U.S. patent application number 12/681757 was filed with the patent office on 2011-04-21 for oligofluorinated cross-linked polymers and uses thereof.
This patent application is currently assigned to Interface Biologics ,Inc.. Invention is credited to Mark J. Ernsting, Roseita Esfand, H. Hung Pham, J. Paul Santerre, Vivian Z. Wang, Meilin Yang.
Application Number | 20110091508 12/681757 |
Document ID | / |
Family ID | 40525811 |
Filed Date | 2011-04-21 |
United States Patent
Application |
20110091508 |
Kind Code |
A1 |
Esfand; Roseita ; et
al. |
April 21, 2011 |
OLIGOFLUORINATED CROSS-LINKED POLYMERS AND USES THEREOF
Abstract
The invention features oligofluorinated cross-linked polymers
and their use in the manufacture of articles and coating
surfaces.
Inventors: |
Esfand; Roseita;
(Mississauga, CA) ; Santerre; J. Paul; (Whitby,
CA) ; Ernsting; Mark J.; (Toronto, CA) ; Pham;
H. Hung; (Brampton, CA) ; Wang; Vivian Z.;
(North York, CA) ; Yang; Meilin; (Mississauga,
CA) |
Assignee: |
Interface Biologics ,Inc.
Toronto
CA
|
Family ID: |
40525811 |
Appl. No.: |
12/681757 |
Filed: |
October 2, 2008 |
PCT Filed: |
October 2, 2008 |
PCT NO: |
PCT/CA2008/001761 |
371 Date: |
January 6, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60997929 |
Oct 5, 2007 |
|
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|
Current U.S.
Class: |
424/400 ;
424/130.1; 424/278.1; 427/372.2; 514/1.1; 514/23; 514/291; 514/44R;
528/26; 528/292; 530/300; 530/391.1; 530/402; 536/123.1; 548/237;
548/954; 548/962; 549/563; 570/126 |
Current CPC
Class: |
A61P 37/02 20180101;
C09D 167/07 20130101; A61L 31/10 20130101; C09D 175/16 20130101;
A61P 35/00 20180101; A61P 31/12 20180101; A61P 7/02 20180101; C08G
18/10 20130101; C08J 2371/02 20130101; A61P 9/00 20180101; C09D
167/04 20130101; C08G 18/4854 20130101; C08G 63/912 20130101; A61P
23/00 20180101; C08G 18/2885 20130101; C08J 5/18 20130101; C08J
2367/07 20130101; C08G 63/06 20130101; A61P 3/02 20180101; A61P
29/00 20180101; C08G 18/771 20130101; A61L 31/04 20130101; A61P
25/00 20180101; C08J 2367/04 20130101; C08G 18/672 20130101 |
Class at
Publication: |
424/400 ;
570/126; 549/563; 548/954; 548/962; 548/237; 530/300; 536/123.1;
530/402; 530/391.1; 528/292; 528/26; 514/1.1; 514/23; 514/291;
424/130.1; 514/44.R; 424/278.1; 427/372.2 |
International
Class: |
A61K 9/00 20060101
A61K009/00; C07C 21/18 20060101 C07C021/18; C07D 303/08 20060101
C07D303/08; C07D 203/06 20060101 C07D203/06; C07D 403/02 20060101
C07D403/02; C07D 403/14 20060101 C07D403/14; C07D 263/08 20060101
C07D263/08; C07K 2/00 20060101 C07K002/00; C07H 99/00 20060101
C07H099/00; C07K 16/00 20060101 C07K016/00; C08G 63/88 20060101
C08G063/88; C08G 77/32 20060101 C08G077/32; A61K 38/02 20060101
A61K038/02; A61K 31/70 20060101 A61K031/70; A61K 31/436 20060101
A61K031/436; A61K 39/395 20060101 A61K039/395; A61K 31/7088
20060101 A61K031/7088; A61P 3/02 20060101 A61P003/02; A61P 35/00
20060101 A61P035/00; A61P 37/02 20060101 A61P037/02; A61P 23/00
20060101 A61P023/00; A61P 29/00 20060101 A61P029/00; A61P 7/02
20060101 A61P007/02; A61P 9/00 20060101 A61P009/00; A61P 31/12
20060101 A61P031/12; A61P 25/00 20060101 A61P025/00; B05D 3/02
20060101 B05D003/02 |
Claims
1. A monomer comprising: i. two or more cross-linking domains, and
ii. an oligomeric segment having a first end covalently tethered to
a first cross-linking domain and a second end covalently tethered
to a second cross-linking domain, wherein at least one of said
cross-linking domains is an oligofluorinated cross-linking
domain.
2. The monomer of claim 1, further described by formula (I):
(D)-[(oligo)-(D)].sub.n (I) wherein oligo is an oligomeric segment;
each D is a cross-linking domain; and n is an integer from 1 to 20,
wherein at least one D is an oligofluorinated cross-linking
domain.
3. The monomer of claim 1, further described by formula (II):
(D)-[(oligo)-(LinkA-F.sub.T)].sub.m-[(oligo)-(D)].sub.n (II)
wherein oligo is an oligomeric segment; each D is a cross-linking
domain; F.sub.T is an oligofluoro group; each LinkA-F.sub.T is an
organic moiety covalently bound to a first oligo, a second oligo,
and F.sub.T; n is an integer from 1 to 20; and m is an integer from
1 to 20, wherein at least one D is an oligofluorinated
cross-linking domain.
4. The monomer of claim 1, wherein said cross-linking domains
include a reactive moiety selected from vinyls, epoxides,
aziridines, and oxazolines.
5. The monomer of any of claims 1-4, wherein said oligofluorinated
cross-linking domain is selected from ##STR00032##
6. The monomer of claim 1, further described by formula (III):
(oligo).sub.n(vinyl).sub.m(F.sub.T).sub.o (III) wherein oligo is an
oligomeric segment; vinyl is a cross-linking domain comprising an
unsaturated moiety capable of undergoing radical initiated
polymerization; F.sub.T is an oligofluoro group covalently tethered
to said vinyl and/or said oligo; and each of n, m, and o is,
independently, an integer from 1 to 5 wherein said monomer
comprises at least one oligofluorinated cross-linking domain.
7. The monomer of claim 6, further described by formula (IV):
##STR00033## wherein oligo is an oligomeric segment; vinyl is a
cross-linking domain comprising an unsaturated moiety capable of
undergoing radical initiated polymerization; F.sub.T is an
oligofluoro group; each LinkA is, independently, an organic moiety
covalently bound to oligo, F.sub.T, and vinyl; and a, b, and c are
integers greater than 0.
8. The monomer of any of claims 3 to 7, wherein F.sub.T has the
formula: CF.sub.3(CF.sub.2).sub.pX,
(CF.sub.3).sub.2CF(CF.sub.2).sub.pX, or
(CF.sub.3).sub.3C(CF.sub.2).sub.pX, wherein X is selected from
CH.sub.2CH.sub.2--, (CH.sub.2CH.sub.2O).sub.n,
CH.sub.2CH(OD)CH.sub.2O--, CH.sub.2CH(CH.sub.2OD)O--, or D-; D is a
moiety capable of chain growth polymerization; p is an integer
between 2 and 20; and n is an integer between 1 and 10.
9. The monomer of any of claims 4-8, wherein said vinyl group is
selected from methylacrylate, acrylate, allyl, vinylpyrrolidone,
and styrene derivatives.
10. The monomer of any of claims 4-8, wherein said oligo is
selected from polyurethane, polyurea, polyamides, polyaklylene
oxide, polycarbonate, polyester, polylactone, polysilicone,
polyethersulfone, polypeptide, polysaccharide, polysiloxane,
polydimethylsiloxane, polypropylene oxide, polyethylene oxide,
polytetramethyleneoxide, and combinations thereof.
11. The monomer of any of claims 1-10, further comprising one or
more biologically active agents covalently tethered to said
monomer.
12. The monomer of claim 11, wherein said biologically active agent
is selected from proteins, peptides, carbohydrates, antibiotics,
antiproliferative agents, rapamycin macrolides, analgesics,
anesthetics, antiangiogenic agents, antithrombotic agents,
vasoactive agents, anticoagulants, immunomodulators, cytotoxic
agents, antiviral agents, antibodies, neurotransmitters,
psychoactive drugs, oligonucleotides, proteins, vitamins, lipids,
and prodrugs thereof.
13. A method for coating an article said method comprising the
steps of (a) contacting said article with a monomer of any of
claims 1-12 and (b) polymerizing said monomer to form a
cross-linked coating.
14. A method for making a shaped article said method comprising the
steps of (a) polymerizing a monomer of any of claims 1-12 to form a
base polymer and (b) shaping said base polymer to form a shaped
article.
15. The method of claim 13 or 14, wherein said shaped article is an
implantable medical device.
16. The method of claim 15, wherein said implantable medical device
is selected from cardiac-assist devices, catheters, stents,
prosthetic implants, artificial sphincters, and drug delivery
devices.
17. The implantable medical device of claim 16, wherein said
implantable medical device is a stent.
18. The method of claim 13 or 14, wherein said shaped article is a
nonimplantable medical device.
19. The method of any of claims 13-18, wherein said polymerizing is
initiated by heat, UV radiation, a photoinitiator, or a
free-radical initiator.
20. The method of claim 19, wherein said polymerizing is initiated
by heat.
21. The method of any of claims 13-18, wherein said polymerizing
further comprises mixing said monomer with a second compound
containing a vinyl group.
22. The method of claim 21, wherein said second compound is a
monomer of any of claims 1-12.
23. The method of claim 22, wherein said second vinyl monomer is
selected from acrylic acid, methyl acrylate, ethyl acrylate,
n-butyl acrylate, 2-hydroxyethyl acrylate, n-butyl acrylate,
glycidyl acrylate, vinyl acrylate, allyl acrylate, 2-hydroxyethyl
acrylate, 2-hydroxy ethyl methacrylate (HEMA), 2-amino ethyl
methacrylate, glycerol monomethacrylate, acrylamide,
methacrylamide, N-(3-aminopropyl)methacrylamide, crotonamide, allyl
alcohol, and 1,1,1-trimethylpropane monoallyl ether.
24. A method for encapsulating a biologically active agent in a
polymer, said method comprising (a) contacting a biologically
active agent with a monomer of any of claims 1-12 and (b)
polymerizing said monomer to form an oligofluorinated cross-linked
polymer.
25. The method of claim 24, wherein said biologically active agent
is selected from proteins, peptides, carbohydrates, antibiotics,
antiproliferative agents, rapamycin macrolides, analgesics,
anesthetics, antiangiogenic agents, antithrombotic agents,
vasoactive agents, anticoagulants, immunomodulators, cytotoxic
agents, antiviral agents, antibodies, neurotransmitters,
psychoactive drugs, oligonucleotides, vitamins, lipids, and
prodrugs thereof.
26. A composition comprising: (i) a first component having a core
substituted with m nucleophilic groups, where m.gtoreq.2; and a
second component having a core substituted with n electrophilic
groups, where n.gtoreq.12 and m+n>4; wherein the composistion
comprises at least one oligofluorinated nucleophilic group or one
oligofluorinated electrophilic group, and wherein the first
component and the second component react to form oligofluorinated
cross-linked polymer.
27. The composition of claim 26, wherein said first component
comprises an oligomeric segment having a first end covalently
tethered to a first nucleophilic group and a second end covalently
tethered to a second nucleophilic group, wherein said first
nucleophilic group or said second nucleophilic group is an
oligofluorinated nucleophilic group.
28. The composition of claim 26, wherein said second component
comprises an oligomeric segment having a first end covalently
tethered to a first electrophilic group and a second end covalently
tethered to a second electrophilic group, wherein said first
electrophilic group or said second electrophilic group is an
oligofluorinated nucleophilic group.
29. The composition of claim 26, wherein said first component or
said second component is further described by formula (V):
(G)-[(oligo)-(G)].sub.n (V) wherein oligo is an oligomeric segment;
G is either a nucleophilic group or an electrophilic group; and n
is an integer from 1 to 5, wherein at least one G is an
oligofluorinated nucleophilic group or oligofluorinated
electroophilic group.
30. The composition of claim 26, wherein said first component or
said second component is further described by formula (VI):
##STR00034## wherein oligo is an oligomeric segment; G is either a
nucleophilic group or an electrophilic group; F.sub.T is an
oligofluoro group; each LinkA is, independently, an organic moiety
covalently bound to oligo, F.sub.T, and G; and a, b, and c are
integers greater than 0.
31. The composition of claim 30, wherein F.sub.T has the formula:
CF.sub.3(CF.sub.2).sub.pX, (CF.sub.3).sub.2CF(CF.sub.2).sub.pX, or
(CF.sub.3).sub.3C(CF.sub.2).sub.pX, wherein X is selected from
CH.sub.2CH.sub.2--, (CH.sub.2CH.sub.2O).sub.n,
CH.sub.2CH(OD)CH.sub.2O--, CH.sub.2CH(CH.sub.2OD)O--, or D-; D is a
moiety capable of chain growth polymerization; p is an integer
between 2 and 20; and n is an integer between 1 and 10.
32. The composition of any of claims 26 to 31, wherein said
nucleophilic groups and said electrophilic groups undergo a
nucleophilic substitution reaction, a nucleophilic addition
reaction, or both.
33. The composition of claim 32, wherein the nucleophilic groups
are selected from primary amines, secondary amines, thiols,
alcohols, and phenols.
34. The composition of claim 32, wherein the electrophilic groups
are selected from carboxylic acid esters, acid chloride groups,
anhydrides, isocyanato, thioisocyanato, epoxides, activated
hydroxyl groups, succinimidyl ester, sulfosuccinimidyl ester,
maleimido, and ethenesulfonyl.
35. The composition of claim 26, wherein the number of nucleophilic
groups in the mixture is approximately equal to the number of
electrophilic groups in the mixture.
36. The composition of claim 35, wherein the ratio of moles of
nucleophilic groups to moles of electrophilic groups is about 2:1
to 1:2.
37. The composition of claim 36, wherein the ratio is 1:1.
38. A method for coating an article said method comprising the
steps of (a) contacting said article with a composition of any of
claims 26-37; and (b) polymerizing said composition on said article
to form a cross-linked coating.
39. A method for making a shaped article said method comprising the
steps of (a) polymerizing a composition of any of claims 26-37 to
form a base polymer and (b) shaping said base polymer to form a
shaped article.
40. The method of claim 38 or 39, wherein said article is an
implantable medical device.
41. The method of claim 40, wherein said implantable medical device
is selected from cardiac-assist devices, catheters, stents,
prosthetic implants, artificial sphincters, and drug delivery
devices.
42. The method of claim 41, wherein said implantable medical device
is a stent.
43. The method of claim 38 or 39, wherein said article is a
nonimplantable medical device.
44. A method for coating a stent comprising initiating a
polymerization reaction on the surface of said stent to form a
polymerized coating.
45. The method of claim 44, wherein said polymerized coating is a
cross-linked polymer coating.
46. The method of claim 45, wherein said polymerized coating is an
oligofluorinated cross-linked polymer coating.
47. The method of claim 44, wherein said polymerization reaction is
a chain growth polymerization reaction.
48. The method of claim 44, wherein said polymerization reaction is
a nucleophilic substitution reaction and/or a nucleophilic addition
reaction.
49. The method of any of claims 44-48, comprising the steps of (a)
contacting said stent with a monomer of any of claims 1-12 or a
composition of any of claims 26-36; and (b) polymerizing said
monomer or polymerizing said composition to form a cross-linked
coating.
50. The method of claim 13 or 38, wherein an uncoated implantable
medical device is coated to produce a coated implantable medical
device, said coated implantable medical device having, upon
implantation into an animal, reduced protein deposition, reduced
fibrinogene deposition, reduced platelet deposition, or reduced
inflammatory cell adhesion in comparison to said uncoated
implantable medical device.
Description
BACKGROUND OF THE INVENTION
[0001] The invention features oligofluorinated cross-linked
polymers. Once cured, the oligofluorinated cross-linked polymers
are useful as a base polymer in the manufacture of articles or as a
fluorinated coating.
[0002] Polymeric materials have been widely used for the
manufacturing of medical devices, such as artificial organs,
implants, medical devices, vascular prostheses, blood pumps,
artificial kidneys, heart valves, pacemaker lead wire insulation,
intra-aortic balloons, artificial hearts, dialyzers and plasma
separators, among others. The polymer used within a medical device
must be biocompatible (e.g., must not produce toxic, allergic,
inflammatory reactions, or other adverse reactions). It is the
physical, chemical and biological processes at the interface,
between the biological system and the synthetic materials used,
which defines the short- and long-term potential applications of a
particular device.
[0003] In general, the exact profile of biocompatibility,
biodegradation and physical stability, including chemical and
physical/mechanical properties i.e., elasticity, stress, ductility,
toughness, time dependent deformation, strength, fatigue, hardness,
wear resistance, and transparency for a biomaterial are extremely
variable. A wide variety of polymers (including polycondensates,
polyolefins, polyvinyls, polypeptides, and polysaccharides, among
others) have been employed in the manufacture of biomedical
devices, drug delivery vehicles, and affinity chromatography
systems. Polymers are selected for the characteristics that make
them useful in any given application.
[0004] Fluoropolymers are generally hydrolytically stable and are
resistant to destructive chemical environments. In addition they
are biocompatible and have been used as components of medical
devices. The combination of chemical inertness, low surface energy,
antifouling properties, hydrophobicity, thermal and oxidative
stability have enabled a great diversity of application for these
materials. Fluoropolymers have been prepared from
tetrafluoroethylene, via chain growth polymerization reactions, and
other fluorinated derivatives, via step growth polymerization
reactions producing infinite network fluoropolymers. A challenge
for the use of these polymers in certain applications is the
processing limitation of working with solid material including,
(e.g., fluorinated polyetherurethanes, made from polyether glycols,
isocyanates, chain extenders and non-fluorinated polyols) rather
than fluids, of which the latter are easily applied into molds or
onto surfaces. The problem is even more difficult and almost
impossible to manage when the above needs to be cross linked for
specific applications. The demand and need for practical
fluoropolymers with specific chemical and physical properties has
directed the molecular design and development of new fluorinated
monomers
[0005] There exists a need for co-polymer systems, which can be
designed to provide the above characteristics that are needed for a
variety of applications, including those in the biomedical
field.
SUMMARY OF THE INVENTION
[0006] The invention features oligofluorinated cross-linked
polymers. Once cured, the oligofluorinated cross-linked polymer is
useful as a base polymer in the manufacture of articles or as an
oligofluorinated coating. The coatings of the invention can also be
used to encapsulate therapeutic agents.
[0007] Accordingly, in a first aspect the invention features a
monomer including (i) two or more cross-linking domains, and (ii)
an oligomeric segment having a first end covalently tethered to a
first cross-linking domain and a second end covalently tethered to
a second cross-linking domain, wherein at least one of the
cross-linking domains is an oligofluorinated cross-linking
domain.
[0008] In certain embodiments, the monomer is further described by
formula (I):
(D)-[(oligo)-(D)].sub.n (I)
In formula (I) oligo is an oligomeric segment; each D is a
cross-linking domain; and n is an integer from 1 to 20, 1 to 15, 1
to 10, 1 to 8, or even 1 to 5, and wherein at least one D is an
oligofluorinated cross-linking domain.
[0009] In other embodiments, the monomer is further described by
formula (II):
(D)-[(oligo)-(LinkA-F.sub.T)].sub.m[(oligo)-(D)].sub.n (II)
In formula (II) oligo is an oligomeric segment; each D is a
cross-linking domain; F.sub.T is an oligofluoro group; each
LinkA-F.sub.T is an organic moiety covalently bound to a first
oligo, a second oligo, and F.sub.T; n is an integer from 1 to 20;
and m is an integer from 1 to 20, wherein at least one D is an
oligofluorinated cross-linking domain.
