 607/36 |
International
Class: |
A61K 8/87 20060101
A61K008/87; C08F 8/30 20060101 C08F008/30; A61K 8/72 20060101
A61K008/72; A61N 1/05 20060101 A61N001/05; A61N 1/39 20060101
A61N001/39; A61N 1/375 20060101 A61N001/375 |
Claims
1. A polyisobutylene urethane, urea or urethane/urea copolymer
comprising a polyisobutylene segment, an additional polymeric
segment that is not a polyisobutylene segment, and a segment
comprising a residue of a diisocyanate.
2. The copolymer of claim 1, wherein the additional polymeric
segment is a soft polymeric segment.
3. The copolymer of claim 2, wherein the soft polymeric segment is
selected from a polyether segment, a fluoropolymer segment, a
polyester segment, a polyacrylate segment, a polymethacrylate
segment, a polysiloxane segment and a polycarbonate segment.
4. The copolymer of claim 2, wherein the additional polymeric
segment is selected form a polytetramethylene oxide segment, a
polydimethylsiloxane segment, a polyperfluoroalkylene oxide
segment, a polyhexamethylene carbonate segment.
5. The copolymer of claim 1, wherein the polyisobutylene segment
comprises a residue of a polyisobutylene diol or a polyisobutylene
diamine and wherein the additional polymeric segment comprises a
residue of a polymeric diol or diamine selected from a
polytetramethylene oxide diol, a polytetramethylene oxide diamine,
a polydimethylsiloxane diol, a polydimethylsiloxane diamine, a
polyperfluoroalkylene oxide diol, a polyperfluoroalkylene oxide
diamine, a polyhexamethylene carbonate diol and a polyhexamethylene
carbonate diamine.
6. The copolymer of claim 1, wherein the diisocyanate is selected
from 4,4'-methylenediphenyl diisocyanate, toluene diisocyanate,
1,5-naphthalene diisocyanate, para-phenylene diisocyanate,
3,3'-tolidene-4,4'-diisocyanate,
3,3'-dimethyl-diphenylmethane-4,4'-diisocyanate, and combinations
thereof.
7. The copolymer of claim 1, further comprising a chain extender
residue.
8. The copolymer of claim 7, wherein the chain extender residue is
selected from an aliphatic diol, an aromatic diol, an aliphatic
diamine or an aromatic diamine.
9. The copolymer of claim 7, wherein the chain extender is an
alpha,omega-C1-C10-alkane diol.
10. The copolymer of claim 7, wherein the chain extender is
selected from 1,2-ethane diol, 1,4-butanediol and 1,6-hexanediol, a
low molecular weight polyisobutylene diol, and a low molecular
weight poly(stryene-b-isobutylene-b-styrene) diol.
11. The copolymer of claim 1, further comprising end groups that
comprise alkyl, alkenyl or alkynyl chains ranging from 1 to 17
carbons atoms in length.
12. The copolymer of claim 11, wherein the end groups are selected
from [--CH.sub.2].sub.n--CH.sub.3 groups,
[--CH.sub.2].sub.n--CF.sub.3 groups,
[--CH.sub.2].sub.n--C.sub.6H.sub.5 groups and combinations thereof,
where n ranges from 1 to 17.
13. The copolymer of claim 1, wherein the additional polymeric
segment is a hard polymeric segment.
14. The copolymer of claim 13, wherein the additional polymeric
segment is selected from a poly(vinyl aromatic) segment, a
poly(alkyl acrylate) segment and a poly(alkyl methacrylate)
segment.
15. The copolymer of claim 13, wherein the additional polymeric
segment is a polystyrene segment.
16. The copolymer of claim 15, wherein the polyisobutylene segment
comprises a residue of a polyisobutylene diol and wherein the
polystyrene segment comprises a residue of a polystyrene diol.
17. The copolymer of claim 15, comprising a
poly(styrene-b-isobutylene-b-styrene) diol residue.
18. An implantable or insertable medical device comprising a
polymeric region that comprises the copolymer of claim 1.
19. The implantable or insertable medical device of claim 18,
wherein the medical device is selected from an implantable
electrical lead, a pacemaker, a defibrillator and a heart failure
device.
20. The implantable or insertable medical device of claim 18,
wherein the medical device comprises an implantable electrical lead
and wherein the polymeric region is a polymeric layer disposed over
an electrical conductor.
21. The implantable or insertable medical device of claim 20,
wherein the electrical lead is selected from a cardiac lead and a
neurostimulation lead.
22. The implantable or insertable medical device of claim 18,
wherein said polymeric region further comprises a therapeutic
agent.
23. The implantable or insertable medical device of claim 18,
wherein said polymeric region further comprises an additional
material selected from a silicate material, alumina, silver
nanoparticles, and silicate/alumina/silver nanoparticle
composites.
24. A polyisobutylene urethane, urea or urethane/urea copolymer
comprising a polyisobutylene segment and further comprising end
groups that comprise alkyl, alkenyl or alkynyl chains ranging from
1 to 17 carbon atoms in length.
25. The copolymer of claim 24, wherein the end groups comprise
moieties selected from [--CH.sub.2].sub.n--CH.sub.3 groups,
[--CH.sub.2].sub.n--CF.sub.3 groups,
[--CH.sub.2].sub.n--C.sub.6H.sub.5 groups and combinations thereof,
where n ranges from 1 to 17.
26. An implantable or insertable medical device comprising a
polymeric region that comprises the copolymer of claim 24.
Description
STATEMENT OF RELATED APPLICATION
[0001] This application claims priority from U.S. provisional
application 61/076,327 filed Jun. 27, 2008, which is incorporated
herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to urethane, urea and
urethane/urea copolymers and to medical devices containing the
same.
BACKGROUND OF THE INVENTION
[0003] The use of polymeric materials in medical devices for
implantation or insertion into the body of a patient is common in
the practice of modern medicine. For example, polymeric materials
such as silicone rubber, polyurethane, and fluoropolymers, for
instance, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE) and
ethylene tetrafluoroethylene (ETFE), are used as coating
materials/insulation for medical leads, providing mechanical
protection, electrical insulation, or both.
[0004] As another example, drug eluting stents are known which have
polymeric coatings over the stent to release a drug to counteract
the effects of in-stent restenosis. Specific examples of drug
eluting coronary stents include commercially available stents from
Boston Scientific Corp. (TAXUS, PROMUS), Johnson & Johnson
(CYPHER), and others. See S. V. Ranade et al., Acta Biomater. 2005
January; 1 (1): 137-44 and R. Virmani et al., Circulation 2004 Feb.