[0010] Cross-linking domains which can be used in the compositions
of the invention include a reactive moiety that capable of chain
growth polymerization, such as, without limitation, vinyls,
epoxides, aziridines, and oxazolines.
[0011] In still other embodiments, the oligofluorinated
cross-linking domain is selected from
##STR00001##
[0012] In certain embodiments, the monomer is further described by
formula (III):
(oligo).sub.n(vinyl).sub.m(F.sub.T).sub.o (III)
In formula (III) oligo is an oligomeric segment; vinyl is a
cross-linking domain including an unsaturated moiety capable of
undergoing radical initiated polymerization; F.sub.T is an
oligofluoro group covalently tethered to the vinyl and/or the
oligo; and each of n, m, and o is, independently, an integer from 1
to 5, wherein the monomer includes at least one oligofluorinated
cross-linking domain. The monomer of formula (III) may further be
described by formula (IV):
##STR00002##
In formula (IV) oligo is an oligomeric segment; vinyl is a
cross-linking domain including an unsaturated moiety capable of
undergoing radical initiated polymerization; F.sub.T is an
oligofluoro group; each LinkA is, independently, an organic moiety
covalently bound to oligo, F.sub.T, and vinyl; and a, b, and c are
integers greater than 0.
[0013] In certain embodiments, the monomers of the invention
include one or more biologically active agents covalently tethered
to the monomer.
[0014] In a related aspect, the invention features a method for
coating an article by (a) contacting the article with a monomer of
the invention and (b) polymerizing the monomer to form a
cross-linked coating.
[0015] In another aspect the invention features a method for making
a shaped article by (a) polymerizing a monomer of the invention to
form a base polymer and (b) shaping the base polymer to form a
shaped article.
[0016] In certain embodiments, the shaped article is an implantable
medical device, such as, without limitation, cardiac-assist
devices, catheters, stents, prosthetic implants, artificial
sphincters, or drug delivery devices. In other embodiments the
shaped article is a nonimplantable medical device.
[0017] The polymerization step resulting in an oligofluorinated
cross-linked polymer of the invention can be initiated, for
example, using heat, UV radiation, a photoinitiator, or a
free-radical initiator. Desirably, the polymerization is initiated
by heat.
[0018] In certain embodiments, the step of polymerizing further
includes mixing the monomer of the invention with a second compound
containing a vinyl group. The second compound can be another
monomer of the invention or a nonfluorinated vinyl compound, such
as acrylic acid, methyl acrylate, ethyl acrylate, n-butyl acrylate,
2-hydroxyethyl acrylate, n-butyl acrylate, glycidyl acrylate, vinyl
acrylate, allyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxy ethyl
methacrylate (HEMA), 2-amino ethyl methacrylate, glycerol
monomethacrylate, acrylamide, methacrylamide, N-(3-aminopropyl)
methacrylamide, crotonamide, allyl alcohol, or
1,1,1-trimethylpropane monoallyl ether.
[0019] The invention also features a method for encapsulating a
biologically active agent in a polymer by (a) contacting a
biologically active agent with a monomer of the invention and (b)
polymerizing the monomer to form an oligofluorinated cross-linked
polymer.
[0020] The invention further features a composition including: (i)
a first component having a core substituted with m nucleophilic
groups, where m.gtoreq.2; and a second component having a core
substituted with n electrophilic groups, where m.gtoreq.2 and
m+n>4; wherein the composition includes at least one
oligofluorinated nucleophilic group or one oligofluorinated
electrophilic group, and wherein the first component and the second
component react to form oligofluorinated cross-linked polymer.
[0021] In certain embodiments, the first component includes an
oligomeric segment having a first end covalently tethered to a
first nucleophilic group and a second end covalently tethered to a
second nucleophilic group, wherein the first nucleophilic group or
the second nucleophilic group is an oligofluorinated nucleophilic
group. In other embodiments, the second component includes an
oligomeric segment having a first end covalently tethered to a
first electrophilic group and a second end covalently tethered to a
second electrophilic group, wherein the first electrophilic group
or the second electrophilic group is an oligofluorinated
electrophilic group.
[0022] In still other embodiments, the first component or the
second component is further described by formula (V):
(G)-[(oligo)-(G)].sub.n (V)
In formula (V) oligo is an oligomeric segment; G is either a
nucleophilic group or an electrophilic group; and n is an integer
from 1 to 5, wherein at least one G is an oligofluorinated
nucleophilic group or oligofluorinated electroophilic group.
[0023] In another embodiment, the first component or the second
component is further described by formula (VI):
##STR00003##
In formula (VI) oligo is an oligomeric segment; G is either a
nucleophilic group or an electrophilic group; F.sub.T is an
oligofluoro group; each LinkA is, independently, an organic moiety
covalently bound to oligo, F.sub.T, and G; and a, b, and c are
integers greater than 0.
[0024] In the above aspect, the nucleophilic groups and the
electrophilic groups undergo a nucleophilic substitution reaction,
a nucleophilic addition reaction, or both upon mixing. The
nucleophilic groups can be selected from, without limitation,
primary amines, secondary amines, thiols, alcohols, and phenols.
The electrophilic groups can be selected from, without limitation,
carboxylic acid esters, acid chloride groups, anhydrides,
isocyanato, thioisocyanato, epoxides, activated hydroxyl groups,
succinimidyl ester, sulfosuccinimidyl ester, maleimido, and
ethenesulfonyl. Desirably, the number of nucleophilic groups in the
mixture is approximately equal to the number of electrophilic
groups in the mixture (i.e., the ratio of moles of nucleophilic
groups to moles of electrophilic groups is about 2:1 to 1:2, or
even about 1:1).
[0025] In a related aspect, the invention features a method for
coating a substrate by (a) contacting the substrate with a
composition of the invention and (b) polymerizing the composition
on the substrate to form a cross-linked coating.
[0026] The invention also features a method for making a shaped
article by (a) polymerizing a composition of the invention to form
a base polymer and (b) shaping the base polymer to form a shaped
article.
[0027] In certain embodiments, the substrate is an implantable
medical device, such as, without limitation, cardiac-assist
devices, catheters, stents, prosthetic implants, artificial
sphincters, or drug delivery devices. In other embodiments the
shaped article is a nonimplantable medical device.
[0028] In any of the above methods or compositions, the oligofluoro
groups can be selected from, without limitation, groups having the
formula:
CF.sub.3(CF.sub.2).sub.pX, (CF.sub.3).sub.2CF(CF.sub.2).sub.pX, or
(CF.sub.3).sub.3C(CF.sub.2).sub.pX,
wherein X is selected from CH.sub.2CH.sub.2--,
(CH.sub.2CH.sub.2O).sub.n, CH.sub.2CH(OD)CH.sub.2O--,
CH.sub.2CH(CH.sub.2OD)O--, or D-; D is a moiety capable of chain
growth polymerization; p is an integer between 2 and 20; and n is
an integer between 1 and 10.
[0029] In any of the above methods or compositions, the vinyl group
can be selected, without limitation, from methylacrylate, acrylate,
allyl, vinylpyrrolidone, and styrene derivatives.
[0030] In any of the above methods or compositions, the oligo can
be selected, without limitation, from polyurethane, polyurea,
polyamides, polyaklylene oxide, polycarbonate, polyester,
polylactone, polysilicone, polyethersulfone, polypeptide,
polysaccharide, polysiloxane, polydimethylsiloxane, polypropylene
oxide, polyethylene oxide, polytetramethyleneoxide, and
combinations thereof.
[0031] In any of the above methods or compositions, the
biologically active agent can be selected, without limitation, from
proteins, peptides, carbohydrates, antibiotics, antiproliferative
agents, rapamycin macrolides, analgesics, anesthetics,
antiangiogenic agents, antithrombotic agents, vasoactive agents,
anticoagulants, immunomodulators, cytotoxic agents, antiviral
agents, antibodies, neurotransmitters, psychoactive drugs,
oligonucleotides, proteins, vitamins, lipids, and prodrugs thereof.
The biologically active agent can be any biologically active agent
described herein.
[0032] The invention also features a method for coating a stent
including initiating a polymerization reaction on the surface of
the stent to form a polymerized coating. In certain embodiments,
the polymerized coating is a cross-linked polymer coating, such as
an oligofluorinated cross-linked polymer coating. The
polymerization reaction can be, for example, a chain growth
polymerization reaction, a nucleophilic substitution reaction, or a
nucleophilic addition reaction. In certain embodiments, the method
includes (a) contacting the stent with a monomer of the invention
or a composition of the invention; and (b) polymerizing the monomer
or polymerizing the composition to form a cross-linked coating.
[0033] In any of the above methods, an uncoated implantable medical
device can be coated to produce a coated implantable medical
device, the coated implantable medical device having, upon
implantation into an animal, reduced protein deposition, reduced
fibrinogene deposition, reduced platelet deposition, or reduced
inflammatory cell adhesion in comparison to the uncoated
implantable medical device.
[0034] By "base polymer" is meant a polymer having a tensile
strength of from about 350 to about 10,000 psi, elongation at break
from about 5%, 25%, 100%, or 300% to about 1500%, an unsupported
thickness of from about 5 to about 100 microns, and a supported
thickness of from about 1 to about 100 microns.
[0035] By "biologically active agent" is meant a compound, be it
naturally-occurring or artificially-derived, that is encapsulated
in a oligofluorinated cross-linked polymer of the invention and
which may be released and delivered to a specific site (e.g., the
site at which a medical device is implanted). Biologically active
agents may include, for example, peptides, proteins, synthetic
organic molecules, naturally occurring organic molecules, nucleic
acid molecules, and components thereof. Desirably, the biologically
active agent is a compound useful for the therapeutic treatment of
a plant or animal when delivered to a site of diseased tissue.
Alternatively, the biologically active agent can be selected to
impart non-therapeutic functionality to a surface. Such agents
include, for example, pesticides, bactericides, fungicides,
fragrances, and dyes.
[0036] As used herein, "covalently tethered" refers to moieties
separated by one or more covalent bonds. For example, where an
oligofluoro group is covalently tethered to a cross-linking domain,
tethered includes the moieties separated by a single bond as well
as both moieties separated by, for example, a LinkA segment to
which both moieties are covalently attached.
[0037] As used herein, "LinkA" refers to a coupling segment capable
of covalently linking a cross-linking domain, an oligo segment, and
an oligofluoro group. Typically, LinkA molecules have molecular
weights ranging from 40 to 700. Preferably the LinkA molecules are
selected from the group of functionalized diamines, diisocyanates,
disulfonic acids, dicarboxylic acids, diacid chlorides and
dialdehydes, wherein the functionalized component has secondary
functional chemistry that is accessed for chemical attachment of an
oligofluoro group or a vinyl group. Such secondary groups include,
for example, esters, carboxylic acid salts, sulfonic acid salts,
phosphonic acid salts, thiols, vinyls and secondary amines.
Terminal hydroxyls, amines or carboxylic acids on the oligo
intermediates can react with diamines to form oligo-amides; react
with diisocyanates to form oligo-urethanes, oligo-ureas,
oligo-amides; react with disulfonic acids to form oligo-sulfonates,
oligo-sulfonamides; react with dicarboxylic acids to form
oligo-esters, oligo-amides; react with diacid chlorides to form
oligo-esters, oligo-amides; and react with dialdehydes to form
oligo-acetal or oligo-imines. It should be noted that in any of the
above cases one of the functional groups of LinkA, e.g., primary
groups of a diamine, could be substituted for another functional
group such that the LinkA would be, e.g., a hetero functional
molecule (such as with an amine and a carboxylic acid as the
primary groups) having a primary and a secondary functional
chemistry.
[0038] By "oligo" or "oligo segment" is meant a non-fluorinated
relatively short length of a repeating unit or units, generally
less than about 50 monomeric units and molecular weights less than
10,000, but preferably <5000, and most preferably between 50 and
5,000 Daltons or between 100 and 5,000 Daltons. Preferably, oligo
is selected from the group consisting of polyurethane, polyurea,
polyamides, polyalkylene oxide, polycarbonate, polyester,
polylactone, polysilicone, polyethersulfone, polyolefin, polyvinyl,
polypeptide, polysaccharide; and ether and amine linked segments
thereof. Alternatively, the oligo segment is as small as
ethylenediamine.
[0039] By "oligofluorinated nucleophilic group" is meant a
nucleophile covalently tethered to an oligofluoro group and
separated by fewer than 25, 22, 18, or even 15 covalent bonds.
Nucleophiles that can be used in the methods and compositions of
the invention include, without limitation, amines, and thiols.
[0040] By "oligofluorinated electrophilic group" is meant an
electrophile covalently tethered to an oligofluoro group and
separated by fewer than 25, 22, 18, or even 15 covalent bonds.
Electrophiles that can be used in the methods and compositions of
the invention include, without limitation, activated acids, epoxy
groups, and isocyanates.
[0041] By "oligofluorinated cross-linking domain" is meant a
cross-linking domain covalently tethered to an oligofluoro group
and separated by fewer than 25, 22, 18, or even 15 covalent bonds.
The oligofluorinated cross-linked polymers of the invention can be
formed from a monomer which contains at least one oligofluorinated
cross-linking domain.
[0042] By "oligofluorinated cross-linked polymer" is meant a
cross-linked polymer including an oligomeric segment and pendant
oligofluoro groups.
[0043] By "cross-linking domain" is meant a moiety capable of
forming covalent linkages via chain growth polymerization
reactions. Chain growth polymerization reactions are reactions in
which unsaturated monomer molecules add on to a growing polymer
chain one at a time, as provided in the following equation:
##STR00004##
Cross-linking domains can be designed to undergo radical initiated
chain polymerization (i.e., in the polymerization of vinyl groups
to produce polyvinyl), cationic chain growth polymerization
reactions (i.e., cationic ring-opening polymerization, such as in
the polymerization of epoxides to produce polyethers, and
oxazolines to produce acylated polyamines), and anionic chain
growth polymerization reactions (i.e., anionic ring-opening
polymerization, such as in the polymerization of epoxides to
produce polyethers, and N-methanesulfonyl-2-methylaziridine to
produce polyamines).
[0044] By "vinyl monomer" is meant an oligo segment covalently
tethered to two or more vinyl groups capable of undergoing radical
initiated polymerization, wherein at least one vinyl group is
contained within an oligofluorinated cross-linking domain.
[0045] Other features and advantages of the invention will be
apparent from the following Detailed Description, the Drawings, and
the Claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0046] FIG. 1 is an image of a UV cured film of Compound 2, with
tensile testing articles punched out, showing Compound 2 processing
capability.
[0047] FIG. 2 is an image of a heat cured film of Compound 2,
demonstrating Compound 2 processing capability.
[0048] FIG. 3 is an image of heat cured shaped articles of Compound
2, showing how an article can be made from Compound 2.
[0049] FIG. 4 is an image of a heat cured film of Compound 6,
demonstrating Compound 6 processing capability.
[0050] FIG. 5 is two SEM images of heat cured films of Compound 6,
before and after toluene extraction, showing the final product
properties to remain intact.
[0051] FIG. 6 is an image of a heat cured film of Compound 12,
demonstrating Compound 12 processing capability.
[0052] FIG. 7 is an image of a heat cured film of Compound 2 and
Compound 6, showing Compound 2 and Compound 6 processing
capability.
[0053] FIG. 8 is an image of a heat cured film of Compound 6 and
Compound 8, showing Compound 6 and Compound 8 processing
capability.
[0054] FIG. 9 is an image of a heat cured film of Compound 6 and
FEO1, demonstrating Compound 6 processing capability.
[0055] FIG. 10 is an image of a heat cured film of Compound 6 and
HEMA, showing Compound 6 processing capability.
[0056] FIG. 11 is an image of a stent coated with heat cured
Compound 2, showing good coverage with minimal webbing.
[0057] FIG. 12 is an image of an air-deployed stent, coated with
heat cured Compound 2, showing good coverage with minimal
webbing.
[0058] FIG. 13 is an image of a stent coated with heat cured
Compound 6, demonstrating good coverage with minimal webbing.
[0059] FIG. 14 is an image of a stent coated with heat cured
Compound 6, extracted with toluene, demonstrating the final product
properties to remain intact.
[0060] FIG. 15 is an image of a stent coated with heat cured
Compound 6, extracted with buffer, showing the final product
properties to remain intact.
[0061] FIG. 16 is an image of a stent coated with heat cured
Compound 8, demonstrating good coverage with minimal webbing.
[0062] FIG. 17 is an image of a stent coated with heat cured
Compound 12 (toluene solvent), showing good coverage with minimal
webbing.
[0063] FIG. 18 is an image of a stent coated with heat cured
Compound 12 (toluene:THF solvent), showing good coverage with
minimal webbing.
[0064] FIG. 19 is an image of a stent coated with heat cured
Compound 2 and Compound 6, showing good coverage with minimal
webbing.
[0065] FIG. 20 is an image of a stent coated with heat cured
Compound 6 and Compound 8, showing good coverage with minimal
webbing.
[0066] FIG. 21 is an image of a stent coated with heat cured
Compound 6 and PTX, showing good coverage with minimal webbing.
[0067] FIG. 22 is a plot of ASA release from a UV cured film of
Compound 2 with 10 wt % ASA, showing the release of ASA from
Compound 2.
[0068] FIG. 23 is a plot of ASA release from a UV cured film of
Compound 2 with 25 wt % ASA, showing the ability of ASA to be
released from Compound 2.
[0069] FIG. 24 is a plot of ibuprofen release from a heat cured
film of Compound 2, demonstrating the ability of ibuprofen to be
released from Compound 2.
[0070] FIG. 25 is a plot of hydrocortisone and dexamethasone
release from heat cured films of Compound 6, demonstrating the
ability to release drugs from Compound 6.
[0071] FIG. 26 is an image of a stent coated with heat cured
Compound 6 with 1 wt % hydrocortisone, showing good coverage.
[0072] FIG. 27 is a plot of U937 adhesion to cured films of
Compounds 2, 6, 8, and 12, cast on PP, demonstrating a significant
reduction in cell adhesion profile.
[0073] FIG. 28 is is a plot of U937 adhesion to cured films of
Compounds 2, 6, 8, and 12, cast on stainless steel, demonstrating a
substantial reduction in cell adhesion profile.
[0074] FIG. 29 is a plot of platelet and fibrinogen interaction
with cured films of Compounds 2 and 6, showing a significant
reduction in platelet adhesion and fibrinogen adsorption.
DETAILED DESCRIPTION
[0075] The invention features oligofluorinated cross-linked
polymers. Once cured, the oligofluorinated cross-linked polymer is
useful as a base polymer in the manufacture of articles or as an
oligofluorinated coating. In certain embodiments, the
oligofluorinated cross-linked polymer is formed from a combination
of both chain growth and step growth polymerization reactions. The
coatings of the invention can also be used to encapsulate
therapeutic agents.
[0076] The oligofluorinated cross-linked polymers of the invention
can be produced via chain growth polymerization reactions,
nucleophilic substitution reactions, and/or a nucleophilic addition
reactions. Regardless of how the oligofluorinated cross-linked
polymer is produced, the resulting polymer will include pendant
oligofluoro groups, an oligomeric segment, and, optionally, LinkA
groups (used to covalently tether the various components
together).
[0077] The quality and performance of the oligofluorinated
cross-linked polymers can be varied depending upon the chemical
composition and cured characteristics of polymerization step.
Desirably, the precursor monomers materials exhibit high
reactivity, resulting in efficient curing and fast curing kinetics.