17, 109 (6) 701-5. Various types of polymeric materials have been
used in such polymeric coatings including, for example,
homopolymers such as poly(n-butyl methacrylate) and copolymers such
as poly(ethylene-co-vinyl acetate), poly(vinylidene
fluoride-co-hexafluoropropylene), and poly(isobutylene-co-styrene),
for example, poly(styrene-b-isobutylene-b-styrene) triblock
copolymers (SIBS), which are described, for instance, in U.S. Pat.
No. 6,545,097 to Pinchuk et al. SIBS triblock copolymers have a
soft, elastomeric low glass transition temperature (Tg) midblock
and hard elevated Tg endblocks. Consequently, SIBS copolymers are
thermoplastic elastomers, in other words, elastomeric (i.e.,
reversibly deformable) polymers that form physical crosslinks which
can be reversed by melting the polymer (or, in the case of SIBS, by
dissolving the polymer in a suitable solvent). SIBS is also highly
biocompatible.
SUMMARY OF THE INVENTION
[0005] The present invention pertains to polyisobutylene urethane
copolymers, to polyisobutylene urea copolymers, to polyisobutylene
urethane/urea copolymers, to methods of making such copolymers and
to medical devices that contain such polymers.
[0006] According to certain aspects of the invention,
polyurethanes, polyureas and polyurethane/polyureas are provided,
which comprise a polyisobutylene segment, an additional polymeric
segment that is not a polyisobutylene segment, and a segment
comprising a residue of a diisocyanate.
[0007] According to other aspects of the invention, polyurethanes,
polyureas and polyurethane/polyureas are provided, which comprise a
polyisobutylene segment and end groups that comprise alkyl-,
alkenyl- or alkynyl-chain-containing end groups.
[0008] These and other aspects and embodiments as well as various
advantages of the present invention will become readily apparent to
those of ordinary skill in the art upon review of the Detailed
Description and any Claims to follow.
DETAILED DESCRIPTION OF THE INVENTION
[0009] A more complete understanding of the present invention is
available by reference to the following detailed description of
numerous aspects and embodiments of the invention. The detailed
description of the invention which follows is intended to
illustrate but not limit the invention.
[0010] As is well known, "polymers" are molecules containing
multiple copies (e.g., from 5 to 10 to 25 to 50 to 100 to 250 to
500 to 1000 or more copies) of one or more constitutional units,
commonly referred to as monomers. As used herein, the term
"monomers" may refer to free monomers and to those that have been
incorporated into polymers, with the distinction being clear from
the context in which the term is used.
[0011] Polymers may take on a number of configurations, which may
be selected, for example, from linear, cyclic and branched
configurations, among others. Branched configurations include
star-shaped configurations (e.g., configurations in which three or
more chains emanate from a single branch point), comb
configurations (e.g., configurations having a main chain and a
plurality of side chains, also referred to as "graft"
configurations), dendritic configurations (e.g., arborescent and
hyperbranched polymers), and so forth.
[0012] As used herein, "homopolymers" are polymers that contain
multiple copies of a single constitutional unit (i.e., monomer).
"Copolymers" are polymers that contain multiple copies of at least
two dissimilar constitutional units.
[0013] As used herein, a "polymeric segment" or "segment" is a
portion of a polymer. Segments can be unbranched or branched.
Segments can contain a single type of constitutional unit (also
referred to herein as "homopolymeric segments") or multiple types
of constitutional units (also referred to herein as "copolymeric
segments") which may be present, for example, in a random,
statistical, gradient, or periodic (e.g., alternating)
distribution.
[0014] As used herein a soft segment is one that displays a Tg that
is below body temperature, more typically from 35.degree. C. to
20.degree. C. to 0.degree. C. to -25.degree. C. to -50.degree. C.
or below. A hard segment is one that displays a Tg that is above
body temperature, more typically from 40.degree. C. to 50.degree.
C. to 75.degree. C. to 100.degree. C. or above. Tg can be measured
by differential scanning calorimetry (DSC), dynamic mechanical
analysis (DMA) and thermomechanical analysis (TMA).
[0015] Polyurethanes are a family of copolymers that are
synthesized from polyfunctional isocyanates (e.g., diisocyanates,
including both aliphatic and aromatic diisocyanates) and polyols
(e.g., macroglycols). Commonly employed macroglycols include
polyester diols, polyether diols and polycarbonate diols.
Typically, aliphatic or aromatic diols or diamines are also
employed as chain extenders, for example, to impart improved
physical properties to the polyurethane. Where diamines are
employed as chain extenders, urea linkages are formed and the
resulting polymers may be referred to as polyurethane/polyureas
[0016] Polyureas are a family of copolymers that are synthesized
from polyfunctional isocyanates and polyamines, for example,
diamines such as polyester diamines, polyether diamines,
polysiloxane diamines, polyhydrocarbon diamines and polycarbonate
diamines. As with polyurethanes, aliphatic or aromatic diols or
diamines may be employed as chain extenders.
[0017] Urethane, urea and urethane/urea copolymers in accordance
with the invention typically comprise one or more polyisobutylene
segments. For example, according to certain aspects of the
invention, polyisobutylene urethane, urea and urethane/urea
copolymers are provided, which contain (a) one or more
polyisobutylene segments, (b) one or more additional polymeric
segments (other than polyisobutylene segments), and (c) one or more
segments that contains one or more diisocyanate residues and,
optionally, one or more chain extender residues.
[0018] Examples of additional polymeric segments include soft
polymeric segments such as polyether segments, fluoropolymer
segments including fluorinated polyether segments, polyester
segments, poly(acrylate) segments, poly(methacrylate) segments,
polysiloxane segments and polycarbonate segments.
[0019] Examples of soft polyether segments include linear, branched
and cyclic homopoly(alkylene oxide) and copoly(alkylene oxide)
segments, including homopolymeric and copolymeric segments formed
from one or more of the following, among others: methylene oxide,
dimethylene oxide (ethylene oxide), trimethylene oxide, propylene
oxide, and tetramethylene oxide.
[0020] Examples of soft fluoropolymer segments include
perfluoroacrylate segments and fluorinated polyether segments, for
example, linear, branched and cyclic homopoly(fluorinated alkylene
oxide) and copoly(fluorinated alkylene oxide) segments, including
homopolymeric and copolymeric segments formed from one or more of
the following, among others: perfluoromethylene oxide,
perfluorodimethylene oxide (perfluoroethylene oxide),
perfluorotrimethylene oxide and perfluoropropylene oxide.