The oligofluorinated cross-linked polymers of the invention can be
designed to result in a wide variety of desired mechanical
properties, release profiles (where a biologically active agent is
incorporated), and reduced protein and cell interactions (e.g.,
when used for in vivo applications). In part, this task entails and
defines the formation of a three dimensional network. As shown in
the examples, the properties can vary with chemical composition of
the oligofluorinated precursor (e.g., altering the oligo segment or
the positioning of the cross linking domain within) and with the
polymerization conditions (e.g., by the inclusion of additives, or
altering the concentration of the oligofluorinated precursor, to
alter the cross-linking density). The extent to which the
properties of the oligofluorinated cross-linked polymer can be
controlled is one of the advantages of the invention.
Oligofluoro Groups
[0078] The monomers of the invention include at least one
oligofluoro group. Typically, the oligofluoro group (F.sub.T) has a
molecular weight ranging from 100 to 1,500 and is incorporated into
the oligomers of the invention by reaction of the corresponding
perfluoroalkyl group with LinkA moiety. Desirably, F.sub.T is
selected from a group consisting of radicals of the general
formula: CF.sub.3(CF.sub.2).sub.pCH.sub.2CH.sub.2,
(CF.sub.3).sub.2CF(CF.sub.2).sub.pCH.sub.2CH.sub.2, or
(CF.sub.3).sub.3C(CF.sub.2).sub.pCH.sub.2CH.sub.2, wherein p is
2-20, preferably 2-8, and
CF.sub.3(CF.sub.2).sub.m(CH.sub.2CH.sub.2O).sub.n,
(CF.sub.3).sub.2CF(CF.sub.2).sub.m(CH.sub.2CH.sub.2O).sub.n, or
(CF.sub.3).sub.3C(CF.sub.2).sub.m(CH.sub.2CH.sub.2O).sub.n, wherein
n is 1-10 and m is 1-20, preferably 1-8. F.sub.T can be
incorporated into a monomer by reaction of an oligofluorinated
alcohol with LinkA or an oligo segment. F.sub.T typically includes
a single fluoro-tail, but are not limited to this feature. A
general formula for the oligomeric fluoro-alcohol of use in the
invention is
H--(OCH.sub.2CH.sub.2).sub.n--(CF.sub.2).sub.m--CF.sub.3, wherein n
can range from 1 to 10, but preferably ranges from 1 to 4, and m
can range from 1 to 20, but preferably ranges from 1-8. A general
guide for the selection of n relative to m is that m should be
equal to or greater than 2n in order to minimize the likelihood of
the (OCH.sub.2CH.sub.2).sub.n segment displacing the
(CF.sub.2).sub.m--CF.sub.3 from the surface following exposure to
water, since the former is more hydrophilic than the fluoro-tail
and will compete with the fluoro-tail for surface dominance in the
polymerized form. The presence of the (OCH.sub.2CH.sub.2).sub.n
segment is believed to have an important function within the
oligofluoro domain, as it provides a highly mobile spacer segment
between the fluoro-tail and the substrate. This spacer effectively
exposes the oligofluorinated surface to, for example, an aqueous
medium.
[0079] Examples of oligofluoro groups that incorporate reactive
moieties for undergoing cross-linking are provided in Table 1. The
examples provided include vinyl groups for undergoing chain growth
polymerizations. Similar oligofluoro groups incorporating
nucleophiles or electrophiles can be prepared for use in the
preparation of oligofluorinated cross-linked polymers made via
nucleophilic substitution reactions, and/or a nucleophilic addition
reactions.
TABLE-US-00001 TABLE 1 ##STR00005## Perfluoro-2-hydroxy acrylates
(generic class, various perfluoro) (FEO1) ##STR00006##
Perfluoro-2-hydroxy- trifluoromethyl acrylates (generic class,
various perfluoro) ##STR00007## Perfluoro-2-hydroxy methacrylates
(generic class, various perfluoro) ##STR00008##
Perfluoro-2-hydroxy- trifluoromethyl methacrylates (generic class,
various perfluoro) (FEO3) ##STR00009## Perfluoren-1-ol (generic
class, various perfluoro) (FEO2) ##STR00010## Perfluoren-1-ol with
longer CH.sub.2 chains (generic class, various perfluoro)
Oligomeric Segment
[0080] The monomers of the invention include at least one
oligomeric segment. The oligo segment is covalently tethered to two
or more cross-linking domains and at least one oligofluoro group.
Oligo segments can include, for example, polytetramethylene oxide,
polycarbonate, polysiloxane, polypropylene oxide, polyethylene
oxide, polyamide, polysaccharide, or any other oligomeric chain.
The oligo segment can include two or more hydroxyls, thiols,
carboxylic acids, diacid chlorides or amides for coupling with
LinkA, a cross-linking domain, and/or an oligofluoro group. Useful
oligo segments include, without limitation, linear diamine or diol
derivatives of polycarbonate, polysiloxanes, polydimethylsiloxanes;
polyethylene-butylene co-polymers; polybutadienes; polyesters;
polyurethane/sulfone co-polymers; polyurethanes, polyamides
including oligopeptides (polyalanine, polyglycine or copolymers of
amino-acids) and polyureas; polyalkylene oxides and specifically
polypropylene oxide, polyethylene oxide and polytetramethylene
oxide. The average molecular weight of the oligo segment can vary
from 50 to 5,000 or 100 to 5,000, but in certain embodiments is
less than 2,500 Daltons. Oligomeric components can be relatively
short in length in terms of the repeating unit or units, and are
generally less than 20 monomeric units.
LinkA
[0081] The monomers of the invention optionally include one or more
LinkA groups. Typically, LinkA groups have molecular weights
ranging from 40 to 700 Da and have multiple functionality in order
to permit coupling of oligo segments, F.sub.T, and/or cross-linking
domains. Examples of LinkA groups include, without limitation,
lysine diisocyanato esters (e.g., lysine diisocyanato methyl
ester); 2,5-diaminobenzenesulfonic acid; 4,4'diamino 2,2'-biphenyl
disulfonic acid; 1,3-diamino 2-hydroxypropane; and
N-(2-aminoethyl)-3-aminopropane sulfonate.
Cross-Linking Domains
[0082] Cross-linking domains can be selected from a variety of
different moieties which can undergo chain growth polymerizations.
For example, cross-linking domains can be designed to undergo
radical initiated chain polymerization (i.e., in the polymerization
of vinyl groups to produce polyvinyl), cationic chain growth
polymerization reactions (i.e., cationic ring-opening
polymerization, such as in the polymerization of epoxides to
produce polyethers, and oxazolines to produce acylated polyamines),
and anionic chain growth polymerization reactions (i.e., anionic
ring-opening polymerization, such as in the polymerization of
epoxides to produce polyethers, and
N-methanesulfonyl-2-methylaziridine to produce polyamines). Many
different chain growth polymerization approaches are known in the
art and can be included in the methods and compositions of the
invention.
[0083] The oligofluorinated cross-linked polymers of the invention
can be formed from a monomer which contains at least one
oligofluorinated cross-linking domain. For example, such monomers
can include at least one pendant oligofluoro chain (F.sub.T)
located adjacent to a step growth resultant functional group
(urethane, urea, amide, ester, etc.) within LinkA, or an oligo
segment, and at least two unreacted pendant cross-linking domains.
The cross-linking domains and F.sub.T can be covalently tethered to
a non-fluorinated oligo segment via LinkA, or F.sub.T can be
directly tethered to a cross-linking domain and, together,
covalently linked to the oligo segment via LinkA. Both LinkA and
the oligo segment may designed to provide for a defined spatial
distribution of F.sub.T groups, where more than one F.sub.T group
is present in the monomer. This distribution simultaneously serves
as a defining parameter, dictating the modulus, protein and cell
interactions, and biochemical stability of the final polymer.
[0084] In certain embodiments, the monomer of the invention
includes at least two vinyl groups. The vinyl groups are
derivatized to include at least one functional group (e.g., a
carboxylic acid, hydroxyl, amine, or thiol group), which is used to
covalently tether the vinyl group to a biologically active agent,
LinkA, and/or oligo. Vinyl groups useful in the methods and
compositions of the invention include, without limitation,
methacrylate, acrylate, cyclic or linear vinyl moieties, and allyl
and styrene containing moieties, and typically have molecular
weights ranging from 40 to 2000.
Oligofluorinated Nucleophilic and Electrophilic Groups
[0085] In invention provides a composition is provided that
contains at least two components having reactive groups thereon,
with the functional groups selected so as to enable reaction
between the components, i.e., crosslinking to form an
oligofluorinated cross-linked polymer. Each component has a core
substituted with reactive groups. Typically, the composition will
contain a first component having a core substituted with
nucleophilic groups and a second component having a core
substituted with electrophilic groups. The composition includes at
least one oligofluorinated nucleophilic group or at least one
oligofluorinated electrophilic group.
[0086] In order for a cross-linked polymer to be formed, there is
preferably plurality of reactive groups present in each of the
first and second components. For example, one component may have a
core substituted with m nucleophilic groups, where m.gtoreq.2, and
the other component has a core substituted with n electrophilic
groups, where n.gtoreq.2 and m+n>4.
[0087] The reactive groups are electrophilic and nucleophilic
groups, which undergo a nucleophilic substitution reaction, a
nucleophilic addition reaction, or both. The term "electrophilic"
refers to a reactive group that is susceptible to nucleophilic
attack, i.e., susceptible to reaction with an incoming nucleophilic
group. Electrophilic groups herein are positively charged or
electron-deficient, typically electron-deficient. The term
"nucleophilic" refers to a reactive group that is electron rich,
has an unshared pair of electrons acting as a reactive site, and
reacts with a positively charged or electron-deficient site.
[0088] Examples of nucleophilic groups suitable for use in the
invention include, without limitation, primary amines, secondary
amines, thiols, phenols, and alcohols. Certain nucleophilic groups
must be activated with a base so as to be capable of reaction with
an electrophilic group. For example, when there are nucleophilic
sulfhydryl and hydroxyl groups in the multifunctional compound, the
compound must be admixed with an aqueous base in order to remove a
proton and provide a thiolate or hydroxylate anion to enable
reaction with the electrophilic group. Unless it is desirable for
the base to participate in the reaction, a non-nucleophilic base is
preferred. In some embodiments, the base may be present as a
component of a buffer solution.
[0089] The selection of electrophilic groups provided on the
multifunctional compound, must be made so that reaction is possible
with the specific nucleophilic groups. Thus, when the X reactive
groups are amino groups, the Y groups are selected so as to react
with amino groups. Analogously, when the X reactive groups are
sulfhydryl moieties, the corresponding electrophilic groups are
sulfhydryl-reactive groups, and the like. Examples of electrophilic
groups suitable for use in the invention include, without
limitation, carboxylic acid esters, acid chloride groups,
anhydrides, isocyanato, thioisocyanato, epoxides, activated
hydroxyl groups, succinimidyl ester, sulfosuccinimidyl ester,
maleimido, and ethenesulfonyl. Carboxylic acid groups typically
must be activated so as to be reactive with a nucleophile.
Activation may be accomplished in a variety of ways, but often
involves reaction with a suitable hydroxyl-containing compound in
the presence of a dehydrating agent such as
dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU). For
example, a carboxylic acid can be reacted with an
alkoxy-substituted N-hydroxy-succinimide or
N-hydroxysulfosuccinimide in the presence of DCC to form reactive
electrophilic groups, the N-hydroxysuccinimide ester and the
N-hydroxysulfosuccinimide ester, respectively. Carboxylic acids may
also be activated by reaction with an acyl halide such as an acyl
chloride (e.g., acetyl chloride), to provide a reactive anhydride
group. In a further example, a carboxylic acid may be converted to
an acid chloride group using, e.g., thionyl chloride or an acyl
chloride capable of an exchange reaction.
[0090] In general, the concentration of each of the components will
be in the range of about 1 to 50 wt %, generally about 2 to 40 wt
%. The preferred concentration will depend on a number of factors,
including the type of component (i.e., type of molecular core and
reactive groups), its molecular weight, and the end use of the
resulting three-dimensional matrix. For example, use of higher
concentrations of the components, or using highly functionalized
components, will result in the formation of a more tightly
crosslinked network, producing a stiffer, more robust composition,
such as for example a gel. In general, the mechanical properties of
the three-dimensional matrix should be similar to the mechanical
properties of the surface to which the matrix (or matrix-forming
components) will be applied. Thus, when the matrix will be used for
an orthopedic application, the gel matrix should be relatively
firm, e.g., a firm gel; however, when the matrix will be used on
soft tissue, as for example in tissue augmentation, the gel matrix
should be relatively soft, e.g., a soft gel.
[0091] Further details of the formation of oligofluorinated
cross-linked polymers is provided in the Examples.
[0092] Substrates which can be coated using the methods and
compositions of the invention include, without limitation, wood,
metals, ceramics, plastics, stainless steels, fibers, and glasses,
among others.
Synthesis
[0093] The oligofluorinated cross-linked polymers of the invention
are synthesized from monomers which can be prepared, for example,
as described in Schemes 1-4 below. In Schemes 1-4, oligo is an
oligomeric segment, LinkA is a linking element as defined herein,
Bio is a biologically active agent, F.sub.T is an oligofluoro
group, and D is a moiety capable of undergoing a chain growth
polymerization reaction, nucleophilic substitution reaction, and/or
a nucleophilic addition reaction.
##STR00011##
##STR00012##
##STR00013##
##STR00014##
[0094] The monomers can be synthesized, for example, using
multi-functional LinkA groups, a multi-functional oligo segment, a
mono-functional F.sub.T group, and cross-linking domains having at
least one functional component that can be covalently tethered to
the oligomeric segment.
[0095] The first step of the synthesis can be carried out by
classical urethane/urea reactions using the desired combination of
reagents. However, the order in which the various components are
assembled can be varied for any particular monomer.
[0096] Further synthetic details are provided in the Examples.
Oligofluorinated Cross-Linked Polymerized Coatings
[0097] The oligofluorinated cross-linked polymers of the invention
can be used to form coatings which provide for the discrete
distribution of mono-dispersed oligofluoro groups in a pendant
arrangement on a surface that is stable (e.g., does not readily
leach from the surface).
[0098] The coatings of the invention can be formed by
polymerization of an oligofluorinated cross-linking domain, such as
a vinyl monomer, or by reaction of a multifunctional nucleophile
with an oligofluorinated electrophile or a multifunctional
electrophile with an oligofluorinated nucleophile.
[0099] The coatings of the invention can impart high water
repellency, low refractive index, soil resistance, reduce fouling,
and improve biocompatibility. For blood dwelling devices the
coatings can reduce the formation of blood clots at the device
surface after implantation.
[0100] The monomer can be applied to a surface alone (e.g., as a
liquid); in the presence of a diluent (e.g., acetone, methanol,
ethanol, ethers, hexane, toluene, or tetrahydrofuran), in
combination with an oligofluorinated precursor. Suitable methods
for applying the monomer to a surface include, without limitation,
spin coating, spraying, roll coating, dipping, brushing, and knife
coating, among others.
[0101] Polymerization of the monomers of the invention can be
achieved by UV radiation, electron beam, or thermal heat in the
presence of a photoinitiator or free-radical thermal initiator,
depending upon the nature of the reactive moiety employed. Many
light energy sources can be used and a typical source is
ultraviolet (UV) radiation. A typical UV lamp is a lamp equipped
with a lamp output of 400 W/in (purchased from Honle UV America
Inc.). The lamp is secured on top of a home-built box (26.5 cm
length, 26.5 cm width and 23.0 cm height). The box is designed to
control the curing environment, using either an air or nitrogen
atmosphere.
[0102] A wide variety of articles can be coated using the
compositions and methods of the invention. For example, articles
which contact bodily fluids, such as medical devices can be coated
to improve their biocompatibility. The medical devices include,
without limitation, catheters, guide wires, vascular stents,
micro-particles, electronic leads, probes, sensors, drug depots,
transdermal patches, vascular patches, blood bags, and tubing. The
medical device can be an implanted device, percutaneous device, or
cutaneous device. Implanted devices include articles that are fully
implanted in a patient, i.e., are completely internal. Percutaneous
devices include items that penetrate the skin, thereby extending
from outside the body into the body. Cutaneous devices are used
superficially. Implanted devices include, without limitation,
prostheses such as pacemakers, electrical leads such as pacing
leads, defibrillarors, artificial hearts, ventricular assist
devices, anatomical reconstruction prostheses such as breast
implants, artificial heart valves, heart valve stents, pericardial
patches, surgical patches, coronary stents, vascular grafts,
vascular and structural stents, vascular or cardiovascular shunts,
biological conduits, pledges, sutures, annuloplasty rings, stents,
staples, valved grafts, dermal grafts for wound healing, orthopedic
spinal implants, orthopedic pins, intrauterine devices, urinary
stents, maxial facial reconstruction plating, dental implants,
intraocular lenses, clips, sternal wires, bone, skin, ligaments,
tendons, and combination thereof. Percutaneous devices include,
without limitation, catheters or various types, cannulas, drainage
tubes such as chest tubes, surgical instruments such as forceps,
retractors, needles, and gloves, and catheter cuffs. Cutaneous
devices include, without limitation, burn dressings, wound
dressings and dental hardware, such as bridge supports and bracing
components.
[0103] The coating of an implantable medical device such as a
vascular stent is of great interest. Stents are commonly used for
the treatment of stenosis. Generally, stent is crimped onto a
balloon catheter, inserted in the coronary vessel of blockage and
the balloon is inflated causing the stent to expand to a desired
diameter hence opening up the blocked artery vessel for blood flow.
However, during this deployment process, damages to the artery wall
can cause elastic recoil of the vessel wall which characterizes the
early phase of restenosis. Stent coating offers a platform for the
delivery of biologically active agents for controling post
deployment restenosis. Using the methods and compositions of the
invention, drug delivery on the stent is achieved by formulating a
solution with a polymer dissolved in a solvent, and a biologically
active agent dispersed in the blend. When the solution is sprayed
on the stent, the solvent is allowed to evaporate, leaving on the
stent surface the polymer with the drug embedded in the polymer
matrix. Alternatively, the biologically active agent is covalently
bound to the oligofluorinated precursor prior to polymerization.
The release of the biologically active agent covalently bound to
the resulting oligofluorinated cross-linked polymer can be
controlled by utilizing a degradable linker (e.g., a ester linkage)
to attach the biologically active agent.
[0104] Alternatively, the coatings of the invention can be applied
to wood for exterior applications (decks and fences), boats, ships,
fabrics, electronic displays, gloves, and apparel.
[0105] One distinctive feature of the intercalative
oligofluorinated cross-linked polymer is the ability to initiate
the polymerization step on the device surface, producing a
continuous polymer coating similar to skin wrap.
Shaped Articles
[0106] Articles can be formed from the oligofluorinated
cross-linked polymers of the invention. For example, the
oligofluorinated precursor can be combined with an initiator using
reaction injection molding to produce a shaped article.
[0107] Any shaped article can be made using the compositions of the
invention. For example, articles suitable for contact with bodily
fluids, such as medical devices can be made using the compositions
described herein. The duration of contact may be short, for
example, as with surgical instruments or long term use articles
such as implants. The medical devices include, without limitation,
catheters, guide wires, vascular stents, micro-particles,
electronic leads, probes, sensors, drug depots, transdermal
patches, vascular patches, blood bags, and tubing. The medical
device can be an implanted device, percutaneous device, or
cutaneous device. Implanted devices include articles that are fully
implanted in a patient, i.e., are completely internal. Percutaneous
devices include items that penetrate the skin, thereby extending
from outside the body into the body. Cutaneous devices are used
superficially. Implanted devices include, without limitation,
prostheses such as pacemakers, electrical leads such as pacing
leads, defibrillarors, artificial hearts, ventricular assist
devices, anatomical reconstruction prostheses such as breast
implants, artificial heart valves, heart valve stents, pericardial
patches, surgical patches, coronary stents, vascular grafts,
vascular and structural stents, vascular or cardiovascular shunts,
biological conduits, pledges, sutures, annuloplasty rings, stents,
staples, valved grafts, dermal grafts for wound healing, orthopedic
spinal implants, orthopedic pins, intrauterine devices, urinary
stents, maxial facial reconstruction plating, dental implants,
intraocular lenses, clips, sternal wires, bone, skin, ligaments,
tendons, and combination thereof. Percutaneous devices include,
without limitation, catheters or various types, cannulas, drainage
tubes such as chest tubes, surgical instruments such as forceps,
retractors, needles, and gloves, and catheter cuffs. Cutaneous
devices include, without limitation, burn dressings, wound
dressings and dental hardware, such as bridge supports and bracing
components.