[0021] Examples of soft polyester segments include linear, branched
and cyclic homopolymeric and copolymeric segments formed from one
or more of the following, among others: alkyleneadipates including
ethyleneadipate, propyleneadipate, tetramethyleneadipate, and
hexamethyleneadipate.
[0022] Examples of soft poly(acrylate) segments include linear,
branched and cyclic homopoly(acrylate) and copoly(acrylate)
segments, including homopolymeric and copolymeric segments formed
from one or more of the following, among others: alkyl acrylates
such as methyl acrylate, ethyl acrylate, propyl acrylate, isopropyl
acrylate, butyl acrylate, sec-butyl acrylate, isobutyl acrylate,
2-ethylhexyl acrylate and dodecyl acrylate
[0023] Examples of soft poly(methacrylate) segments include linear,
branched and cyclic homopoly(methacrylate) and copoly(methacrylate)
segments, including homopolymeric and copolymeric segments formed
from one or more of the following, among others: alkyl
methacrylates such as hexyl methacrylate, 2-ethylhexyl
methacrylate, octyl methacrylate, dodecyl methacrylate and
octadecyl methacrylate.
[0024] Examples of soft polysiloxane segments include linear,
branched and cyclic homopolysiloxane and copolysiloxane segments,
including homopolymeric and copolymeric segments formed from one or
more of the following, among others: dimethyl siloxane, diethyl
siloxane, and methylethyl siloxane.
[0025] Examples of soft polycarbonate segments include those
comprising one or more types of carbonate units,
##STR00001##
where R may be selected from linear, branched and cyclic alkyl
groups. Specific examples include homopolymeric and copolymeric
segments formed from one or more of the following monomers, among
others: ethylene carbonate, propylene carbonate, and hexamethylene
carbonate.
[0026] Examples of additional polymeric segments also include hard
polymeric segments such as poly(vinyl aromatic) segments,
poly(alkyl acrylate) and poly(alkyl methacrylate) segments.
[0027] Examples of hard poly(vinyl aromatic) segments include
linear, branched and cyclic homopoly(vinyl aromatic) and
copoly(vinyl aromatic) segments, including homopolymeric and
copolymeric segments formed from one or more of the following vinyl
aromatic monomers, among others: styrene, 2-vinyl naphthalene,
alpha-methyl styrene, p-methoxystyrene, p-acetoxystyrene,
2-methylstyrene, 3-methylstyrene and 4-methylstyrene.
[0028] Examples of hard poly(acrylate) segments include linear,
branched and cyclic homopoly(alkyl acrylate) and copoly(alkyl
acrylate) segments, including homopolymeric and copolymeric
segments formed from one or more of the following acrylate
monomers, among others: tert-butyl acrylate, hexyl acrylate and
isobornyl acrylate.
[0029] Examples of hard poly(alkyl methacrylate) segments include
linear, branched and cyclic homopoly(alkyl methacrylate) and
copoly(alkyl methacrylate) segments, including homopolymeric and
copolymeric segments formed from one or more of the following alkyl
methacrylate monomers, among others: methyl methacrylate, ethyl
methacrylate, isopropyl methacrylate, isobutyl methacrylate,
t-butyl methacrylate, and cyclohexyl methacrylate.
[0030] The various polymeric segments described herein can vary
widely in molecular weight, but typically are composed of between 2
and 100 repeat units (monomer units).
[0031] The various polymeric segments described herein can be
incorporated into the polyurethanes, polyureas and
polyurethane/polyureas of the invention by providing them in the
form of polyols (e.g., diols, triols, etc.) and polyamines (e.g.,
diamines, triamines, etc.). Although the discussion to follow is
generally based on the use of polyols, it is to be understood that
analogous methods may be performed and analogous compositions may
be created using polyamines and polyol/polyamine combinations.
[0032] Specific examples of polyisobutylene polyols include linear
polyisobutylene diols and branched (three-arm) polyisobutylene
triols. See, e.g., J. P. Kennedy et al., "Designed Polymers by
Carbocationic Macromolecular Engineering: Theory and Practice,"
Hanser Publishers 1991, pp. 191-193, Joseph P. Kennedy, Journal of
Elastomers and Plastics 1985 17: 82-88, and the references cited
therein. Further examples of polyisobutylene polyols include
poly(styrene-co-isobutylene) diols include
poly(styrene-b-isobutylene-b-styrene) diols which may be formed,
for example, using methods analogous to those described in the
preceding Kennedy references. Examples of polyether polyols include
polytetramethylene oxide diols, which are available from various
sources including Signa-Aldrich Co., Saint Louis, Mo., USA and E.
I. duPont de Nemours and Co., Wilmington, Del., USA. Examples of
polysiloxane polyols include polydimethylsiloxane diols, available
from various sources including Dow Corning Corp., Midland Mich.,
USA, Chisso Corp., Tokyo, Japan. Examples of polycarbonate polyols
include polyhexamethylene carbonate diols such as those available
from Sigma-Aldrich Co. Examples of polyfluoroalkylene oxide diols
include ZDOLTX, Ausimont, Bussi, Italy, a copolyperfluoroalkylene
oxide diol containing a random distribution of
--CF.sub.2CF.sub.2O-- and --CF.sub.2O-- units, end-capped by
ethoxylated units, i.e.,
H(OCH.sub.2CH.sub.2).sub.nOCH.sub.2CF.sub.2O(CF.sub.2CF.sub.2O).sub.p(CF.-
sub.2O).sub.qCF.sub.2CH.sub.2--O--(CH.sub.2CH.sub.2O).sub.nH, where
n, p and q are integers. Polystyrene diol
(.alpha.,.omega.-dihydroxy-terminated polystyrene) of varying
molecular weight is available from Polymer Source, Inc., Montreal,
Canada. Polystyrene diols and three-arm triols may be formed, for
example, using procedures analogous to those described in M.
WeiBmuller et al., "Preparation and end-linking of
hydroxyl-terminated polystyrene star macromolecules,"
Macromolecular Chemistry and Physics 200 (3), 1999, 541-551.
[0033] In some embodiments, polyols (e.g., diols, triols, etc.) are
employed which are based on block copolymers. Examples of such
block copolymer polyols include poly(tetramethylene
oxide-b-isobutylene) diol, poly(tetramethylene
oxide-b-isobutylene-b-alkylene oxide) diol, poly(dimethyl
siloxane-b-isobutylene) diol, poly(dimethyl
siloxane-b-isobutylene-b-dimethyl siloxane) diol,
poly(hexamethylene carbonate-b-isobutylene) diol,
poly(hexamethylene carbonate-b-isobutylene-b-hexamethylene
carbonate) diol, poly(methyl methacrylate-b-isobutylene) diol,
poly(methyl methacrylate-b-isobutylene-b-methyl methacrylate) diol,
poly(styrene-b-isobutylene) diol and
poly(styrene-b-isobutylene-b-styrene) diol (SIBS diol).
[0034] As noted above, polyisobutylene urethane, urea and
urethane/urea copolymers in accordance with the invention typically
contain one or more segments that contain one or more diisocyanate
residues and, optionally, one or more chain extender residues.
[0035] Diisocyanates for use in forming the urethane, urea and
urethane/urea copolymers of the invention include aromatic and
non-aromatic (e.g., aliphatic) diisocyanates. Aromatic
diisocyanates may be selected from suitable members of the
following, among others: 4,4'-methylenediphenyl diisocyanate (MDI),
2,4- and/or 2,6-toluene diisocyanate (TDI), 1,5-naphthalene
diisocyanate (NDI), para-phenylene diisocyanate,
3,3'-tolidene-4,4'-diisocyanate and
3,3'-dimethyl-diphenylmethane-4,4'-diisocyanate. Non-aromatic
diisocyanates may be selected from suitable members of the
following, among others: 1,6-hexamethylene diisocyanate (HDI),
4,4'-dicyclohexylmethane diisocyanate,
3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (isophorone
diisocyanate or IPDI), cyclohexyl diisocyanate, and
2,2,4-trimethyl-1,6-hexamethylene diisocyanate (TMDI).
[0036] Optional chain extenders are typically aliphatic or aromatic
diols (in which case a urethane bond is formed upon reaction with
an isocyanate group) or aliphatic or aromatic diamines (in which
case a urea bond is formed upon reaction with an isocyanate group).
Chain extenders may be selected from suitable members of the
following, among others: alpha,omega-alkane diols such as ethylene
glycol (1,2-ethane diol), 1,4-butanediol, 1,6-hexanediol,
alpha,omega-alkane diamines, such as ethylene diamine, dibutylamine
(1,4-butane diamine) and 1,6-hexanediamine, or 4,4'-methylene
bis(2-chloroaniline).
[0037] Chain extenders may be also selected from suitable members
of the following, among others: short chain diol polymers (e.g.,
alpha,omega-dihydroxy-terminated polymers having a molecular weight
less than or equal to 1000) based on hard and soft polymeric
segments (more typically soft polymeric segments) such as those
described above, including short chain polyisobutylene diols, short
chain polyether polyols such as polytetramethylene oxide diols,
short chain polysiloxane diols such as polydimethylsiloxane diols,
short chain polycarbonate diols such as polyhexamethylene carbonate
diols, short chain poly(fluorinated ether) diols, short chain
polyester diols, short chain polyacrylate diols, short chain
polymethacrylate diols, and short chain poly(vinyl aromatic) diols.
As is known in the polyurethane art, chain extenders can increase
the hard segment length (or, stated another way, can increase the
ratio of hard segment material to soft segment material in the
urethane, urea or urethane/urea polymer), which can in turn result
in a polymer with higher modulus, lower elongation at break and
increased strength.
[0038] In certain other aspects of the invention, polyisobutylene
urethane, urea and urethane/urea copolymers are provided, which
comprise (a) one or more polyisobutylene segments, (b) optionally,
one or more additional segments other than polyisobutylene
segments, (c) one or more diisocyanate residues, (d) optionally,
one or more chain extender residues, and (e) end groups that
comprise alkyl, alkenyl or alkynyl chains ranging from 1 to 18
carbons in length. For example, such end groups may be selected
from [--CH.sub.2].sub.n--CH.sub.3 groups,
[--CH.sub.2].sub.n--CF.sub.3 groups,
[--CH.sub.2].sub.n--C.sub.6H.sub.5 groups (i.e.,
[--CH.sub.2].sub.n-ph) and combinations thereof, among others,
where n ranges from 1 to 17 (e.g., 1 to 2 to 3 to 4 to 5 to 6 to 7
to 8 to 9 to 10 to 11 to 12 to 13 to 14 to 15 to 16 to 17).
[0039] Polyisobutylene urethane, urea and urethane/urea copolymers
in accordance with the invention may the synthesized, for example,
in bulk or using a suitable solvent (e.g., one capable or
dissolving the various species that participate in the
polymerization reaction).
[0040] Various synthetic strategies may be employed to create
polyisobutylene urethane, urea and urethane/urea polymers in
accordance with the invention. These strategies typically involved
the reaction of (a) one or more polyol (commonly diol) species and
one or more polyisocyanate (commonly diisocyanate) species, (b) one
or more polyamine (commonly diamine) species and one or more
polyisocyanate species, or (c) one or more polyol species, one or
more polyamine species and one or more polyisocyanate species.
Reaction may be conducted, for example, in organic solvents, or
using supercritical CO.sub.2 as a solvent. Ionomers can be used for
polymer precipitation.
[0041] As previously indicated, although the discussion to follow
is generally based on the use of polyols, it is to be understood
that analogous methods may be performed and analogous compositions
may be created using polyamines and polyol/polyamine
combinations.
[0042] For example, in certain embodiments, a one step method may
be employed in which a first macrodiol (M1) (e.g., a block
copolymer diol such as SIBS diol, etc.) and a diisocyante (DI)
(e.g., MDI, TDI, etc.) are reacted in a single step. Molar ratio of
diisocyanate relative to the first macrodiol is 1:1. Using this
technique a polyurethane having alternating macrodiol and
diisocyante residues, i.e., -[DI-M1-].sub.n, where n is an integer,
may be formed. In some embodiments, a diol or diamine chain
extender (CE) (e.g., 1,2-ethane diol, 1,4-butanediol,
1,6-hexanediol, etc.) is included in the reaction mixture, in which
case the molar ratio of diisocyanate relative to the combination of
the first macrodiol and the chain extender is 1:1. For example, the
ratio DI:M1:CE may equal 2:1:1, may equal 2:1.5:0.5, may equal
2:0.5:1.5, among many other possibilities. Where a ratio of
DI:M1:CE equal to 2:1:1 is employed, a polyurethane having the
following structure may be formed -[DI-M1-DI-CE-].sub.n. Reactions
of this type have been reported to follow a statistical
distribution, so M1 and CE residues are not likely to be perfectly
alternating as shown. See, e.g., F. Wang, "Polydimethylsiloxane
Modification of Segmented Thermoplastic Polyurethanes and
Polyureas, Ph.D. dissertation, Virginia Polytechnic Institute and
State University, Apr. 13, 1998.