Biologically Active Agents
[0108] Biologically active agents can be encapsulated within the
coatings and articles of the invention. The encapsulation can be
achieved either by coating the article to be treated with a
biologically active agent prior to application and polymerization
of the monomer, or by mixing the monomer and the biologically
active agent together and applying the mixture to the surface of
the article prior to polymerization. Biologically active agents
include therapeutic, diagnostic, and prophylactic agents. They can
be naturally occurring compounds, synthetic organic compounds, or
inorganic compounds. Biologically active agents that can be used in
the methods and compositions of the invention include, but are not
limited to, proteins, peptides, carbohydrates, antibiotics,
antiproliferative agents, rapamycin macrolides, analgesics,
anesthetics, antiangiogenic agents, vasoactive agents,
anticoagulants, immunomodulators, cytotoxic agents, antiviral
agents, antithrombotic drugs, such as terbrogrel and ramatroban,
antibodies, neurotransmitters, psychoactive drugs,
oligonucleotides, proteins, lipids, and any biologically active
agent described herein.
[0109] Exemplary therapeutic agents include growth hormone, for
example human growth hormone, calcitonin, granulocyte macrophage
colony stimulating factor (GMCSF), ciliary neurotrophic factor, and
parathyroid hormone. Other specific therapeutic agents include
parathyroid hormone-related peptide, somatostatin, testosterone,
progesterone, estradiol, nicotine, fentanyl, norethisterone,
clonidine, scopolomine, salicylate, salmeterol, formeterol,
albeterol, valium, heparin, dermatan, ferrochrome A,
erythropoetins, diethylstilbestrol, lupron, estrogen estradiol,
androgen halotestin, 6-thioguanine, 6-mercaptopurine, zolodex,
taxol, lisinopril/zestril, streptokinase, aminobutytric acid,
hemostatic aminocaproic acid, parlodel, tacrine, potaba, adipex,
memboral, phenobarbital, insulin, gamma globulin, azathioprine,
papein, acetaminophen, ibuprofen, acetylsalicylic acid,
epinephrine, flucloronide, oxycodone percoset, dalgan, phreniline
butabital, procaine, novocain, morphine, oxycodone, aloxiprin,
brofenac, ketoprofen, ketorolac, hemin, vitamin B-12, folic acid,
magnesium salts, vitamine D, vitamin C, vitamin E, vitamin A,
Vitamin U, vitamin L, vitamin K, pantothenic acid,
aminophenylbutyric acid, penicillin, acyclovir, oflaxacin,
amoxicillin, tobramycin, retrovior, epivir, nevirapine, gentamycin,
duracef, ablecet, butoxycaine, benoxinate, tropenzile, diponium
salts, butaverine, apoatropine, feclemine, leiopyrrole,
octamylamine, oxybutynin, albuterol, metaproterenol, beclomethasone
dipropionate, triamcinolone acetamide, budesonide acetonide,
ipratropium bromide, flunisolide, cromolyn sodium, ergotamine
tartrate, and protein or peptide drugs such as TNF antagonists or
interleukin antagonists. For example, the biologically active agent
can be an antiinflammatory agent, such as an NSAID, corticosteriod,
or COX-2 inhibitor, e.g., rofecoxib, celecoxib, valdecoxib, or
lumiracoxib.
[0110] Exemplary diagnostic agents include imaging agents, such as
those that are used in positron emission tomography (PET), computer
assisted tomography (CAT), single photon emission computerized
tomography, X-ray, fluoroscopy, and magnetic resonance imaging
(MRI). Suitable materials for use as contrast agents in MRI include
gadolinium chelates, as well as iron, magnesium, manganese, copper,
and chromium chelates. Examples of materials useful for CAT and
X-rays include iodine based materials.
[0111] A preferred biologically active agent is a substantially
purified peptide or protein. Proteins are generally defined as
consisting of 100 amino acid residues or more; peptides are less
than 100 amino acid residues. Unless otherwise stated, the term
protein, as used herein, refers to both proteins and peptides. The
proteins may be produced, for example, by isolation from natural
sources, recombinantly, or through peptide synthesis. Examples
include growth hormones, such as human growth hormone and bovine
growth hormone; enzymes, such as DNase, proteases, urate oxidase,
alronidase, alpha galactosidase, and alpha glucosidase; antibodies,
such as trastuzumab.
[0112] Rapamycin Macrolides
[0113] Rapamycin (Sirolimus) is an immunosuppressive lactam
macrolide that is produced by Streptomyces hygroscopicus. See, for
example, McAlpine, J. B., et al., J. Antibiotics 44: 688 (1991);
Schreiber, S. L., et al., J. Am. Chem. Soc. 113: 7433 (1991); and
U.S. Pat. No. 3,929,992, incorporated herein by reference.
Exemplary rapamycin macrolides which can be used in the methods and
compositions of the invention include, without limitation,
rapamycin, CCI-779, Everolimus (also known as RAD001), and ABT-578.
CCI-779 is an ester of rapamycin (42-ester with
3-hydroxy-2-hydroxymethyl-2-methylpropionic acid), disclosed in
U.S. Pat. No. 5,362,718. Everolimus is an alkylated rapamycin
(40-O-(2-hydroxyethyl)-rapamycin, disclosed in U.S. Pat. No.
5,665,772.
[0114] Antiproliferative Agents
[0115] Exemplary antiproliferative agents which can be used in the
methods and compositions of the invention include, without
limitation, mechlorethamine, cyclophosphamide, iosfamide,
melphalan, chlorambucil, uracil mustard, estramustine, mitomycin C,
AZQ, thiotepa, busulfan, hepsulfam, carmustine, lomustine,
semustine, streptozocin, dacarbazine, cisplatin, carboplatin,
procarbazine, methotrexate, trimetrexate, fluouracil, floxuridine,
cytarabine, fludarabine, capecitabine, azacitidine, thioguanine,
mercaptopurine, allopurine, cladribine, gemcitabine, pentostatin,
vinblastine, vincristine, etoposide, teniposide, topotecan,
irinotecan, camptothecin, 9-aminocamptothecin, paclitaxel,
docetaxel, daunorubicin, doxorubicin, dactinomycin, idarubincin,
plicamycin, mitomycin, amsacrine, bleomycin, aminoglutethimide,
anastrozole, finasteride, ketoconazole, tamoxifen, flutamide,
leuprolide, goserelin, Gleevec.TM. (Novartis), leflunomide
(Pharmacia), SU5416 (Pharmacia), SU6668 (Pharmacia), PTK787
(Novartis), Iressa.TM. (AstraZeneca), Tarceva.TM., (Oncogene
Science), trastuzumab (Genentech), Erbitux.TM. (ImClone), PKI166
(Novartis), GW2016 (GlaxoSmithKline), EKB-509 (Wyeth), EKB-569
(Wyeth), MDX-H210 (Medarex), 2C4 (Genentech), MDX-447 (Medarex),
ABX-EGF (Abgenix), CI-1033 (Pfizer), Avastin.TM. (Genentech),
IMC-1C11 (ImClone), ZD4190 (AstraZeneca), ZD6474 (AstraZeneca),
CEP-701 (Cephalon), CEP-751 (Cephalon), MLN518 (Millenium), PKC412
(Novartis), 13-cis-retinoic acid, isotretinoin, retinyl palmitate,
4-(hydroxycarbophenyl)retinamide, misonidazole, nitracrine,
mitoxantrone, hydroxyurea, L-asparaginase, interferon alfa,
AP23573, Cerivastatin, Troglitazone, CRx-026DHA-paclitaxel,
Taxoprexin, TPI-287, Sphingosine-based lipids, and mitotane.
[0116] Corticosteroids
[0117] Exemplary corticosteroids which can be used in the methods
and compositions of the invention include, without limitation,
21-acetoxypregnenolone, alclomerasone, algestone, amcinonide,
beclomethasone, betamethasone, betamethasone valerate, budesonide,
chloroprednisone, clobetasol, clobetasol propionate, clobetasone,
clobetasone butyrate, clocortolone, cloprednol, corticosterone,
cortisone, cortivazol, deflazacon, desonide, desoximerasone,
dexamethasone, diflorasone, diflucortolone, difluprednate,
enoxolone, fluazacort, flucloronide, flumethasone, flumethasone
pivalate, flunisolide, flucinolone acetonide, fluocinonide,
fluorocinolone acetonide, fluocortin butyl, fluocortolone,
fluorocortolone hexanoate, diflucortolone valerate,
fluorometholone, fluperolone acetate, fluprednidene acetate,
fluprednisolone, flurandenolide, formocortal, halcinonide,
halometasone, halopredone acetate, hydrocortamate, hydrocortisone,
hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone
phosphate, hydrocortisone 21-sodium succinate, hydrocortisone
tebutate, mazipredone, medrysone, meprednisone, methylprednicolone,
mometasone furoate, paramethasone, prednicarbate, prednisolone,
prednisolone 21-diedryaminoacetate, prednisolone sodium phosphate,
prednisolone sodium succinate, prednisolone sodium
21-m-sulfobenzoate, prednisolone sodium 21-stearoglycolate,
prednisolone tebutate, prednisolone 21-trimethylacetate,
prednisone, prednival, prednylidene, prednylidene
21-diethylaminoacetate, tixocortol, triamcinolone, triamcinolone
acetonide, triamcinolone benetonide and triamcinolone hexacetonide.
Structurally related corticosteroids having similar
anti-inflammatory properties are also intended to be encompassed by
this group.
[0118] NSAIDs
[0119] Exemplary non-steroidal antiinflammatory drugs (NSAIDs)
which can be used in the methods and compositions of the invention
include, without limitation, naproxen sodium, diclofenac sodium,
diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam,
indomethacin, ibuprofen, nabumetone, choline magnesium
trisalicylate, sodium salicylate, salicylsalicylic acid
(salsalate), fenoprofen, flurbiprofen, ketoprofen, meclofenamate
sodium, meloxicam, oxaprozin, sulindac, and tolmetin.
[0120] Analgesics
[0121] Exemplary analgesics which can be used in the methods and
compositions of the invention include, without limitation,
morphine, codeine, heroin, ethylmorphine, O-carboxymethylmorphine,
O-acetylmorphine, hydrocodone, hydromorphone, oxymorphone,
oxycodone, dihydrocodeine, thebaine, metopon, ethorphine,
acetorphine, diprenorphine, buprenorphine, phenomorphan,
levorphanol, ethoheptazine, ketobemidone, dihydroetorphine and
dihydroacetorphine.
[0122] Antimicrobials
[0123] Exemplary antimicrobials which can be used in the methods
and compositions of the invention include, without limitation,
penicillin G, penicillin V, methicillin, oxacillin, cloxacillin,
dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin,
ticarcillin, mezlocillin, piperacillin, azlocillin, temocillin,
cepalothin, cephapirin, cephradine, cephaloridine, cefazolin,
cefamandole, cefuroxime, cephalexin, cefprozil, cefaclor,
loracarbef, cefoxitin, cefmatozole, cefotaxime, ceftizoxime,
ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime,
ceftibuten, cefdinir, cefpirome, cefepime, BAL5788, BAL9141,
imipenem, ertapenem, meropenem, astreonam, clavulanate, sulbactam,
tazobactam, streptomycin, neomycin, kanamycin, paromycin,
gentamicin, tobramycin, amikacin, netilmicin, spectinomycin,
sisomicin, dibekalin, isepamicin, tetracycline, chlortetracycline,
demeclocycline, minocycline, oxytetracycline, methacycline,
doxycycline, erythromycin, azithromycin, clarithromycin,
telithromycin, ABT-773, lincomycin, clindamycin, vancomycin,
oritavancin, dalbavancin, teicoplanin, quinupristin and
dalfopristin, sulphanilamide, para-aminobenzoic acid, sulfadiazine,
sulfisoxazole, sulfamethoxazole, sulfathalidine, linezolid,
nalidixic acid, oxolinic acid, norfloxacin, perfloxacin, enoxacin,
ofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin,
grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin,
gatifloxacin, moxifloxacin, gemifloxacin, sitafloxacin,
metronidazole, daptomycin, garenoxacin, ramoplanin, faropenem,
polymyxin, tigecycline, AZD2563, and trimethoprim.
[0124] Local Anesthetics
[0125] Exemplary local anesthetics which can be used in the methods
and compositions of the invention include, without limitation,
cocaine, procaine, lidocaine, prilocaine, mepivicaine, bupivicaine,
articaine, tetracaine, chloroprocaine, etidocaine, and
ropavacaine.
[0126] Antispasmodic
[0127] Exemplary antispasmodics which can be used in the methods
and compositions of the invention include, without limitation,
atropine, belladonna, bentyl, cystospaz, detrol (tolterodine),
dicyclomine, ditropan, donnatol, donnazyme, fasudil, flexeril,
glycopyrrolate, homatropine, hyoscyamine, levsin, levsinex, librax,
malcotran, novartin, oxyphencyclimine, oxybutynin, pamine,
tolterodine, tiquizium, prozapine, and pinaverium.
[0128] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how the methods and compounds claimed herein are
performed, made, and evaluated, and are intended to be purely
exemplary of the invention and are not intended to limit the scope
of what the inventors regard as their invention.
[0129] The following acronyms denote the listed compounds used in
the preparation of the polymers, polymer complexes, and polymer
conjugates described herein. [0130] AEMA aminoethyl methacrylate
[0131] ALLYL allyl alcohol [0132] ASA acetylsalicylic acid [0133]
BAL poly(difluoromethylene),.alpha.-fluoro-.omega.-(2-hydroxyethyl)
[0134] BHT butylated hydroxy toluene [0135] BPO benzoyl peroxide
[0136] C8 1-octanol [0137] CDCl.sub.3 deuterated chloroform [0138]
DBDL dibutyltin dilaurate [0139] DCM dichloromethane [0140] DMAc
dimethylacetamide [0141] DMAP 4-(dimethyamino)pyridine [0142] DMF
dimethylformamide [0143] DMSO dimethylsulphoxide [0144] EDC
1-ethyl-3-(3-dimethylamino-propyl)carbodiimide.HCl [0145] EVA
poly(ethylene-co-vinyl acetate) [0146] FEO1
4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11
heptadecafluoro-2-hydroxyundecyl acrylate [0147] FEO2 1H, 1H, 2H,
3H nonafluorohept-2-en-ol [0148] FEO3
3-(perfluoro-3-methylbutyl)-2-hydroxypropyl methacrylate [0149]
HEMA hydroxyethyl methacrylate [0150] HCl hydrochloric acid [0151]
HMP 2-hydroxy-2-methylpropiophenone [0152] KBr potassium bromide
[0153] LDI lysine diisocyanate [0154] MAA methacrylic acid [0155]
MeOH methanol [0156] MgSO.sub.4 magnesium sulphate [0157] MMA
methyl methacrylate [0158] NaOH sodium hydroxide [0159] PBS
phosphate buffer solution [0160] PCL polycaprolactone [0161] PSi
polydimethylsiloxane-bis(3-aminopropyl) terminated [0162] PTMO
polytetramethylene oxide [0163] PTX paclitaxel [0164] SIBS
poly(stryrene-isobutylene-styrene) [0165] TEA triethylamine [0166]
TEGMA triethylene glycol dimethacrylate [0167] TFAc trifluoroacetic
acid [0168] THF tetrahydrofuran [0169] VP 1-vinyl-2-pyrrolidone
[0170] List of monomers: methacrylic acid, isobutyl acrylate,
tertiarybutyl acrylate, tertiarybutyl methacrylate, 2-hydroxyethyl
acrylate, 2-hydroxypropyl acrylate, butanediol monoacrylate,
ethyldiglycol acrylate, lauryl acrylate, dimethylaminoethyl
acrylate, dihydrodicyclopentadienyl acrylate, N-vinylformamid,
cyclohexyl methacrylate, 2-isocyanotomethacrylate, glycidyl
methacrylate, cyanoacrylate, isobornyl acrylate, 4-hydroxybutyl
vinyl ether, di((meth)ethylene glycol)vinyl ether, maleic and
fumaric acid, triethylene glycol dimethacrylate, 1,6 hexanediol
methacrylate, 1,4 butanediol dimethacrylate, and urethane
dimethacrylate. [0171] List of initiators:
1,1'-Azobis(cyclohexanecarbonitrile), 2,2'-Azobisisobutyronitrile
(AIBN), 2,2'-Azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride,
Tert-Butyl peracetate, 4,4-Azobis(4-cyanovaleric acid),
2,2'-Azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride,
2,2'-Azobis[2-(2-imidazolin-2-yepropane]disulfate dihydrate,
2,2'-Azobis(2-methylpropionamidine)dihydrochloride,
2,2'-Azobis[N-(2-carboxyethyl)-2-methylpropionamidine]hydrate,
2,2'-Azobis{2-[1-(2-hydroxyethyl)-2-imidazolin-2-yl]propane}dihydrochlori-
de, 2 Peracetic acid, 2'-Azobis[2-(2-imidazolin-2-yl)propane],
2,2'-Azobis(1-imino-1-pyrrolidino-2-ethylpropane)dihydrochloride,
2,2'-Azobis{2-methyl-N-[1,1-bis(hydroxymethyl)-2-hydroxyethl]propionamide-
}, 2,2'-Azobis[2-methyl-N-(2-hydroxyethyl)propionamide],
2,2'-Azobis(4-methoxy-2,4-dimethyl valeronitrile),
2,2'-Azobis(2,4-dimethyl valeronitrile), Dimethyl
2,2'-azobis(2-methylpropionate),
2,2'-Azobis(2-methylbutyronitrile),
1,1'-Azobis(cyclohexane-1-carbonitrile),
2,2'-Azobis[N-(2-propenyl)-2-methylpropionamide],
1-[(1-cyano-1-methylethyl)azo]formamide,
2,2'-Azobis(N-butyl-2-methylpropionamide),
2,2'-Azobis(N-cyclohexyl-2-methylpropionamide), Tert-Amyl
peroxybenzoate, Benzoyl peroxide, Potassium persulphate,
2,2-Bis(tert-butylperoxy)butane,
1,1-Bis(tert-butylperoxy)cyclohexane,
2,5-Bis(tert-butylperoxy)-2,5-dimethyl-3-hexyne,
Bis(1-(tert-butylperoxy)-1-methylethyl)benzene, 1,1-B
is(tert-butylperox)-3,3,5-trimethylcyclohexane, Tert-butyl
hydroperoxide, Tert-butyl peroxide, Cyclohexanone peroxide,
2,4-pentadione peroxide, Lauroyl peroxide, Dicumyl peroxide,
Tert-butyl peroxybenzoate, Cumene hydroperoxide, Tert-butylperoxy
isopropyl carbonate, Camphorquinone,
Diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide,
2-tert-Butylanthraquinone, 9,10-Phenanthrenequinone,
Anthraquinone-2-sulfonic acid sodium salt monohydrate,
Phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide,
1-Hydroxycyclohexyl phenyl ketone, 2-Hydroxy-2-methylpropiophenone,
2-Benzyl-2-(dimethylamino)-4'-morpholinobutyrophenone,
2,2-Diethoxyacetophenone,
2-Hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone,
2-Methyl-4'-(methylthio)-2-morpholinopropiophenone,
3'-Hydroxyacetophenone, 4'-Ethoxyacetophenone,
4'-Hydroxyacetophenone, 4'-Phenoxyacetophenone,
4'-tert-Butyl-2',6'-dimethylacetophenone,
Diphenyl(2,4,6-trimethylbenzoyl)phosphine
oxide/2-hydroxy-2-methylpropiophenone,
2,2-Dimethoxy-2-phenylacetophenone, 4,4'-Dimethoxybenzoin,
3-Methylbenzophenone, Benzoin, 3-Hydroxybenzophenone,
3,4-Dimethylbenzophenone, 2-Methylbenzophenone,
Benzophenone-3,3',4,4'-tetracarboxylic dianhydride,
4-Methylbenzophenone, 4-Hydroxybenzophenone, 4-Benzoylbiphenyl,
4-(Dimethylamino)benzophenone, 4-(Diethylamino)benzophenone,
Michler's ketone, 4,4'-Bis[2-(1-propenyl)phenoxy]benzophenone,
mixture of cis and trans 4,4'-Dihydroxybenzophenone,
4,4'-Bis(diethylamino)benzophenone, Methyl benzoylformate, Benzoin
methyl ether, Benzoin isobutyl ether, 4,4'-Dimethylbenzil, Benzoin
ethyl ether, (4-Bromophenyl)diphenylsulfonium triflate,
(4-Chlorophenyl)diphenylsulfonium triflate, Triphenylsulfonium
perfluoro-1-butanesufonate,
N-Hydroxy-5-norbornene-2,3-dicarboximide
perfluoro-1-butanesulfonate, Triphenylsulfonium triflate,
Diphenyliodonium 9,10-dimethoxyanthracene-2-sulfonate,
Tris(4-tert-butylphenyl)sulfonium perfluoro-1-butanesulfonate, and
Tris(4-tert-butylphenyl)sulfonium triflate.