[0043] In other embodiments, a two-step reaction is employed
wherein the first macrodiol and diisocyante are reacted in a single
step at a DI:M1 molar ratio of .gtoreq.2:1 in order to form
isocyanate-end-capped "prepolymers," DI-M1-DI. Then, in a second
step, a chain extender is added, along with additional
diisocyanate, if required to maintain an overall molar ratio of
diisocyanate relative to the combination of the first macrodiol and
the chain extender of 1:1. As above, where a molar ratio of
DI:M1:CE equal to 2:1:1 is employed, a polyurethane having the
following structure may be formed -[DI-M1-DI-CE-].sub.n, although
the M1 and CE residues may not be perfectly alternating as shown.
Due to enhanced reaction control, polyurethanes made by the
two-step method tend to have a more regular structure than
corresponding polyurethanes made by the one step method.
[0044] In certain other embodiments, a one step method may be
employed in which a first macrodiol (M1) (e.g., a polyisobutylene
diol, a SIBS diol, etc.), a second macrodiol (M2) (e.g., a
polyether diol, a fluoropolymer diol, a polysiloxane diol, a
polycarbonate diol, a polyester diol, a polyacrylate diol, a
polymethacrylate diol, a polystyrene diol, etc.) and a diisocyante
(DI) (e.g., MDI, TDI, etc.) are reacted in a single step. Molar
ratio of diisocyanate relative to the first and second diols is
1:1. For example, the ratio DI:M1:M2 may equal 2:1:1, may equal
2:1.5:0.5, may equal 2:0.5:1.5, among many other possibilities.
Where a ratio of DI:M1:M2 equal to 2:1:1 is employed, a
polyurethane having the following structure may be formed
-[DI-M1-DI-M2-].sub.n although the chains are unlikely to be
perfectly alternating as shown. In some embodiments, a chain
extender is added to the reaction mixture, such that the molar
ratio of diisocyanate relative to the first and second macrodiols
and chain extender is 1:1. For example, the ratio DI:M1:M2:CE may
equal 4:1:1:2, may equal 2:0.67:0.33:1, may equal 2:0.33:0.67:1, or
may equal 5:1:1:3, among many other possibilities. Where a ratio of
DI:M1:M2:CE equal to 4:1:1:2 is employed, a polyurethane having the
following structure may be formed
-[DI-M1-DI-CE-DI-M2-DI-CE-].sub.n, although the chains are unlikely
to be perfectly alternating as shown.
[0045] In some embodiments, a two-step method is employed in which
first and second macrodiols and diisocyante are reacted in a ratio
of DI:M1:M2 of .gtoreq.2:1:1 in a first step to form isocyanate
capped first and second macrodiols, for example DI-M1-DI and
DI-M2-DI. In a second step, a chain extender is added which reacts
with the isocyanate end caps of the macrodiols. In some
embodiments, the number of moles of hydroxyl or amine groups of the
chain extender may exceed the number of moles of isocyanate end
caps for the macrodiols, in which case additional diisocyante may
be added in the second step as needed to maintain a suitable
overall stoichiometry. As above, the molar ratio of diisocyanate
relative to the total of the first macrodiol, second macrodiol, and
chain extender is typically 1:1, for example, DI:M1:M2:CE may equal
4:1:1:2, which may in theory yield an idealized polyurethane having
the following repeat structure -[DI-M1-DI-CE-DI-M2-DI-CE-].sub.n,
although the chains are unlikely to be perfectly alternating as
shown. In other examples, the DI:M1:M2:CE ratio may equal
4:1.5:0.5:2 or may equal 5:1:1:3, among many other
possibilities.
[0046] In some embodiments, three, four or more steps may be
employed in which a first macrodiol and diisocyante are reacted in
a first step to form isocyanate capped first macrodiol, typically
in a DI:M1 ratio of .gtoreq.2:1 such that isocyanate end caps are
formed at each end of the first macrodiol (although other ratios
are possible including a DI:M1 ratio of 1:1, which would yield an
average of one isocyanate end caps per macrodiol). This step is
followed by second step in which the second macrodiol is added such
that it reacts with one or both isocyanate end caps of the
isocyanate capped first macrodiol. Depending on the relative ratios
of DI, M1 and M2, this step may be used to create structures (among
other statistical possibilities) such as M2-DI-M1-DI-M2 (for a
DI:M1:M2 ratio of 2:1:2), M2-DI-M1-DI (for a DI:M1:M2 ratio of
2:1:1), or M1-DI-M2 (for a DI:M1:M2 ratio of 1:1:1).
[0047] In certain embodiments, a mixed macrodiol prepolymer, such
as one of those in the prior paragraph, among others (e.g.,
M2-DI-M1-DI-M2, M1-DI-M2-DI-M1, DI-M1-DI-M2, etc.) is reacted
simultaneously with a diol or diamine chain extender and a
diisocyanate, as needed to maintain stoichiometry. For example, the
chain extension process may be used to create idealized structures
along the following lines, among others:
-[DI-M2-DI-M1-DI-M2-DI-CE-].sub.n,
-[DI-M1-DI-M2-DI-M1-DI-CE-].sub.n or -[DI-M1-DI-M2-DI-CE-].sub.n,
although it is again noted that the chains are not likely to be
perfectly alternating as shown.
[0048] In certain other embodiments, a mixed macrodiol prepolymer
is reacted with sufficient diisocyanate to form isocyanate end caps
for the mixed macrodiol prepolymer (e.g., yielding
DI-M2-DI-M1-DI-M2-DI, DI-M1-DI-M2-DI-M1-DI or DI-M1-DI-M2-DI, among
other possibilities). This isocyanate-end-capped mixed macrodiol
can then be reacted with a diol or diamine chain extender (and a
diisocyanate, as needed to maintain stoichiometry). For example,
the isocyanate-end-capped mixed macrodiol can be reacted with an
equimolar amount of a chain extender to yield idealized structures
of the following formulae, among others:
-[DI-M2-DI-M1-DI-M2-DI-CE-].sub.n,
-[DI-M1-DI-M2-DI-M1-DI-CE-].sub.n or
-[DI-M1-DI-M2-DI-CE-].sub.n.