Experimental Protocols
[0172] Purification and analytical methods mentioned in the
examples are described below.
[0173] Cationic Solid Phase Extraction (SCX-SPE): A pre-packed
cationic silica gel column (plastic) is used to remove small
cationic compounds from the reaction mixtures.
[0174] Fluorous Solid Phase Extraction (F-SPE): SPE substrates
modified with perfluorinated ligands (F-SPE) are used to
selectively retain perfluorinated oligomers, allowing the
separation of non-fluorinated compounds.
[0175] Contact angle analysis: Droplets of MilliQ water are applied
to films, and the shape of the droplets are analyzed using a Kruss
DSA instrument.
[0176] Elemental analysis: samples are combusted, and the liberated
fluorine is absorbed into water and analyzed by ion-selective
electrode.
[0177] FTIR analysis: a sample is dissolved as a 20 mg/mL solution
in a suitable volatile solvent and 50 .mu.L of this solution is
cast on a KBr disk. Once dried, the sample is analyzed.
[0178] Gel extraction: samples of film are weighed and then
extracted with a suitable solvent for 12 hours. The films are
removed from the solvent, weighed, and then vacuum dried and
weighed again. Gel content is calculated as the percentage of mass
that is not extracted. Swell ratio is calculated at the percentage
increase in mass before the sample is vacuum dried.
[0179] GPC analysis: samples are dissolved as a 20 mg/mL solution
in a suitable solvent (THF, dioxane, DMF) and are analyzed using a
polystyrene column calibrated with polystyrene standards.
[0180] NMR: samples are dissolved at 20 mg/mL in a suitable solvent
and are analyzed using a 300 or 400 MHz NMR spectrometer.
[0181] SEM: surfaces were coated with gold.
[0182] Tensile testing: films are cut into test specimens and are
analyzed according to ASTM D 1708 guidelines.
[0183] XPS analysis: films are analyzed using a 90.degree. take-off
angle.
EXAMPLE 1
Synthesis of .alpha.,.omega.-BAL-Poly(LDI(HEMA)/PTMO) with Pendent
Vinyl Groups (Compound 2)
##STR00015##
[0185] Polytetramethylene oxide (PTMO) (15 grams, 14 mmol) was
weighed into a 500 mL 2-neck flask and degassed overnight at
30.degree. C., and was then dissolved in anhydrous DMAc (40 mL)
under N.sub.2. LDI (5.894 g, 28 mmol) was weighed into a 2-neck
flask and was dissolved in anhydrous DMAc (40 mL) under N.sub.2.
DBDL was added to the LDI solution, and this mixture was added
dropwise to the PTMO solution. The flask was kept sealed and
maintained under N.sub.2 at 70.degree. C. for two hours.
Fluoroalcohol (13.151 g, 31 mmol) was weighed into a 2-neck flask
and degassed at room temperature, was dissolved in anhydrous DMAc
(40 mL) and was added dropwise to the reaction mixture. The
reaction solution was sealed under N.sub.2 and was stirred
overnight at room temperature. The product was precipitated in
water (3 L), washed several times, and dried. The product was
dissolved in MeOH and the tin catalyst was extracted by SCX SPE.
The final product (Compound 1-ester) was dried under vacuum.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. (ppm) 4.24-4.46
(--CH.sub.2--O, BAL), 3.94-4.13 (--CH.sub.2--O--CO PTMO), 3.74
(CH.sub.3, LDI), 3.28-3.50 (CH.sub.2--O PTMO), 2.98-3.28
(CH.sub.2--NH, LDI), 2.29-2.60 (--CH.sub.2--CF.sub.2--, BAL),
1.16-1.96 (PTMO and LDI CH.sub.2). .sup.19F NMR (300 MHz,
CDCl.sub.3) .delta. (ppm) -81.23 (CF.sub.3), -114.02 (CF.sub.2),
-122.34 (CF.sub.2), -123.34 (CF.sub.2), -123.30 (CF.sub.2), -124.03
(CF.sub.2), -126.56 (CF.sub.2). Elemental analysis: theoretical
based on reagent stoichiometry (%): C, 48.49; H, 6.57; F, 23.85; N,
2.81; O, 18.27. Measured: C, 48.70; H, 6.56; F, 22.81; N, 2.63.
HPLC analysis (reversed phase, C18 column, methanol and pH 9 PBS
mobile phase (gradient)): retention time of 39.5 minutes. DSC
analysis: Tg=-66.6.degree. C. IR analysis was in accordance with
the chemical structure: 3327.29 cm.sup.-1 v(N--H) H-bonded, 2945.10
cm.sup.-1 v(C--H) CH.sub.2 asymmetric stretching, 2865.69 cm.sup.-1
v(C--H) CH.sub.2 symmetric stretching, 1717.91 cm.sup.-1 v(C.dbd.O)
urethane amide, 1533.54 cm.sup.-1 v(C--N) stretching mode, 1445.56
cm.sup.-1 v(C--N) stretching mode, 1349.31 cm.sup.-1 v(C--O)
stretching, 1400-1000 cm.sup.-1 v(C--F) monofluoroalkanes absorb to
the right in the range, while polyfluoroalkanes give multiple
strong bands over the range from 1350-1100 cm.sup.-1.
[0186] Compound 1-ester (15.0 g, .about.16 mmol ester) was weighed
into a flask, dissolved in MeOH (150 mL) and once dissolved, 1N
NaOH solution (17 mL) was added dropwise. After six hours of
stirring at room temperature, the solution was neutralized using 1N
HCl (17.7 mL), and the product was precipitated in water, washed
with water, and dried under vacuum at 60.degree. C. The conversion
of ester groups to acid functional groups was confirmed by NMR
analysis. Proton NMR indicated the disappearance of methoxy groups
at 3.75 ppm. .sup.19F NMR (300 MHz, CDCl.sub.3) .delta. (ppm)
-81.23 (CF.sub.3), -114.02 (CF.sub.2), -122.34 (CF.sub.2), -123.34
(CF.sub.2), -123.30 (CF.sub.2), -124.03 (CF.sub.2), -126.56
(CF.sub.2). HPLC analysis: retention time of 33.4 minutes (Compound
1-acid). Reversed phase HPLC, C18 column, MeOH and pH 9 PBS mobile
phase (gradient). DSC analysis: Tg=-65.degree. C. Elemental
analysis: theoretical based on reagent stoichiometry (%): C, 47.96;
H, 6.48; F, 24.19; N, 2.86; O, 18.53. Measured: C, 46.92; H, 6.16;
F, 26.43; N, 2.94. Compound 1-acid (10.0 gram, .about.8 mmol acid),
DMAP (0.488 gram, 4 mmol), HEMA (6.247 gram, 48 mmol) and DCM (50
mL) were added to a 250 mL flask, and stirred until all compounds
were dissolved. EDC (4.600 gram, 24 mmol) was added to the DCM
solution, and once the EDC was dissolved, the solution was stirred
at room temperature for 24 hours under N.sub.2 and protection from
light. The reaction mixture was reduced to a viscous liquid by
rotary evaporation (25.degree. C.) and washed three times with
water (3.times.400 mL). The washed product was dissolved in diethyl
ether (100 mL, 100 ppm BHT), and water was removed by mixing the
solution with MgSO.sub.4 for 1 hour. The solution was clarified by
gravity filtration into a 250 mL flask, and the solvent was removed
by rotary evaporation (25.degree. C.). The product (Compound 2) was
re-dissolved in DMF and was purified by fluorous SPE (F-SPE) and
recovered by rotary evaporation. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. (ppm) 6.09-6.15 (HEMA vinyl H), 5.58-5.63 (HEMA vinyl H),
4.27-4.49 (--CH.sub.2--O, BAL, CH.sub.2HEMA), 4.01-4.15
(--CH.sub.2--O--CO PTMO), 3.75 (small CH.sub.3 signal, LDI),
3.31-3.50 (CH.sub.2--O PTMO), 3.07-3.23 (CH.sub.2--NH, LDI),
2.36-2.56 (--CH.sub.2--CF.sub.2--, BAL), 1.91-1.96 (HEMA CH.sub.3)
1.27-1.74 (PTMO and LDI CH.sub.2). .sup.19F NMR (300 MHz,
CDCl.sub.3) .delta. (ppm) -81.23 (CF.sub.3), -114.02 (CF.sub.2),
-122.34 (CF.sub.2), -123.34 (CF.sub.2), -123.30 (CF.sub.2), -124.03
(CF.sub.2), -126.56 (CF.sub.2). GPC analysis: the product was
dissolved in dioxane and run on a GPC system with a polystyrene
column and UV detector. No free HEMA monomer detected in this
analysis. HPLC analysis: retention time of 39.8 minutes (Compound
2), no free HEMA monomer detected in this analysis. Reversed phase
HPLC, C18 column, MeOH and pH 9 PBS mobile phase (gradient). IR
analysis was in accordance with the chemical structure: 3318
cm.sup.-1 v(N--H) H-bonded, 2935 cm.sup.-1 v(C--H) CH.sub.2
asymmetric stretching, 2854 cm.sup.-1 v(C--H) CH.sub.2 symmetric
stretching, 1722 cm.sup.-1 v(C.dbd.O) urethane amide, 1634
cm.sup.-1 (vinyl C.dbd.C stretching), 1532 cm.sup.-1 v(C--N)
stretching mode, 1456 cm.sup.-1 v(C--N) stretching mode, 1349.31
cm.sup.-1 v(C--O) stretching, 1400-1000 cm.sup.-1 v(C--F)
monofluoroalkanes absorb to the right in the range, while
polyfluoroalkanes give multiple strong bands over the range from
1350-1100 cm.sup.-1. Elemental analysis: theoretical based on
reagent stoichiometry (%): C, 49.64; H, 6.53; F, 21.71; N, 2.56; O,
19.55. Measured: C, 50.78; H, 6.89; F, 19.33; N, 2.50.
EXAMPLE 2
Synthesis of .alpha.,.omega.-BAL-Poly(LDI(Allyl)/PTMO) with Pendent
Vinyl Groups (Compound 3)
##STR00016##
[0188] Compound 1-acid (12.03 g, 12.11 mmol), DMAP (0.74 g, 6.05
mmol), allyl alcohol (4.22 g, 72.64 mmol) and anhydrous DCM (100
mL) were weighed into a 250 mL flask equipped with a stir bar. The
contents of the flask were magnetically stirred until all
ingredients were dissolved. Then EDC (6.96 g, 36.32 mmol) white
solid was added to the flask. The reaction flask was wrapped with
aluminium foil and the solution was stirred at room temperature
under N.sub.2 for 3 days. After 3 days, DCM was removed by rotary
evaporator at 25.degree. C. to yield a viscous crude product. The
crude product was washed three times with aqueous HCl (each time
using a mixture of 30 mL of 0.1N HCl and 60 mL distilled water),
and finally with distilled water (100 mL) itself. Extracting
organic soluble materials (includes the desired product) into
diethyl ether solvent, drying the organic solvent over solid
MgSO.sub.4, and removing the solvent by rotary evaporator at room
temperature yielded a slightly yellow liquid. Column chromatography
of the liquid using first diethyl ether, diethyl ether/DCM (50/50,
w/w) mixture, DCM itself, and then a DCM/MeOH (80/20, w/w) mixture
yielded an opaque liquid (Compound 3), 6.34 g (50.6%). Elemental
analysis: Theoretical based on reagent stoichiometry (%): C, 49.61;
H, 6.60; F, 23.24; N, 2.75; O, 17.80. Measured: C, 49.47; H, 6.64;
F, 24.87; N, 2.65. .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 5.92
(CH.sub.2CHCH.sub.2, allyl), 5.30 (CH.sub.2CHCH.sub.2 (geminal,
allyl)), 4.74 (NH), 4.64 (CH.sub.2CHCH.sub.2, allyl), 4.37
(OCH.sub.2, BAL, and NHCH, LDI), 4.08 (NH(O)COCH.sub.2, PTMO), 3.42
(OCH.sub.2CH.sub.2, PTMO), 3.15 (NHCH.sub.2, LDI), 2.46
(OCH.sub.2CH.sub.2, BAL), 1.87-1.20 (CH.sub.2, LDI, and CH.sub.2,
PTMO). Based on integration of BAL at 2.47 ppm and allyl alcohol at
6.12 ppm, the amount of allyl alcohol attached onto the oligomer
after the reaction was estimated to be 72%. The absolute
number-average molecular weight (Mn) was estimated, using
pentafluorobenzene (6.90 ppm) as the external reference against BAL
at 2.46 ppm, PTMO at 3.42 ppm, LDI at 3.15 ppm and allyl at 5.92
ppm, to be 1845 g/mol. .sup.19F-NMR (CDCl.sub.3, 300 MHz,
CFCl.sub.3 as the internal reference standard): .delta. -81.26
(CF.sub.3), -114.02 (CF.sub.2), -122.41 (CF.sub.2), -123.40
(CF.sub.2), -124.15 (CF.sub.2), -126.75 (CF.sub.2). GPC analysis:
the product was dissolved in dioxane and run on a GPC system with a
polystyrene column and UV detector: no free monomer was detected.
HPLC analysis: retention time of 40 minutes (Compound 3), no free
allyl monomer detected. Reversed phase HPLC, C18 column, MeOH and
pH 9 PBS mobile phase (gradient). FT-IR (KBr disc, neat): 3318
(N--H, broad), 2933-2794 (aliphatic C--H), 1704 (C.dbd.O), 1650
(C.dbd.C), 1530, 1436, 1355, 1255, 1100, 843, 809, 778, 745, 734,
707, 697 cm.sup.-1.
EXAMPLE 3
Synthesis of .alpha.,.omega.-Allyl-Poly(LDI(BAL)/PTMO) with Pendent
Vinyl Groups (Compound 4)
[0189] Compound 4 was prepared by conjugating fluorinated groups to
Compound 13 from Example 11.
##STR00017##
[0190] Compound 13-acid from Example 11 (7.52 g, 10.95 mmol), DMAP
(0.67 g, 5.48 mmoL), BAL (23.06 g, 65.71 mmol, M.sub.n=351 Daltons
determined by .sup.1H-NMR using pentafluorobenzene as the external
reference), and anhydrous DCM (100 g) were weighed into a 250 mL
flask equipped with a stir bar. The flask was magnetically stirred
until all ingredients were dissolved. Then EDC (6.30 g, 32.86 mmol)
white solid was added to the flask. The reaction flask was wrapped
with aluminium foil and the solution was stirred at room
temperature under N.sub.2 for 5 days. After 5 days, DCM was removed
by rotary evaporator at 25.degree. C. to yield a yellow crude
product. The crude product was washed three times with aqueous HCl
(each time using a mixture of 30 mL of 0.1N HCl and 60 mL distilled
water), and finally with distilled water (100 mL) itself.
Extracting organic soluble materials (includes the desired product)
into diethyl ether solvent, drying the organic solvent over solid
MgSO.sub.4, and removing the solvent by rotary evaporator at room
temperature yielded a slightly yellow liquid. The liquid was
dissolved in a small amount of acetone, and dropwise the acetone
solution was added into a beaker containing methoxyperfluorobutane
solvent (150 g), forming an emulsion. Centrifuging the emulsion at
3400 rpm and discarding the fluorinated solvent yielded a clear
liquid, Compound 4. Elemental analysis: Theoretical based on
reagent stoichiometry (%): C, 49.61; H, 6.60; F, 23.24; N, 2.74; O,
17.80. Measured: C, 53.42; H, 7.76; F, 16.25; N, 2.70. .sup.1H-NMR
(CDCl.sub.3, 300 MHz): .delta. 5.92 (CH.sub.2CHCH.sub.2, allyl),
5.25 (CH.sub.2CHCH.sub.2 (geminal, allyl)), 4.74 (NH), 4.57
(CH.sub.2CHCH.sub.2, allyl), 4.44 (OCH.sub.2, BAL), 4.32 (NHCH,
LDI), 4.08 (NH(O)COCH.sub.2, PTMO), 3.42 (OCH.sub.2, PTMO), 3.17
(NHCH.sub.2, LDI), 2.50 (OCH.sub.2CH.sub.2, BAL), 1.87-1.20
(CH.sub.2, LDI, and CH.sub.2, PTMO). Based on integration of BAL at
2.47 ppm and LDI at 3.17 ppm, the amount of BAL attached onto the
oligomer after the reaction was estimated to be 67%. The absolute
number-average molecular weight (Mn) was estimated, using
pentafluorobenzene (6.90 ppm) as the external reference against
allyl at 5.92 ppm, PTMO at 3.42 ppm, BAL at 2.50 ppm and LDI at
3.17 ppm, to be 2007 g/mol. .sup.19F-NMR (CDCl.sub.3, 300 MHz,
CFCl.sub.3 as the internal reference standard): .delta. -81.14
(CF.sub.3), -113.86 (CF.sub.2), -122.19 (CF.sub.2), -123.30
(CF.sub.2), -123.89 (CF.sub.2), -126.46 (CF.sub.2). GPC analysis:
the product was dissolved in dioxane and run on a GPC system with a
polystyrene column and UV detector: no free monomer was detected.
HPLC analysis: no free monomer detected. Reversed phase HPLC, C18
column, MeOH and pH 9 PBS mobile phase (gradient). FTIR (KBr,
neat): 3315 (N--H, broad), 2933-2794 (aliphatic C--H), 1720
(C.dbd.O), 1644 (C.dbd.C), 1530, 1436, 1365, 1247, 1110, 778, 742,
733, 706, 696 cm.sup.-1.
EXAMPLE 4
Synthesis of .alpha.,.omega.-BAL-Poly(LDI/PTMO) with Pendent Amino
Ethyl Methacrylate (Compound 5)
##STR00018##
[0192] Compound 1-acid (0.5 gram, .about.0.43 mmol acid) was
weighed into a 2-neck flask, degassed, and dissolved in DMF (5 mL).