[0049] As noted above, in some embodiments of the invention,
urethane, urea and urethane/urea molecules having alkyl-, alkenyl-
or alkynyl-chain-containing end groups such as
[--CH.sub.2].sub.n--CH.sub.3 or [--CH.sub.2].sub.n--CF.sub.3 or
[--CH.sub.2].sub.n--C.sub.6H.sub.5 end groups, among many others,
are formed. For example, such polymers may be formed by reacting a
urethane, urea or urethane/urea copolymer such as one of those
described above with a molecule of the formula
HO[--CH.sub.2].sub.n--CH.sub.3 or of the formula
[0050] HO[--CH.sub.2].sub.n--CF.sub.3 or of the formula
HO[--CH.sub.2].sub.n--C.sub.6H.sub.5, preferably after ensuring
that the urethane, urea or urethane/urea copolymer is provided with
isocyanate end caps.
[0051] In accordance with various aspects of the invention,
implantable and insertable medical devices are provided, which
contain one or more polymeric regions containing one or more
polyisobutylene urethane, urea or urethane/urea copolymers. As used
herein, a "polymeric region" is a region (e.g., an entire device, a
device component, a device coating layer, etc.) that contains
polymers, for example, from 50 wt % or less to 75 wt % to 90 wt %
to 95 wt % to 97.5 wt % to 99 wt % or more polymers.
[0052] Examples of medical devices for the practice of the present
invention include implantable or insertable medical devices, for
example, implantable electrical stimulation systems including
neurostimulation systems such as spinal cord stimulation (SCS)
systems, deep brain stimulation (DBS) systems, peripheral nerve
stimulation (PNS) systems, gastric nerve stimulation systems,
cochlear implant systems, and retinal implant systems, among
others, and cardiac systems including implantable pacemaker
systems, implantable cardioverter-defibrillators (ICD's), and
cardiac resynchronization and defibrillation (CRDT) devices,
including polymeric components for leads including lead insulation,
outer body insulation, and components for the foregoing implantable
electrical stimulation systems, stents (including coronary vascular
stents, peripheral vascular stents, cerebral, urethral, ureteral,
biliary, tracheal, gastrointestinal and esophageal stents), stent
coverings, stent grafts, vascular grafts, valves including heart
valves and vascular valves, abdominal aortic aneurysm (AAA) devices
(e.g., AAA stents, AAA grafts, etc.), vascular access ports,
dialysis ports, embolization devices including cerebral aneurysm
filler coils (including Guglilmi detachable coils and metal coils),
embolic agents, tissue bulking devices, catheters (e.g., renal or
vascular catheters such as balloon catheters and various central
venous catheters), guide wires, balloons, filters (e.g., vena cava
filters and mesh filters for distil protection devices), septal
defect closure devices, myocardial plugs, patches, ventricular
assist devices including left ventricular assist hearts and pumps,
total artificial hearts, shunts, anastomosis clips and rings, and
tissue engineering scaffolds for cartilage, bone, skin and other in
vivo tissue regeneration, urethral slings, hernia "meshes",
artificial ligaments, orthopedic prosthesis, dental implants,
biopsy devices, as well as any coated substrate (which can
comprise, for example, metals, polymers, ceramics and combinations
thereof) that is implanted or inserted into the body.
[0053] In some embodiments, the polymeric regions of the present
invention correspond to an entire medical device. In other
embodiments, the polymeric regions correspond to one or more
portions of a medical device. For instance, the polymeric regions
can be in the form of medical device components, in the form of one
or more fibers which are incorporated into a medical device, in the
form of one or more polymeric layers formed over all or only a
portion of an underlying substrate, and so forth. Materials for use
as underlying medical device substrates include ceramic, metallic
and polymeric substrates. Layers can be provided over an underlying
substrate at a variety of locations and in a variety of shapes
(e.g., in the form of a series of rectangles, stripes, or any other
continuous or non-continuous pattern). As used herein a "layer" of
a given material is a region of that material whose thickness is
small compared to both its length and width. As used herein a layer
need not be planar, for example, taking on the contours of an
underlying substrate. Layers can be discontinuous (e.g.,
patterned).
[0054] In certain preferred embodiments, polyisobutylene urethane,
urea and urethane/urea copolymers in accordance with the present
invention may be used to form inner or outer coatings for
implantable electrical leads, may be used to form lead body
components (e.g., seal O-rings, etc.), or may be used to form
polymeric components of pacemakers, defibrillators or heart failure
devices, among many other applications.
[0055] In addition to one or more polymers, the polymeric regions
for use in the medical devices of the present invention may
optionally contain one or more supplemental agents.
[0056] For example, in some embodiments, an organically modified
silicate is blended with the polymers forming the polymeric region
as a supplemental agent. Such an agent may act to create a tortuous
pathway for moisture thereby decreasing the moisture permeability
of the region. Moreover, such silicates may maintain the strength
and increase the modulus of the material. Supplemental agents
further include agents such as alumina, silver nanoparticles, and
silicate/alumina/silver nanoparticle composites.
[0057] In some embodiments, one or more therapeutic agents are
included beneath, within (e.g., blended with), or attached to
(e.g., covalently or non-covalently bound to) polymeric regions in
accordance with the invention. "Therapeutic agents," "drugs,"
"pharmaceutically active agents," "pharmaceutically active
materials," and other related terms may be used interchangeably
herein.
[0058] A wide variety of therapeutic agents can be employed in
conjunction with the present invention including those used for the
treatment of a wide variety of diseases and conditions (i.e., the
prevention of a disease or condition, the reduction or elimination
of symptoms associated with a disease or condition, or the
substantial or complete elimination of a disease or condition).
[0059] Exemplary therapeutic agents for use in conjunction with the
present invention include the following: (a) anti-thrombotic agents
such as heparin, heparin derivatives, urokinase, clopidogrel, and
PPack (dextrophenylalanine proline arginine chloromethylketone);
(b) anti-inflammatory agents such as dexamethasone, prednisolone,
corticosterone, budesonide, estrogen, sulfasalazine and mesalamine;
(c) antineoplastic/antiproliferative/anti-miotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin, angiopeptin, monoclonal
antibodies capable of blocking smooth muscle cell proliferation,
and thymidine kinase inhibitors; (d) anesthetic agents such as
lidocaine, bupivacaine and ropivacaine; (e) anti-coagulants such as
D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing
compound, heparin, hirudin, antithrombin compounds, platelet
receptor antagonists, anti-thrombin antibodies, anti-platelet
receptor antibodies, aspirin, prostaglandin inhibitors, platelet
inhibitors and tick antiplatelet peptides; (f) vascular cell growth
promoters such as growth factors, transcriptional activators, and
translational promotors; (g) vascular cell growth inhibitors such
as growth factor inhibitors, growth factor receptor antagonists,
transcriptional repressors, translational repressors, replication
inhibitors, inhibitory antibodies, antibodies directed against
growth factors, bifunctional molecules consisting of a growth
factor and a cytotoxin, bifunctional molecules consisting of an
antibody and a cytotoxin; (h) protein kinase and tyrosine kinase
inhibitors (e.g., tyrphostins, genistein, quinoxalines); (i)
prostacyclin analogs; (j) cholesterol-lowering agents; (k)
angiopoietins; (l) antimicrobial agents such as triclosan,
cephalosporins, aminoglycosides and nitrofurantoin; (m) cytotoxic
agents, cytostatic agents and cell proliferation affectors; (n)
vasodilating agents; (o) agents that interfere with endogenous
vasoactive mechanisms; (p) inhibitors of leukocyte recruitment,
such as monoclonal antibodies; (q) cytokines; (r) hormones; (s)
inhibitors of HSP 90 protein (i.e., Heat Shock Protein, which is a
molecular chaperone or housekeeping protein and is needed for the
stability and function of other client proteins/signal transduction
proteins responsible for growth and survival of cells) including
geldanamycin, (t) alpha receptor antagonist (such as doxazosin,
Tamsulosin) and beta receptor agonists (such as dobutamine,
salmeterol), beta receptor antagonist (such as atenolol,
metaprolol, butoxamine), angiotensin-II receptor antagonists (such
as losartan, valsartan, irbesartan, candesartan and telmisartan),
and antispasmodic drugs (such as oxybutynin chloride, flavoxate,
tolterodine, hyoscyamine sulfate, diclomine) (u) bARKct inhibitors,
(v) phospholamban inhibitors, (w) Serca 2 gene/protein, (x) immune
response modifiers including aminoquizolines, for instance,
imidazoquinolines such as resiquimod and imiquimod, (y) human
apolioproteins (e.g., AI, AII, AIII, AIV, AV, etc.), (z) selective
estrogen receptor modulators (SERMs) such as raloxifene,
lasofoxifene, arzoxifene, miproxifene, ospemifene, PKS 3741, MF 101
and SR 16234, (aa) PPAR agonists, including PPAR-alpha, gamma and
delta agonists, such as rosiglitazone, pioglitazone, netoglitazone,
fenofibrate, bexaotene, metaglidasen, rivoglitazone and
tesaglitazar, (bb) prostaglandin E agonists, including PGE2
agonists, such as alprostadil or ONO 8815Ly, (cc) thrombin receptor
activating peptide (TRAP), (dd) vasopeptidase inhibitors including
benazepril, fosinopril, lisinopril, quinapril, ramipril, imidapril,
delapril, moexipril and spirapril, (ee) thymosin beta 4, (ff)
phospholipids including phosphorylcholine, phosphatidylinositol and
phosphatidylcholine, (gg) VLA-4 antagonists and VCAM-1 antagonists,
(hh) non-fouling, protein resistant agents such as polyethyelene
glycol and (ii) prohealing agents.
[0060] Numerous therapeutic agents, not necessarily exclusive of
those listed above, have been identified as candidates for vascular
treatment regimens, for example, as agents targeting restenosis
(antirestenotics). Such agents are useful for the practice of the
present invention and include one or more of the following: (a)
Ca-channel blockers including benzothiazapines such as diltiazem
and clentiazem, dihydropyridines such as nifedipine, amlodipine and
nicardapine, and phenylalkylamines such as verapamil, (b) serotonin
pathway modulators including: 5-HT antagonists such as ketanserin
and naftidrofuryl, as well as 5-HT uptake inhibitors such as
fluoxetine, (c) cyclic nucleotide pathway agents including
phosphodiesterase inhibitors such as cilostazole and dipyridamole,
adenylate/Guanylate cyclase stimulants such as forskolin, as well
as adenosine analogs, (d) catecholamine modulators including
.alpha.-antagonists such as prazosin and bunazosine,
.beta.-antagonists such as propranolol and
.alpha./.beta.-antagonists such as labetalol and carvedilol, (e)
endothelin receptor antagonists such as bosentan, sitaxsentan
sodium, atrasentan, endonentan, (f) nitric oxide donors/releasing
molecules including organic nitrates/nitrites such as
nitroglycerin, isosorbide dinitrate and amyl nitrite, inorganic
nitroso compounds such as sodium nitroprusside, sydnonimines such
as molsidomine and linsidomine, nonoates such as diazenium diolates
and NO adducts of alkanediamines, S-nitroso compounds including low
molecular weight compounds (e.g., S-nitroso derivatives of
captopril, glutathione and N-acetyl penicillamine) and high
molecular weight compounds (e.g., S-nitroso derivatives of
proteins, peptides, oligosaccharides, polysaccharides, synthetic
polymers/oligomers and natural polymers/oligomers), as well as
C-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds and
L-arginine, (g) Angiotensin Converting Enzyme (ACE) inhibitors such
as cilazapril, fosinopril and enalapril, (h) ATII-receptor
antagonists such as saralasin and losartin, (i) platelet adhesion
inhibitors such as albumin and polyethylene oxide, (j) platelet
aggregation inhibitors including cilostazole, aspirin and
thienopyridine (ticlopidine, clopidogrel) and GP IIb/IIIa
inhibitors such as abciximab, epitifibatide and tirofiban, (k)
coagulation pathway modulators including heparinoids such as
heparin, low molecular weight heparin, dextran sulfate and
.beta.-cyclodextrin tetradecasulfate, thrombin inhibitors such as
hirudin, hirulog, PPACK (D-phe-L-propyl-L-arg-chloromethylketone)
and argatroban, FXa inhibitors such as antistatin and TAP (tick
anticoagulant peptide), Vitamin K inhibitors such as warfarin, as
well as activated protein C, (l) cyclooxygenase pathway inhibitors
such as aspirin, ibuprofen, flurbiprofen, indomethacin and
sulfinpyrazone, (m) natural and synthetic corticosteroids such as
dexamethasone, prednisolone, methprednisolone and hydrocortisone,
(n) lipoxygenase pathway inhibitors such as nordihydroguairetic
acid and caffeic acid, (o) leukotriene receptor antagonists, (p)
antagonists of E- and P-selectins, (q) inhibitors of VCAM-1 and
ICAM-1 interactions, (r) prostaglandins and analogs thereof
including prostaglandins such as PGE1 and PGI2 and prostacyclin
analogs such as ciprostene, epoprostenol, carbacyclin, iloprost and
beraprost, (s) macrophage activation preventers including
bisphosphonates, (t) HMG-CoA reductase inhibitors such as
lovastatin, pravastatin, atorvastatin, fluvastatin, simvastatin and
cerivastatin, (u) fish oils and omega-3-fatty acids, (v)
free-radical scavengers/antioxidants such as probucol, vitamins C
and E, ebselen, trans-retinoic acid SOD (orgotein) and SOD mimics,
verteporfin, rostaporfin, AGI 1067, and M40419, (w) agents
affecting various growth factors including FGF pathway agents such
as bFGF antibodies and chimeric fusion proteins, PDGF receptor
antagonists such as trapidil, IGF pathway agents including
somatostatin analogs such as angiopeptin and ocreotide, TGF-.beta.