The solution was chilled to 0.degree. C., and to it was added EDC
(0.245 g, 1.28 mmol) pre-dissolved in DMF (1 mL). The solution was
raised to room temperature and stirred under nitrogen atmosphere
and protection from light for two hours. Then, DMAP (0.026 g, 0.21
mmol) and AEMA.HCl (0.035 g, 0.21 mmol) were added to the flask,
and stirred till all compounds were dissolved. The solution was
kept stirring for one hour. The product (Compound 5) was
precipitated and washed with water. The product was resuspended in
acetone, dried with MgSO4, and the solvent was evaporated off at
room temperature. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm)
6.13 (AEMA vinyl H), 5.61 (AEMA vinyl H), 4.36 (O--CH.sub.2-- BAL),
4.25 (CH.sub.2, AEMA), 4.07 (--CH.sub.2--O--CO PTMO), 3.75 (minor
LDI ester CH.sub.3), 3.41 (CH.sub.2--O PTMO), 3.18 (CH.sub.2--NH,
LDI), 2.45 (--CH.sub.2--CF.sub.2-- BAL), 1.95 (--CH.sub.3, AEMA),
1.62 (PTMO and LDI CH.sub.2). GPC analysis: Compound 5 was
dissolved in THF and run on a GPC system with a polystyrene column
and UV detector. No free AEMA monomer detected in this
analysis.
EXAMPLE 5
Synthesis of .alpha.,.omega.-FEO1-Poly(LDI/PTMO) with Pendent Vinyl
Groups (Compound 6)
##STR00019##
[0194] PTMO (10 g, 10 mmol, degassed) was dissolved in anhydrous
DMAc (50 mL). LDI (4.11 g, 20 mmol, distilled) and DBDL catalyst
were dissolved in anhydrous DMAc (25 mL) and added dropwise to the
PTMO solution, and the reaction was maintained at 70.degree. C. for
two hours under N.sub.2. The
hydroxyperfluoroacrylate(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11
heptadecafluoro-2-hydroxyundecyl acrylate) (FEO1, 12.058 g, 22
mmol) was dissolved in DMAc (25 mL) with DBDL and added dropwise to
the reaction solution. The reactor was kept sealed under N.sub.2
and stirred overnight at room temperature. The product was
precipitated in water (2 L) and re-dissolved in diethyl ether (100
mL, 100 ppm BHT), dried with MgSO.sub.4 and filtered. The ether
solution was dropped into hexane (400 mL) to precipitate the
product and extract un-reacted reagent. The hexane was decanted and
the solvent extraction procedure was repeated twice. The purified
product (Compound 6) was dissolved in diethyl ether (50 mL), and
the solvent removed by rotary evaporation at room temperature.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 6.40-6.52 (FEO1
vinyl H), 6.09-6.23 (FEO1 vinyl H), 5.80-5.95 (FEO1 vinyl H),
4.15-4.53 (C--H FEO1, O--CH.sub.2-- FEO1), 4.00-4.15
(--CH.sub.2--O--CO PTMO), 3.75 (LDI ester CH.sub.3), 3.31-3.50
(CH.sub.2--O PTMO), 3.05-3.25 (CH.sub.2--NH, LDI), 2.35-2.61
(--CH.sub.2--CF.sub.2-- FEO1), 1.25-1.73 (PTMO and LDI CH.sub.2).
GPC analysis: Compound 6 was dissolved in dioxane and run on a GPC
system with a polystyrene column and UV detector. No free FEO1
monomer detected in this analysis. IR analysis: 1634
cm.sup.-1(C.dbd.C)
EXAMPLE 6
Synthesis of .alpha.,.omega.-FEO2-Poly(LDUPTMO) with Pendent Vinyl
Groups (Compound 7)
##STR00020##
[0196] PTMO (2.012 g, 2 mmol, degassed) was dissolved in anhydrous
DMAc (10 mL). LDI (0.848 g, 4 mmol, distilled) and DBDL catalyst
were dissolved in anhydrous DMAc (5 mL) and was added dropwise to
the PTMO solution. The pre-polymer reaction was maintained at
60-70.degree. C. for two hours under N.sub.2. The perfluor-en-ol
(1H, 1H, 2H, 3H nonafluorohept-2-en-ol) (FEO2, 1.214 g, 4.4 mmol)
was dissolved in DMAc (5 mL) with DBDL and added dropwise to the
pre-polymer solution. The reactor was kept sealed under N.sub.2 and
stirred overnight at room temperature. The product was precipitated
in water (0.5 L) and re-dissolved in diethyl ether (20 mL, 100 ppm
BHT), dried with MgSO.sub.4 and filtered. The ether solution was
dropped into hexane (80 mL) to precipitate the product and extract
un-reacted reagent. The hexane was decanted and the solvent
extraction procedure was repeated twice. The purified product
(Compound 7) was dissolved in diethyl ether (50 mL), and the
solvent removed by rotary evaporation at room temperature. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 6.37-6.51 (vinyl H, FEO2),
5.76-5.95 (vinyl H, FEO2), 5.80-5.95 (FEO1 vinyl H), 4.66-4.87
(CH.sub.2, FEO2), 4.24-4.38 ((--CH.sub.2--O--CO LDI), 3.97-4.12
(--CH.sub.2--O--CO PTMO), 3.66-3.77 (LDI ester CH.sub.3), 3.27-3.52
(CH.sub.2--O PTMO), 3.05-3.23 (CH--NH, LDI), 1.28-1.94 (PTMO and
LDI CH.sub.2). GPC analysis: (Compound 7) was dissolved in dioxane
and run on a GPC system with a polystyrene column and UV detector.
No free FEO2 monomer detected in this analysis. IR analysis: 1634
cm.sup.-1 (C.dbd.C).
EXAMPLE 7
Synthesis of .alpha.,.omega.-FEO3-Poly(LDI/PTMO) with Pendent Vinyl
Groups (Compound 8)
##STR00021##
[0198] PTMO (10 g, 10 mmol, degassed) was dissolved in anhydrous
DMAc (50 mL). LDI (4.241 g, 20 mmol, distilled) and DBDL catalyst
were dissolved in anhydrous DMAc (22 mL) and was added dropwise to
the PTMO solution. The pre-polymer reaction was maintained at
60-70.degree. C. for two hours under N.sub.2. The
hydroxyperfluoroacrylate
(3-(perfluoro-3-methylbutyl)-2-hydroxypropyl methacrylate) (FEO3,
9.068 g, 22 mmol) was dissolved in DMAc (23 mL) with DBDL and added
dropwise to the pre-polymer solution. The reactor was kept sealed
under N.sub.2 and stirred overnight at room temperature. The
product was precipitated in water (2 L) and re-dissolved in diethyl
ether (100 mL, 100 ppm BHT), dried with MgSO.sub.4 and filtered.
The ether solution was dropped into hexane (400 mL) to precipitate
the product and extract un-reacted reagent. The hexane was decanted
and the solvent extraction procedure was repeated two times. The
purified product (Compound 8) was dissolved in diethyl ether (50
mL), and the solvent removed by evaporation in a flow hood at room
temperature. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm)
6.10-6.16 (FEO3 vinyl H), 5.66-5.89 (FEO3 vinyl H), 4.27-4.41
(--O--CH.sub.2-- FEO3), 4.15-4.27 (--O--CH.sub.2-- FEO3) 4.00-4.14
(--CH.sub.2--O--CO PTMO), 3.75 (LDI ester CH.sub.3), 3.27-3.52
(CH.sub.2--O PTMO), 3.05-3.21 (CH.sub.2--NH, LDI), 2.34-2.61
(--CH.sub.2--CF.sub.2-- FEO3), 1.90-1.99 (CH.sub.3, FEO3),
1.22-1.90 (PTMO and LDI CH.sub.2). GPC analysis: Compound 8 was
dissolved in dioxane and run on a GPC system with a polystyrene
column and UV detector. No free FEO3 monomer detected in this
analysis. IR analysis: 1634 cm.sup.-1 (C.dbd.C).
EXAMPLE 7'
Synthesis of
.alpha.,.omega.-C8-Poly(LDI(hydroxyperfluoroacrylate)/PTMO) with
Pendent Vinyl Groups (Compound 9')
##STR00022##
[0200] PTMO (10.0 g, 10.0 mmol) was weighed into a 250 mL round
bottom flask equipped with a stir bar. The flask was heated to
30.degree. C. using an oil bath, and was held under vacuum for 2
hours to remove trace amounts of water. The flask was cooled to
room temperature and anhydrous DMAc (50 mL) was added to dissolve
the PTMO. LDI (3.18 g, 15.0 mmol), DBDL and anhydrous DMAc (5 mL)
were mixed and transferred to the flask via syringe. The reaction
flask was heated to 70.degree. C. in an oil bath, and the reaction
mixture was stirred for 2 hours. Then, 1-octanol (1.43 g, 11 mmol)
was introduced into the reactor by syringe injection, and the
reaction mixture was kept stirring at room temperature overnight
(17 hours). The next day, the reaction mixture was precipitated
into 3 L of distilled water. The wash procedure was repeated twice
with distilled water (3 L). The product was dried under a vacuum to
yield the final product, Compound 8'-ester. .sup.1H-NMR
(CDCl.sub.3, 300 MHz): .delta. 4.07 (NH(O)COCH.sub.2, PTMO), 3.74
(--OCH.sub.3, LDI), 3.41 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO,
and (O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 3.16
(NHCH.sub.2, LDI), 1.62 (CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH, LDI,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO, and
(O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 0.88
((O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol). The MW of
Compound 8'-ester was higher compared to Compound 1 MW, as detected
by GPC measurement.
[0201] Compound 8'-ester (5.0 g, 5.2 mmol ester) was weighed in a
250 mL beaker and was dissolved in acetone (50 mL). NaOH 1.0N (5.18
mL) was added dropwise to the beaker and the mixture was stirred at
room temperature for 6 hours. The reaction mixture was then
neutralized with 5.70 mL of 1.0 N aqueous HCl, and additional water
was added to yield a white precipitate. Once the wash water was
removed, the intermediate product was recovered and was washed
twice with distilled water (1.0 L). The final product was dried
under vacuum for 18 hours to yield an opaque viscous product,
Compound 8'-acid. .sup.1H-NMR (CDCl.sub.3, 300 MHz): the singlet at
3.74 (--OCH.sub.3) was used to monitor the degree of hydrolysis of
the ester group.
[0202] Compound 8'-acid (0.43 g, 0.46 mmol acid), DMAP (27.2 mg,
0.22 mmoL), FEO1 (1.46 g, 2.67 mmol) and anhydrous DCM (7 mL) were
weighed into a 50 mL flask equipped with a stir bar. The contents
of the flask were magnetically stirred until all ingredients were
dissolved. Then EDC (0.256 g, 1.3 mmol) white solid was added to
the flask. The reaction flask was wrapped with aluminium foil and
the solution was stirred at room temperature under N.sub.2
overnight. The following day, the DCM was removed by rotary
evaporation at 25.degree. C. to yield a crude product. The crude
product was washed using solvent and water extraction, dried over
MgSO.sub.4, and the solvent was removed by rotary evaporation. The
final product (Compound 9') was dried under vacuum. .sup.1H-NMR
(CDCl.sub.3, 300 MHz): .delta. 6.45, 6.19, 5.43 (vinyl H, FEO1),
4.07 (NH(O)COCH.sub.2, PTMO), 3.74 (minor --OCH.sub.3, LDI), 3.41
(OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO, and
(O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 3.16 (NHCH.sub.2,
LDI), 2.42 (--CH.sub.2--CF.sub.2--, FEO1), 1.62
(CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH, LDI,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO, and
(O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 0.88
((O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol). GPC analysis:
Compound 9' was dissolved in dioxane and run on a GPC system with a
polystyrene column and UV detector. No free FEO1 monomer was
detected in this analysis.
[0203] The above conjugation of FEO1 was reproduced using FEO3.
Compound 8'-acid (2.5 g, 2.59 mmol acid), DMAP (0.158 g, 1.29
mmoL), FEO3 (6.396 g, 15.52 mmol) and anhydrous DCM (13 mL) were
weighed into a 100 mL flask equipped with a stir bar. The contents
of the flask were magnetically stirred until all ingredients were
dissolved. Then EDC (1.487 g, 7.76 mmol) was added to the flask.
The remaining synthesis and purification steps were identical to
the FEO1 reaction. .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 6.14,
5.64 (vinyl H, FEO3), 4.07 (NH(O)COCH.sub.2, PTMO), 3.74 (minor
--OCH.sub.3, LDI), 3.41 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO,
and (O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 3.16
(NHCH.sub.2, LDI), 2.4 (--CH.sub.2--CF.sub.2--, FEO3), 1.94
(CH.sub.3, FEO3), 1.62 (CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH, LDI,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO, and
(O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 0.88
((O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol). GPC analysis:
Compound 9' (b) was dissolved in dioxane and run on a GPC system
with a polystyrene column and UV detector. No free FEO3 monomer was
detected in this analysis.
EXAMPLE 8
Synthesis of .alpha.,.omega.-BAL-Poly(LDI(HEMA)/PSi) with Pendent
Vinyl Groups (Compound 10)
##STR00023##
[0205] Poly(dimethylsiloxane), bis(3-aminopropyl) terminated (30.2
g, 12.1 mmol, M.sub.n=2500, Aldrich) were weighed into a 250 mL
round bottom flask equipped with a stir bar. The flask was heated
to 45.degree. C. using an oil bath, and under vacuum pumping for 2
hours to remove trace amounts of water. The flask was removed from
the oil bath and allowed to cool to room temperature before it was
transferred to a glove box with LDI, BAL, a 1 L bottle containing
anhydrous DCM solvent and a flame-dry empty 250 mL round bottom
flask equipped with a stir bar. In the glove box, LDI (5.13 g, 24.2
mmol) and anhydrous DCM (100 mL) was transferred to the empty
flask. Anhydrous DCM (50 mL) was also transferred to the flask
containing dry poly(dimethylsiloxane), and the flask was swirled
until the content completely dissolved. The solution of
poly(dimethylsiloxane) was then added dropwise to the flask
containing LDI solution as the reaction mixture was stirred at room
temperature. The addition complete in 10 minutes, and the reaction
mixture was kept stirring for another 20 minutes. Then, BAL (8.48
g, 24.2 mmol, M.sub.n=351 g/mol determined by .sup.1H-NMR using
pentafluorobenzene as the external reference) was transferred into
the reactor. The reactor was capped by a rubber septum and removed
from the glove box. While the reaction mixture was heated to
65.degree. C. in an oil bath under N.sub.2, DBDL (0.02 mL) was
transferred to the reactor via. a syringe. The reactor was kept
stirring at 65.degree. C. overnight (17 hours). The next day, the
reaction mixture was cooled to room temperature, and DCM solvent
was removed by rotary evaporator to yield a liquid product
(Compound 9-ester).
[0206] Compound 9-ester (30.5 g, 16.8 mmol) and DCM (100 mL) were
transferred to a 500 mL flask containing a stir bar. Deionized
water (3.33 g, 18.5 mmol) and NaOH in MeOH (0.10 N, 185 mL, 18.5
mmol) were added to the reactor. Note that if the ester-precursor
solution turned cloudy during the addition of NaOH solution and
water, more DCM solvent was required until the mixture became
transparent. The reaction mixture was kept stirring at room
temperature for 8 hours, and then neutralized with a 1.0 N
HCl.sub.(aq) (20 mL, 20.0 mmol). Transferred the reaction mixture
to a separatory funnel, washed it twice with deionized water and
removed organic solvents by rotary evaporator yielded slightly
yellow viscous liquid. Complete removal of residual organic
solvents afforded transparent viscous liquid, Compound 9-acid.
[0207] Compound 9-acid (20.8 g, 11.56 mmol), DMAP (0.71 g, 5.78
mmol), HEMA (9.03 g, 69.37 mmol) and anhydrous DCM (150 mL) were
transferred into a 500 mL flask equipped with a stir bar. The
content of the flask were magnetically stirred until all
ingredients were dissolved. Then white solid EDC (6.65 g, 34.69
mmol) was added to the flask. The reaction flask was wrapped with
aluminium foil and kept stirring at room temperature under N.sub.2
for 3 days. After 3 days, DCM was removed by rotary evaporator at
25.degree. C. to yield a viscous crude product. The crude product
was washed three times with distilled water (150 mL each time).
Extracting organic soluble materials into diethyl ether solvent,
drying the organic solvent over solid MgSO.sub.4, and removing the
solvent by rotary evaporator at room temperature yielded a viscous
liquid. The viscous liquid was washed three times with MeOH (HPLC
grade, 150 mL each time) to remove unreacted HEMA. MeOH solvent was
discarded and removed completely by a vacuum pump to afford a
transparent viscous liquid, Compound 10.
EXAMPLE 9
Synthesis of .alpha.,.omega.-BAL-Poly(LDI(HEMA)/PCL) with Pendent
Vinyl Groups (Compound 11')
##STR00024##
[0209] Polycaprolactone diol (PCL diol) (10 grams, 8 mmol,
degassed) was dissolved in anhydrous DMAc (50 mL). LDI (3.39 g, 16
mmol, distilled) and DBDL catalyst was dissolved in anhydrous DMAc
(18 mL) and was added dropwise to the PCL diol solution. The
pre-polymer reaction was maintained at 60-70.degree. C. for two
hours under N.sub.2. BAL (7.39 g, 18 mmol) and DBDL were dissolved
in anhydrous DMAc (25 mL) and were added dropwise to the
pre-polymer solution. The reactor was kept sealed under N.sub.2 and
stirred overnight at room temperature. The product (Compound
11-ester) was precipitated in water (3 L), re-suspended in acetone,
and purified by passing the acetone solution through SCX SPE
columns. The acetone solution was evaporated at 40.degree. C. in a
flow oven, and the product was dried under vacuum. PCL diol and
Compound 11-ester were dissolved in dioxane and were analyzed by
GPC using polystyrene columns and UV detection: the Compound
11-ester chromatogram does not contain un-reacted PCL diol. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 4.28-4.46
(--CH.sub.2--O--CONH--, BAL), 4.16-4.27 (--CH--O--CONH--, PCL),
3.98-4.11 (--CH.sub.2--O--, PCL), 3.71-3.77 (CH.sub.3, LDI),
3.09-3.22 (CH.sub.2--O--CONH--, LDI), 2.38-2.54
(CH.sub.2--CF.sub.2, BAL), 2.26-2.38 (O--CO--CH.sub.2--, PCL),
1.45-1.76 (--CH.sub.2--, PCL), 1.20-1.45 (--CH.sub.2--, PCL).
[0210] Compound 11-ester (0.5 g, 0.4 mmol LDI ester) was dissolved
in acetone (5 mL) and once dissolved, 1 N NaOH (0.4 mL, 0.4 mmol)
was added with good stirring at room temperature for three hours.
The product was neutralized with 1 N HCl (0.4 mL, 0.4 mmol) and
water was added to complete the precipitation and wash the product.
The product (Compound 11-acid) was dried under vacuum at 60.degree.
C. The conversion of ester functional groups to acid groups was
monitored by proton NMR analysis.
[0211] Compound 11-acid (2.0 gram, .about.2.4 mmol acid), DMAP
(0.145 g, 1.19 mmol), HEMA (1.863 g, 14.3 mmol) and DCM (10 mL)
were added to a 100 mL flask, and were stirred until all compounds
are dissolved. EDC (1.372 g, 7.16 mmol) was added to the DCM
solution, and once the EDC was dissolved, the solution was stirred
at room temperature for 24 hours under nitrogen atmosphere and
protection from light. The reaction mixture was reduced to a
viscous liquid by rotary evaporation and washed with water. The
washed product was dissolved in ether and water was removed by
mixing the solution with MgSO.sub.4 for 1 hour. The solution was
clarified by gravity filtration and the solvent was removed by
rotary evaporation. The product (Compound 11') was re-dissolved in
ether, and was purified by precipitation through hexane. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 6.08-6.17 (vinyl H, HEMA),
5.57-5.64 (vinyl H, HEMA), 4.30-4.54 (--CH--O--CONH--, BAL),
4.21-4.27 (--CH--O--CONH--, PCL), 3.99-4.13 (--CH.sub.2--O--, PCL),
3.62-3.77 (minor, CH.sub.3, LDI), 3.09-3.22 (CH.sub.2--O--CONH--,
LDI), 2.43-2.56 (CH.sub.2--CF.sub.2, BAL), 2.24-2.40
(O--CO--CH.sub.2--, PCL), 1.92-1.99 (CH3, HEMA), 1.30-1.90
(--CH.sub.2--, PCL).
EXAMPLE 10
Synthesis of .alpha.,.omega.-FEO1-Poly(LDI/PCL) with Pendent Vinyl
Groups (Compound 12)
##STR00025##
[0213] PCL diol (10 g, 8 mmol, degassed) was dissolved in anhydrous
DMAc (50 mL). LDI (3.39 g, 16 mmol, distilled) and DBDL catalyst
was dissolved in anhydrous DMAc (17 mL) and was added dropwise to
the PCL diol solution. The pre-polymer reaction was maintained at
60-70.degree. C. for two hours under N.sub.2. FEO1 (9.648 g, 18
mmol) was dissolved in DMAc (24 mL) with DBDL and added dropwise to
the pre-polymer solution. The reactor was kept sealed under N.sub.2
and stirred overnight at room temperature. The product was
precipitated in water (3 L) and re-dissolved in chloroform (100 mL,
100 ppm BHT), dried with MgSO.sub.4, centrifuged and the
supernatant decanted. The chloroform solution was dropped into
hexane (400 mL) to precipitate the product and extract un-reacted
reagent. The hexane was decanted and the solvent extraction
procedure was repeated twice. The purified product (Compound 12)
was dissolved in chloroform (50 mL), and the solvent removed at
room temperature in a flow hood. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ppm) 6.41-6.49 (FEO1 vinyl H), 6.10-6.21 (FEO1 vinyl H),
5.87-5.94 (FEO1 vinyl H), 4.29-4.37 (O--CH.sub.2, FEO1), 4.17-4.27
(--CH.sub.2--O--CONH--, PCL, O--CH.sub.2, FEO1), 3.98-4.11
(--CH.sub.2--O--, PCL), 3.73-3.78 (CH.sub.3, LDI), 3.64-3.73 (C--H,
FEO1) 3.10-3.21 (CH.sub.2--O--CONH--, LDI), 2.40-2.58
(CH.sub.2--CF.sub.2, FEO1), 2.26-2.38 (O--CO--CH.sub.2--, PCL),
1.45-1.74 (--CH.sub.2--, PCL), 1.18-1.44 (--CH.sub.2--, PCL). GPC
analysis: Compound 12 was dissolved in THF and run on a GPC system
with a polystyrene column and UV detector. No free FEO1 monomer
detected in this analysis. IR analysis: 1634 cm.sup.-1
(C.dbd.C).
EXAMPLE 11
Synthesis of .alpha.,.omega.-Allyl-Poly(LDI/PTMO) with Pendent
Vinyl Groups (Compound 13)
##STR00026##
[0215] PTMO (20.00 g, 23.23 mmol, M.sub.n=861 Daltons determined by
.sup.1H-NMR using pentafluorobenzene as the external reference) was
weighed into a 250 mL round bottom flask equipped with a stir bar.
The flask was heated to 45.degree. C. using an oil bath, and was
held under vacuum for 2 hours to remove trace amounts of water. The
flask was removed from the oil bath and allowed to cool to room
temperature before LDI (9.86 g, 46.46 mmol) and anhydrous DMAc (100
mL) were transferred to the flask via. two separate syringes. The
reaction flask was heated to 65.degree. C. in the oil bath and DBDL
was syringed onto the flask. The reaction mixture was stirred at
65.degree. C. for 3 hours, and then cooled to room temperature in
an ice bath. Then, liquid allyl alcohol (2.70 g, 46.46 mmoL) was
introduced into the reactor by syringe injection, and the reaction
mixture was kept stirring at room temperature overnight (17 hours).
The next day, the reaction mixture was poured into a 1 L beaker
containing 900 mL distilled water in order to precipitate the
polymer. Removing the wash water yielded a crude liquid product.
Repeating the washing twice with distilled water (500 mL) generated
a slightly yellow liquid. The liquid was dried under a vacuum for
18 hours, and yielded a liquid (Compound 13-ester). Elemental
analysis: Theoretical based on reagent stoichiometry (%): C, 60.64;
H, 9.46; N, 4.00; O, 25.90. Measured: C, 60.52; H, 9.55; N, 3.77;
O, 25.36. .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 5.92
(CH.sub.2CHCH.sub.2, allyl), 5.25 (CH.sub.2CHCH.sub.2, geminal,
allyl), 4.74 (NH), 4.57 (CH.sub.2CHCH.sub.2, allyl), 4.34 (NHCH,
LDI), 4.08 (NH(O)COCH.sub.2, PTMO), 3.74 (--OCH.sub.3, LDI), 3.42
(OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO), 3.17 (NHCH.sub.2, LDI),
1.87-1.20 (CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH, LDI, and
OCH.sub.2CH.sub.2CHCH.sub.2O, PTMO). Based on integration numbers
of LDI at 3.17 ppm and allyl at 2.47 ppm, the 5.92 ppm, the amount
of allyl groups attached onto the oligomer after the reaction was
estimated to be 71%. The absolute number-average molecular weight
(Mn) was estimated, using pentafluorobenzene (6.90 ppm) as the
external reference against allyl at 5.92 ppm, PTMO at 3.42 ppm and
LDI at 3.17 ppm, to be 1099 g/mol. GPC (DMF, 1 mL/min, linear PS as
standards, UV at 280 nm and RI detector). FTIR (KBr, neat): 3315
(N--H, broad), 2933-2794 (aliphatic C--H), 1720 (C.dbd.O), 1644
(C.dbd.C), 1530, 1436, 1365, 1247, 1110, 778, 742 cm.sup.-1.
[0216] Compound 13-ester (25.0 g, 35.67 mmoL) was weighed in a 500
mL flask containing 150 mL MeOH (HPLC grade) and a stir bar. A base
solution of 1.62 g (40.5 mmoL) solid NaOH dissolved in 4.20 g of
distilled water was added dropwise to the flask and the mixture was
stirred at room temperature for 18 hours. The next day, the
reaction mixture was neutralized with 7.0 mL of 6.0 N aqueous HCl,
and then poured into a 2 L beaker containing 1.4 L distilled water,
to yield a white precipitate. Extracting organic soluble materials
(includes the desired product) into diethyl ether solvent, drying
the organic solvent over solid MgSO.sub.4, and removing the solvent
by rotary evaporator at room temperature yielded a clear liquid.
The organic solvent was further dried under vacuum for 18 hours to
yield a clear viscous product, Compound 13-acid. Elemental
analysis: Theoretical based on reagent stoichiometry (%): C, 60.13;
H, 9.36; N, 4.08; O, 26.46. Measured: C, 60.05; H, 9.58; N, 3.36;
O, 25.64. .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 5.92
(CH.sub.2CHCH.sub.2, allyl), 5.25 (CH.sub.2CHCH.sub.2, geminal,
allyl), 4.74 (NH), 4.57 (CH.sub.2CHCH.sub.2, allyl), 4.34 (NHCH,
LDI), 4.08 (NH(O)COCH.sub.2, PTMO), 3.42
(OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO), 3.17 (NHCH.sub.2, LDI),
1.87-1.20 (CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH, LDI, and
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO). The singlet at 3.74
(--OCH.sub.3) disappeared almost completely, confirming the
hydrolysis of the ester group. Based on the peak integration the
estimated conversion of ester to acid group was 97%. FTIR (KBr,
neat): 3315 (N--H, broad), 2933-2794 (aliphatic C--H), 1720
(C.dbd.O), 1644 (C.dbd.C), 1530, 1436, 1365, 1247, 1110, 778, 742
cm.sup.-1.
EXAMPLE 12
Synthesis of .alpha.,.omega.-C8-Poly(LDI(HEMA)/PTMO) with Pendent
Vinyl Groups (Compound 15)
##STR00027##
[0218] PTMO (41.29 g, 40.01 mmol, Mn=1032 Daltons, determined by
titration of hydroxyl groups) was weighed into a 250 mL round
bottom flask equipped with a stir bar. The flask was heated to
45.degree. C. using an oil bath, and was held under vacuum for 2
hours to remove trace amounts of water. The flask was removed from
the oil bath and allowed to cool to room temperature before LDI
(16.97 g, 80.02 mmol) and anhydrous DMAc (100 mL) were transferred
to the flask via. two separate syringes. The reaction flask was
heated to 65.degree. C. in the oil bath and DBDL (0.05 mL) was
syringed into the flask. The reaction mixture was stirred at
65.degree. C. for 3 hours. Then, 1-octanol (10.42 g, 80.02 mmoL)
was introduced into the reactor by syringe injection, and the
reaction mixture was kept stirring at 65.degree. C. overnight (17
hours). The next day, the reaction mixture was cooled to room
temperature and poured into a 1 L beaker containing 900 mL
distilled water in order to precipitate the polymer. Removing the
wash water yielded a crude liquid product. Repeating the washing
twice with distilled water (500 mL) generated a slightly yellow
liquid (Compound 14-ester). The liquid was dried under a vacuum for
18 hours, and yielded a liquid with increased viscosity. Elemental
analysis: Theoretical, based on reagent stoichiometry (%): C,
63.13; H, 10.24; N, 3.26; O, 23.36. Measured: C, 62.28; H, 10.13;
N, 3.33; O, 24.19. .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 5.23
(NH), 4.72 (NH), 4.34 (NHCH, LDI), 4.08 (NH(O)COCH.sub.2, PTMO),
3.74 (--OCH.sub.3, LDI), 3.42 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O,
PTMO, and (O)COCH(CH.sub.2).sub.6CH.sub.3, octanol), 3.17
(NHCH.sub.2, LDI), 1.84-1.18 (CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH,
LDI, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO, and
(O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 0.89
((O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol). Based on
integration numbers of LDI at 3.17 ppm and octanol at 0.89 ppm, the
amount of octanol attached onto the oligomer after the reaction was
estimated to be 89%. The absolute number-average molecular weight
(Mn) was estimated, using pentafluorobenzene (6.90 ppm) as the
external reference against octanol at 0.89 ppm, PTMO at 3.42 ppm
and LDI at 3.17 ppm, to be 1425 g/mol. FTIR (KBr, neat): 3314
(N--H, broad), 2933-2728 (aliphatic C--H), 1710 (C.dbd.O), 1524,
1437, 1364, 1245, 1238, 1204, 1107, 778 cm.sup.-1.
[0219] Compound 14-ester (45.0 g, 52.4 mmoL) was weighed in a 500
mL flask containing 150 mL MeOH (HPLC grade) and a stir bar. A base
solution of 2.31 g (57.7 mmoL) solid NaOH dissolved in 6 g of
distilled water was added dropwise to the flask and the mixture was
stirred at room temperature for 21 hours. The next day, the
reaction mixture was neutralized with 11.0 mL of 6.0 N aqueous HCl,
and then poured into a 2 L beaker containing 1.4 L distilled water,
to yield a white precipitate. Once the wash water was removed, a
crude waxy product was obtained. This was washed twice with
distilled water (1.0 L), and the final product was dried under
vacuum for 18 hours to yield an opaque viscous product (Compound
14-acid). Elemental analysis: Theoretical, based on reagent
stoichiometry (%): C, 62.76; H, 10.18; N, 3.32; O, 23.74. Measured:
C, 62.08; H, 10.15; N, 3.32; O, 23.19. .sup.1H-NMR (CDCl.sub.3, 300
MHz): .delta. .delta. 5.23 (NH), 4.72 (NH), 4.34 (NHCH, LDI), 4.08
(NH(O)COCH.sub.2, PTMO), 3.42 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O,
PTMO, and (O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 3.17
(NHCH.sub.2, LDI), 1.84-1.18 (CHCH.sub.2CH.sub.2CHCH.sub.2NH, LDI,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO, and
(O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 0.89
((O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol). The singlet at
3.74 (--OCH.sub.3) disappeared, confirming the hydrolysis of the
ester group. Based on the peak integration the estimated conversion
of ester to acid group was 81%. The absolute number-average
molecular weight (Mn) was estimated, using pentafluorobenzene (6.90
ppm) as the external reference against octanol at 0.89 ppm, PTMO at
3.42 ppm and LDI at 3.17 ppm, to be 1430 g/mol. FTIR (KBr, neat):
3314 (N--H, broad), 2933-2728 (aliphatic C--H), 1710 (C.dbd.O),
1524, 1437, 1364, 1245, 1238, 1204, 1107, 778 cm.sup.-1.
[0220] Compound 14-acid (12.20.0 g, 14.45 mmol), DMAP (0.88 g, 7.23
mmoL), HEMA (11.28 g, 86.70 mmol) and anhydrous DCM (150 g) were
weighed into a 250 mL flask equipped with a stir bar. The contents
of the flask were magnetically stirred until all ingredients were
dissolved. Then EDC (8.31 g, 43.35 mmol) was added to the flask.
The reaction flask was wrapped with aluminium foil and the solution
was stirred at room temperature under N.sub.2 for 5 days. After 5
days, DCM was removed by rotary evaporator at 25.degree. C. to
yield a viscous crude product. The crude product was washed three
times with aqueous HCl (each time using a mixture of 30 mL of 0.1N
HCl and 60 mL distilled water), and finally with distilled water
(100 mL) itself. Extracting organic soluble materials (includes the
desired product) into diethyl ether solvent, drying the organic
solvent over solid MgSO.sub.4, and removing the solvent by rotary
evaporator at room temperature yielded a slightly yellow liquid.
Column chromatography of the viscous liquid using first diethyl
ether, a diethyl ether/DCM mixture (50/50, w/w), DCM itself, and
then a DCM/MeOH mixture (70/30, w/w) yielded a clear viscous liquid
(Compound 15), 6.35 g (46%). Elemental analysis: Theoretical, based
on reagent stoichiometry (%): C, 62.95; H, 9.83; N, 2.93; O, 24.31.
Measured: C, 62.17; H, 9.84; N, 3.18; O, 24.11. .sup.1H-NMR
(CDCl.sub.3, 300 MHz): .delta. 6.12 (geminal CH, HEMA), 5.60
(geminal CH, HEMA), 5.24 (NH), 5.23 (NH), 4.77 (NH), 4.34 (NHCH,
LDI, and OCH.sub.2CH.sub.2O, HEMA), 4.08 (NH(O)COCH.sub.2, PTMO),
3.51-3.30 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO, and
(O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 3.14 (NHCH.sub.2,
LDI), 1.95 ((O)CC(CH.sub.3)CH.sub.2, HEMA), 1.84-1.18
(CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH, LDI,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO, and
(O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 0.89
((O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol). The estimate
conversion of COOH to CO-HEMA is 48% based on .sup.1H-NMR shift
area of 6.12 ppm (HEMA) and 3.14 ppm (LDI). The absolute
number-average molecular weight (Mn) was estimated, using
pentafluorobenzene (6.90 ppm) as the external reference against
octanol at 0.89 ppm, PTMO at 3.42 ppm and LDI at 3.17 ppm, to be
1722 g/mol. GPC analysis: the product was dissolved in dioxane and
run on a GPC system with a polystyrene column and UV detector: no
free monomer was detected. HPLC analysis: retention time of 41
minutes (Compound 15), no free monomer detected. Reversed phase
HPLC, C18 column, MeOH and pH 9 PBS mobile phase (gradient). FTIR
(KBr, neat): 3314 (N--H, broad), 2933-2728 (aliphatic C--H), 1710
(C.dbd.O), 1636 (C.dbd.C), 1524, 1437, 1364, 1245, 1238, 1204,
1107, 778 cm.sup.-1.
EXAMPLE 13
Synthesis of .alpha.,.omega.-C8-Poly(LDI(Allyl)/PTMO) with Pendent
Vinyl Groups (Compound 16)
##STR00028##
[0222] Compound 14-acid (9.83 g, 11.64 mmol), DMAP (0.71 g, 5.82
mmol), allyl alcohol (4.06, 69.86 mmol) and anhydrous DCM (100 g)
were weighed into a 250 mL flask equipped with a stir bar. The
contents of the flask were magnetically stirred until all
ingredients were dissolved. Then EDC (6.70 g, 34.93 mmol) white
solid was added to the flask. The reaction flask was wrapped with
aluminium foil and the solution was stirred at room temperature
under N.sub.2 for 3 days. After 3 days, DCM was removed by rotary
evaporator at 25.degree. C. to yield a viscous crude product. The
crude product was washed three times with aqueous HCl (each time
using a mixture of 30 mL of 0.1N HCl and 60 mL distilled water),
and finally with distilled water (100 mL) itself. Extracting
organic soluble materials (includes the desired product) into
diethyl ether solvent, drying the organic solvent over solid
MgSO.sub.4, and removing the solvent by rotary evaporator at room
temperature yielded a clear liquid. Column chromatography of the
viscous liquid using first diethyl ether, a diethyl ether/DCM
mixture (50/50, w/w), DCM itself, and then a DCM/MeOH mixture
(70/30, w/w) yielded a clear viscous product (Compound 16), 6.21 g
(60% yield). Elemental analysis: Theoretical based on reagent
stoichiometry (%): C, 63.99; H, 10.17; N, 3.17; O, 22.67. Measured:
C, 62.51; H, 9.97; N, 3.19; O, 24.01. .sup.1H-NMR (CDCl.sub.3, 300
MHz): .delta. 5.92 (CH.sub.2CHCH.sub.2, allyl), 5.28
(CH.sub.2CHCH.sub.2 (geminal, allyl)), 4.74 (NH), 4.64
(CH.sub.2CHCH.sub.2, allyl), 4.35 (NHCH, LDI), 4.08
(NH(O)COCH.sub.2, PTMO), 3.42 (OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O,
PTMO, and (O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 3.15
(NHCH.sub.2, LDI), 1.84-1.18 (CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH,
LDI, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O, PTMO, and
(O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol), 0.89
((O)COCH.sub.2(CH.sub.2).sub.6CH.sub.3, octanol). The estimate
conversion of COOH to CO-allyl alcohol is 38% based on .sup.1H-NMR
shift area of 5.92 ppm (allyl) and 3.15 ppm (LDI). The absolute
number-average molecular weight (Mn) was estimated, using
pentafluorobenzene (6.90 ppm) as the external reference against
octanol at 0.89 ppm, allyl at 5.92 ppm, PTMO at 3.42 ppm and LDI at
3.17 ppm, to be 1576 g/mol. GPC analysis: the product was dissolved
in dioxane and run on a GPC system with a polystyrene column and UV
detector: no free monomer was detected. HPLC analysis: retention
time of 41 minutes (Compound 16), no free monomer detected.
Reversed phase HPLC, C18 column, MeOH and pH 9 PBS mobile phase
(gradient). FTIR (KBr, neat): 3314 (N--H, broad), 2933-2728
(aliphatic C--H), 1710 (C.dbd.O), 1650 (C.dbd.C), 1524, 1437, 1364,
1245, 1238, 1204, 1107, 778 cm.sup.-1.
Cured System Based on Homo Cross-Linking
EXAMPLE 14
Homo Cross-Linked Films of Compound 2 Prepared by UV Cure in
Air
[0223] Compound 2 (0.50 g) and HMP (0.0025 g) were weighed a 20 mL
vial. A small amount of MeOH (HPLC grade, 0.3 g) was added to the
vial to reduce the viscosity of the mixture and to ensure good
mixing. The vial was vortexed until the components were completely
well blended. The mixture was cast onto various substrates
including stainless steel discs or plates, an aluminum weighing pan
and a KBr disc. MeOH solvent was allowed to evaporate at room
temperature for 1 h under an aluminum foil. The stainless steel
substrates, weighing pan and KBr disc containing liquid samples
were placed in the center of the UV box before the UV lamp was
turned on for 5 minutes, to yield the solid polymer films. All
substrates were removed from the box and cooled to room temperature
before carrying out film analysis.