pathway agents such as polyanionic agents (heparin, fucoidin),
decorin, and TGF-.beta. antibodies, EGF pathway agents such as EGF
antibodies, receptor antagonists and chimeric fusion proteins,
TNF-.alpha. pathway agents such as thalidomide and analogs thereof,
Thromboxane A2 (TXA2) pathway modulators such as sulotroban,
vapiprost, dazoxiben and ridogrel, as well as protein tyrosine
kinase inhibitors such as tyrphostin, genistein and quinoxaline
derivatives, (x) matrix metalloprotease (MMP) pathway inhibitors
such as marimastat, ilomastat, metastat, batimastat, pentosan
polysulfate, rebimastat, incyclinide, apratastat, PG 116800, RO
1130830 or ABT 518, (y) cell motility inhibitors such as
cytochalasin B, (z) antiproliferative/antineoplastic agents
including antimetabolites such as purine analogs (e.g.,
6-mercaptopurine or cladribine, which is a chlorinated purine
nucleoside analog), pyrimidine analogs (e.g., cytarabine and
5-fluorouracil) and methotrexate, nitrogen mustards, alkyl
sulfonates, ethylenimines, antibiotics (e.g., daunorubicin,
doxorubicin), nitrosoureas, cisplatin, agents affecting microtubule
dynamics (e.g., vinblastine, vincristine, colchicine, Epo D,
paclitaxel and epothilone), caspase activators, proteasome
inhibitors, angiogenesis inhibitors (e.g., endostatin, angiostatin
and squalamine), olimus family drugs (e.g., sirolimus, everolimus,
tacrolimus, zotarolimus, etc.), cerivastatin, flavopiridol and
suramin, (aa) matrix deposition/organization pathway inhibitors
such as halofuginone or other quinazolinone derivatives,
pirfenidone and tranilast, (bb) endothelialization facilitators
such as VEGF and RGD peptide, (cc) blood rheology modulators such
as pentoxifylline and (dd) glucose cross-link breakers such as
alagebrium chloride (ALT-711).
[0061] Where a therapeutic agent is present, a wide range of
loadings may be used in conjunction with the medical devices of the
present invention. Typical therapeutic agent loadings range, for
example, from than 1 wt % or less to 2 wt % to 5 wt % to 10 wt % to
25 wt % or more of the polymeric region.
[0062] Numerous techniques are available for forming polymeric
regions in accordance with the present invention.
[0063] For example, where the polyisobutylene urethane, urea or
urethane/urea copolymers of the invention have thermoplastic
characteristics, a variety of standard thermoplastic processing
techniques may be used to form polymeric regions from the same.
Using these techniques, a polymeric region can be formed, for
instance, by (a) first providing a melt that contains polymer(s)
and any other optional agents such as silicates, therapeutic
agents, and so forth, and (b) subsequently cooling the melt.
Examples of thermoplastic processing techniques include compression
molding, injection molding, blow molding, spraying, vacuum forming
and calendaring, extrusion into sheets, fibers, rods, tubes and
other cross-sectional profiles of various lengths, and combinations
of these processes. Using these and other thermoplastic processing
techniques, entire devices or portions thereof can be made.
[0064] Other processing techniques besides thermoplastic processing
techniques may also be used to form the polymeric regions of the
present invention, including solvent-based techniques. Using these
techniques, polymeric regions can be formed, for instance, by (a)
first providing a solution or dispersion that contains polymer(s)
and any optional agents such as therapeutic agents, silicates and
so forth, and (b) subsequently removing the solvent. The solvent
that is ultimately selected will contain one or more solvent
species, which are generally selected based on their ability to
dissolve the polymer(s) that form the polymeric region, in addition
to other factors, including drying rate, surface tension, etc. In
certain embodiments, the solvent is selected based on its ability
to dissolve or disperse the optional agents, if any. Thus, optional
agents such as therapeutic agents, silicates, and so forth may be
dissolved or dispersed in the coating solution. Preferred
solvent-based techniques include, but are not limited to, solvent
casting techniques, spin coating techniques, web coating
techniques, spraying techniques, dipping techniques, techniques
involving coating via mechanical suspension including air
suspension, ink jet techniques, electrostatic techniques, and
combinations of these processes.
[0065] In some embodiments of the invention, a polymer containing
solution (where solvent-based processing is employed) or a polymer
containing melt (where thermoplastic processing is employed) is
applied to a substrate to form a polymeric region. For example, the
substrate can correspond to all or a portion of an implantable or
insertable medical device to which a polymeric coating is applied,
for example, by spraying, extrusion, and so forth. The substrate
can also be, for example, a template, such as a mold, from which
the polymeric region is removed after solidification. In other
embodiments, for example, extrusion and co-extrusion techniques,
one or more polymeric regions are formed without the aid of a
substrate. In a specific example, an entire medical device is
extruded. In another example, a polymeric coating layer is
co-extruded along with and underlying medical device body. In
another example, a polymeric tube is extruded which is then
assembled over a medical device substrate (e.g., on an electrical
lead, either as an electrically insulating or electrically
non-insulating jacket).
[0066] Although various embodiments are specifically illustrated
and described herein, it will be appreciated that modifications and
variations of the present invention are covered by the above
teachings and are within the purview of the appended claims without
departing from the spirit and intended scope of the invention.
* * * * *