[0224] Gel content, swell ratio, contact angle measurements, DSC
and TGA analysis were performed on films prepared on stainless
steel substrates. The typical thickness of these films was 0.4 mm.
XPS analysis was performed on films cast in weighing pans. Gel
content: 98%.+-.3 (n=3). Swell ratio: 1.6.+-.0.2 (n=3). Contact
angle: 131.0.degree..+-.2.7 (5 spots, 3 measurements/spot). XPS
analysis (90.degree.): (top surface: C: 68.84%, N: 4.08%, O:14.24%,
F:28.44%.) DSC: negative heat flow: -70.34.degree. C. (T.sub.g of
PTMO). TGA: 2 onset points: (A) 259.1.degree. C., 28.3% mass loss,
and (B) 404.9.degree. C., 69.4% mass loss. The C.dbd.C group
conversion was monitored on films prepared on KBr discs: C.dbd.C
conversion was recorded.
EXAMPLE 15
Homo Cross-Linked Films of Compound 2 Prepared by UV Cure Under
Argon with Two Different Concentrations of Initiator (0.5 and 1 wt
%)
[0225] Compound 2 (2.9815 g or 2.9542 g) and HMP (0.0145 g or
0.0298 g) were weighed in a 20 mL vial. MeOH (HPLC grade, 5 g) was
added to the vial to reduce the viscosity of the mixture and to
ensure good mixing. The vial was vortexed until the components were
completely well blended. If air bubbles appeared, the vial was
allowed to sit at room temperature until all bubbles dissipated,
before the mixture was cast onto the desired substrates such as
Teflon molds, stainless steel discs, an aluminum weighing pan and a
KBr disc. MeOH solvent was allowed to evaporate at room temperature
for 1 hour or 24 hours under an aluminum foil. After 1 hour, the
stainless steel discs, aluminum weighing pan and KBr disc
containing liquid samples were placed in the center of the UV box.
The box was purged with argon gas for 10 minutes before the UV lamp
was turned on for 5 minutes. All substrates were removed from the
box and cooled to room temperature before carrying out film
analysis. After 24 hours, the UV cure procedure was repeated to
samples cast on Teflon molds. Gel content, swell ratio, contact
angle measurements, TGA analysis were performed on films prepared
on stainless steel discs. The typical thickness of these films was
0.4 mm. XPS analysis was performed on films cast in weighing pans.
The C.dbd.C group conversion was monitored by FTIR and performed on
films prepared on KBr discs. The average thickness of these latter
two films was about 0.03 mm. For tensile measurements, transparent
polymer films free of air bubbles were removed from the molds and
cut into to dog-bone shape (FIG. 1). The dog-bone samples were
air-tightened on an instron machine for subsequent tensile test
measurements. An Instron 4301 system was used to test the samples
with a cross-head load of 50 N at the rate of 10 mm/min, at
23.degree. C. and relative humidity of 57%. Sample thickness was
measured by a caliper ranged from 0.1 to 0.3 mm. The results of
each example represent an average of 4 or 5 dog-bone samples.
TABLE-US-00002 TABLE 2 Polymer film properties after Compound 2 was
UV cured with 0.5 and 1.0 wt % photoinitiator under an inert
atmosphere. 0.5 wt % photoinitiator 1.0 wt % photoinitiator C = C
conver- Recorded Recorded sion (%) Gel content (%) 98 .+-. 3 (n =
3) 97 .+-. 1 (n = 3) Swell ratio 1.43 .+-. 0.05 (n = 3) 1.41 .+-.
0.04 (n = 3) Contact angle 133.4 .+-. 2.2 132.4 .+-. 2.2 (.degree.)
XPS (90.degree.) C: 53.39%, N: 4.24%, C: 52.03%, N: 4.06%, O:
14.15%, F: 28.12%. O: 14.17%, F: 29.50%. TGA 265.1.degree. C.,
27.8% mass loss 251.7.degree. C., 18.2% mass loss 412.9.degree. C.,
69.6% mass loss 401.9.degree. C., 75.9% mass loss Tensile testing n
= 3 n = 3 Stress at break: 3.0 MPa Stress at break: 2.9 MPa Strain
at break: 41% Strain at break: 37.5% Initial modulus (10% Initial
modulus (10% strain): 0.084 strain): 0.085 Toughness: 66.4 MPa
Toughness: 61.6 MPa
EXAMPLE 16
Homo Cross-Linked Films of Compound 3 Prepared by UV Cure
[0226] Compound 3 (0.5934 g), HMP (0.0029 g) and MeOH (HPLC grade,
0.3 g) were weighed in a 20 mL vial. The vial was vortexed until
all the components were well blended. If air bubbles appeared, the
vial was allowed to sit at room temperature until all bubbles
dissipated, before the mixture was cast onto the desired substrates
(stainless steel discs, an aluminum weighing pan and a KBr disc).
MeOH solvent was allowed to evaporate at room temperature for 1 h
under an aluminum foil. The stainless steel discs, aluminum
weighing pan and KBr disc containing liquid samples were placed in
the center of the UV box. The box was purged with argon gas for 10
minutes before the UV lamp was turned on for 5 minutes. All
substrates were removed from the box and cooled to room temperature
before carrying out film analysis. Gel content, swell ratio,
contact angle measurements, DSC and TGA analysis were performed on
films prepared on stainless steel disks. The typical thickness of
these films was 0.4 mm. XPS analysis was performed on films cast in
aluminum weighing pans. The C.dbd.C group conversion was monitored
by FTIR, and performed on films prepared on KBr disks. The average
thickness of the latter two films was about 0.03 mm. Gel content:
56.3% Contact angle: spread and detached in about 4.5 minutes, with
an average angle of detached droplet=71.degree.. DSC: negative heat
flow -67.degree. C. TGA: 2 onset points: (A) 240.8.degree. C.,
34.09% mass loss, (B) 417.5.degree. C., 62.99% mass loss. XPS: C:
56.2%, N: 3.80%, O: 14.14%, F: 25.79%.
EXAMPLE 17
Homo Cross-Linked Films of Compound 4 Prepared by UV Cure
[0227] Compound 4 (0.4056 g) and HMP (0.0022 g) were weighed in a
20 mL vial. A small amount of MeOH (HPLC grade, 0.3 g) was added to
the vial to reduce the viscosity of the mixture and to ensure good
mixing. The vial was vortexed until all components were well mixed.
The mixture was cast onto various substrates including stainless
steel discs, an aluminum weighing pan and a KBr disc. MeOH solvent
was allowed to evaporate at room temperature for 1 h under an
aluminum foil. The stainless steel substrates, aluminum weighing
pans and KBr disc containing opaque liquid samples were placed in
the center of the UV box. The box was purged with argon gas for 10
minutes before the UV lamp was turned on for 5 minutes. All
substrates were removed from the box and cooled to room temperature
before carrying out film analysis. Gel content, swell ratio,
contact angle measurements, DSC and TGA analysis were performed on
films prepared on stainless steel discs. The typical thickness of
these films was 0.4 mm. XPS analysis was performed on films cast in
aluminum weighing pans. The C.dbd.C group conversion was monitored
by FTIR, and performed on films prepared on KBr disks. The average
thickness of the latter two films was about 0.03 mm. Gel extraction
analysis (acetone): 56.3% gel, 550% swelling. Contact angle:
Spreading as water droplet contact the surface and detached from
the needle in about 1 minute. DSC: negative heat flow -68.degree.
C. TGA: 2 onset points: (A) 288.4.degree. C., 31.4% mass loss, (B)
411.8.degree. C., 67.2% mass loss. XPS: C: 58.31%, N: 2.86%, O:
15.97%, F: 21.89%.
EXAMPLE 18
Homo Cross-Linked Films of Compound 10 Prepared by UV Cure
[0228] Compound 10 (3.9782 g) and HMP (0.0191 g) were weighed in a
20 mL vial. DCM (6 g) was added to the vial to reduce the viscosity
of the mixture and to ensure good mixing. The vial was vortexed
until all components were well mixed. The solution appeared
transparent. If air bubbles appeared, the vial was allowed to sit
at room temperature until all bubbles dissipated, before the
mixture was cast onto the desired substrates such as Teflon molds,
stainless steel discs, an aluminum weighing pan and a KBr disc. DCM
solvent was allowed to evaporate at room temperature for 1 hour or
24 hours under an aluminum foil. After 1 hour, the stainless steel
discs, aluminum weighing pan and KBr disc containing liquid samples
were placed in the center of the UV box. Samples appeared
transparent. The box was purged with argon gas for 10 minutes
before the UV lamp was turned on for 5 minutes. All substrates were
removed from the box and cooled to room temperature before carrying
out film analysis. After 24 hours, the UV cure procedure was
repeated for samples cast on Teflon molds. Film characteristics
were recorded.
EXAMPLE 19
Homo Cross-Linked Films of Compound 2 Prepared by Heat Cure with a
Range of BPO Initiator Concentration
[0229] A range of BPO concentrations (0, 0.05, 0.1, 0.5, and 1 wt %
BPO) were evaluated for effectiveness of cure of Compound 2.
Compound 2 was dissolved in toluene (0.1 g/mL) prepared with BPO
(0, 0.05, 0.1, 0.5, and 1 wt %). 500 .mu.L of these solutions were
cast into 4 mL glass vials, the toluene was evaporated off at room
temperature, and the films were cured at 60.degree. C. in an
N.sub.2 purged oven. Films prepared with 0, 0.05, and 0.1 wt % BPO
content did not cure enough to permit physical manipulation. Films
prepared with 0.5 and 1 wt % BPO were analyzed for gel content
(acetone extraction): 1 wt % BPO film (100% gel), 0.5 wt % BPO film
(58% gel). Equivalent films were also prepared on KBr disks using
25 .mu.L of the polymer solutions, and these films were analyzed by
FTIR. The films prepared with 0-0.1 wt % BPO have signal at 1634
cm.sup.-1 (C.dbd.C peak), whereas films prepared with 0.5 and 1 wt
% BPO have no visible 1634 cm.sup.-1 signal.
[0230] Larger films of Compound 2 with 1 wt % BPO initiator were
prepared for further analysis. Compound 2 was dissolved in toluene
(0.1 g/mL) containing BPO initiator (1 mg, 1 wt % of Compound 2
mass). The toluene solution was cast into a 4 cm.times.4 cm PTFE
wells (6 mL per well), and the PTFE casting plate was placed in a
semi-enclosed chamber at room temperature for 1 day. The Compound 2
films were then cured for 12 hours in an N.sub.2 purged 60.degree.
C. oven. The resulting films were clear and elastomeric (FIG. 2).
Gel extraction analysis (acetone): 95% gel, 129% swelling. Contact
angle analysis: water: 118.degree., porcine plasma: 113.degree.,
porcine blood: 121.degree.. XPS analysis (90.degree.): (top
surface: C: 41.4%, N: 1.1%, O: 9.9%, F: 45.4%.) (bottom surface: C:
46.3%, N: 2.2%, O: 11.1%, F: 39.5%). DSC analysis: Tg=-69.degree.
C. TGA analysis: decomposition onset at 174.degree. C.
[0231] Films of Compound 2 were prepared with 1 wt % V-70
initiator, and were cured in the same manner as the BPO cured film.
By DSC analysis, the V-70 was found to be an effective
initiator.
[0232] Shaped articles of Compound 2 were prepared. Compound 2 was
dissolved in toluene (0.1 g/mL) containing BPO initiator (1 mg, 1
wt % of Compound 2 mass). The toluene solution was cast into
circular and hexagonal molds, and the molds were placed in a
semi-enclosed chamber at room temperature for 1 day. The Compound 2
films were then cured for 12 hours in an N.sub.2 purged 60.degree.
C. oven. The resulting shaped articles could be removed from the
molds, and were elastomeric (FIG. 3).
EXAMPLE 20
Homo Cross-Linked Films of Compound 6 Prepared by Heat Cure
[0233] Compound 6 was dissolved in toluene (0.1 g/mL) prepared with
BPO (0, 0.05, 0.1, 0.5, and 1 wt %). 1.5 mL of each solution were
cast into 24 mL glass vials, the toluene was evaporated off at room
temperature, and the films were cured at 60.degree. C. in an
N.sub.2 purged oven. All films excepting the 0% BPO film were firm
and clear. The film prepared with 0% BPO was soft and tacky. Gel
content (acetone extraction): 0 wt % BPO film (completely
dissolved), 0.05, 0.1, 0.5 and 1 wt % BPO films (>99% gel). The
acetone extraction solutions were reduced to dryness, and analyzed
by .sup.1H NMR (400 MHz, CDCl.sub.3): all extractions had NMR
signatures consistent with the Compound 6 spectra. The 0 and 0.05
wt % BPO film extraction spectra contained vinyl signals (5.80-6.40
ppm) consistent with un-cured Compound 6, whereas the remaining
extraction spectra did not show evidence of vinyl chemistry.
Extractions of films containing BPO also had weak signals at 7.1
and 8.1 ppm, suggestive of the BPO initiator. Cured films were also
prepared on KBr disks using 25 .mu.L of the above polymer
solutions, and these films were analyzed by FTIR.
[0234] Larger films of Compound 6 with 1 wt % BPO were prepared for
further analysis. Compound 6 films were prepared using 1 wt % BPO.
Compound 6 was dissolved in toluene (0.05 or 0.1 g/mL) containing
BPO initiator (1 wt % of Compound 6). The toluene solutions (6 mL)
were cast into 4 cm.times.4 cm PTFE wells, and the PTFE casting
plates were placed in a casting tank at room temperature for 1 day.
The Compound 6 films were cured for 12 hours in an N.sub.2 purged
60.degree. C. oven. The resulting films were clear and elastomeric
(FIG. 4). Gel content of 0.1 g/mL films (acetone extraction): 96%
gel, 126% swelling. Gel content of 0.05 mg/mL films (toluene
extraction): 92% gel, 193% swelling. Gel content of 0.1 mg/mL films
(toluene extraction): >99% gel, 180% swelling. FIG. 5 shows
films of cured Compound 6 prepared using the 0.05 and 0.1 g/mL
solutions, before and after toluene exposure, indicating no change
to film morphology. Contact angle analysis: water: 114.degree.,
porcine plasma: 119.degree., porcine blood: 116.degree.. XPS
analysis (90.degree.): (top surface: C: 56.5%, N: 2.6%, O: 16.4%,
F: 23.7%.) (bottom surface: C: 52.6%, N: 2.4%, O: 14.0%, F: 30.3%).
DSC analysis: T.sub.g=-65.degree. C. TGA analysis: decomposition
onset at 200.degree. C. Tensile testing: stress at break=2.4 MPa,
strain at break=42%. Films of Compound 6 were also prepared with 1
wt % V-70 initiator, and were cured in the same manner as the BPO
cured film. By DSC analysis, the V-70 was found to be an effective
initiator.
EXAMPLE 21
Homo Cross-Linked Films of Compound 8 Prepared by Heat Cure
[0235] Compound 8 was dissolved in toluene (0.1 gram/mL) containing
BPO (1 wt % of Compound 8). The toluene solution (6 mL) was cast
into 4 cm.times.4 cm PTFE wells, and the PTFE casting plate was
placed in a casting tank at room temperature for 1 day. The
Compound 8 films were cured for 12 hours in an N.sub.2 purged
60.degree. C. oven. The resulting films were clear, tacky, and
elastomeric. Gel extraction analysis: 91% gel, 117% swelling.
Contact angle analysis: advancing angle: 119.degree.. XPS analysis
(90.degree.): (top surface: C: 59.9%, N: 2.8%, O: 17.5%, F: 19.8%.)
(bottom surface: C: 58.0%, N: 2.5%, O: 16.3%, F: 23%). Tensile
testing: stress at break=1.5 MPa, strain at break=35%. Films of
Compound 8 were also prepared with 1 wt % V-70 initiator, and were
cured in the same manner as the BPO cured film. By DSC analysis,
the V-70 was found to be an effective initiator.
EXAMPLE 22
Homo Cross-Linked Films of Compound 12 Prepared by Heat Cure
[0236] Compound 12 was dissolved in THF (0.1 gram/mL) containing
BPO (1 wt % of Compound 12). The THF solution (6 mL) was cast into
4 cm.times.4 cm PTFE wells, and the PTFE casting plate was placed
in a casting tank at room temperature for 1 day. The Compound 12
films were cured for 12 hours in an N.sub.2 purged 60.degree. C.
oven. The resulting films were translucent and elastomeric (FIG.
6). Gel extraction analysis (acetone): 97% gel, 136% swelling.
Contact angle analysis: advancing angle: 118.degree.. XPS analysis
(90.degree.): (top surface: C: 50.6%, N: 1.9%, O: 14.5%, F: 32.8%.)
(bottom surface: C: 49.7%, N: 1.7%, O: 13.3%, F: 35.3%). Tensile
testing: stress at break=2.0 MPa, strain at break=33%.
Cured System Based on Hertero Cross-Linking
EXAMPLE 23
Hetero Cross-Linked Films of Blended Compound 2 and Compound 15,
Prepared by UV Cure
[0237] Compound 2 (2.0311 g), Compound 15 (2.0345 g) and HMP
(0.0195 g) were weighed in a 20 mL vial. MeOH (HPLC grade, 5 g) was
added to the vial to reduce the viscosity of the mixture and to
ensure good mixing. The vial was vortexed until the compounds were
all very well mixed. If air bubbles appeared, the vial was allowed
to sit at room temperature until all bubbles dissipated, before the
mixture was cast onto the desired substrates (Teflon molds,
stainless steel discs, an aluminum weighing pan and a KBr disc).
The solution appeared transparent. MeOH solvent was allowed to
evaporate at room temperature for 1 hour and 24 hours under an
aluminum foil. All films appeared opaque. The stainless steel
substrates, aluminum weighing pans and KBr disc containing opaque
liquid samples were placed in the center of the UV box. The box was
purged with argon gas for 10 minutes before the UV lamp was turned
on for 5 minutes. All substrates were removed from the box and
cooled to room temperature before carrying out film analysis. After
24 hours, the UV cure procedure was repeated to samples cast on
Teflon molds. Gel content, swell ratio, contact angle measurements,
and TGA analysis were performed on films prepared on stainless
steel discs. The typical thickness of these films was 0.4 mm. XPS
analysis was performed on films cast in aluminum weighing pans. The
C.dbd.C group conversion was monitored by FTIR, and performed on
films prepared on KBr disc. The average thickness of these latter
two films was about 0.03 mm. For tensile measurements, opaque
polymer films free of air bubbles were removed from the molds and
cut into to dog-bone shape. The dog-bone samples were air-tightened
on an instron machine for subsequent tensile test measurements. An
Instron 4301 system was used to test the samples with a cross-head
load of 50 N at the rate of 10 mm/min, at 23.degree. C. and
relative humidity of 57%. Sample thickness measured by a caliber
ranged from 0.1 to 0.3 mm. The results of each example represented
an average of 5 dog-bone samples.
TABLE-US-00003 TABLE 3 Comparison of film properties prepared from
a blend of Compound 2 and Compound 15 to films prepared from
Compound 15 itself. Photoinitiator concentration in both systems
was kept at 0.5 wt %. Blend of Compound 2 and Compound 15 Compound
15 C = C conversion (%) Recorded Recorded Gel content (%) 83 88
Contact angle (.degree.) From 138 down to 75 in 5 104.1 .+-. 2.8
minutes. Remained intact after 5 minutes XPS C: 51.45%, N: 4.56%,
C: 52.89%, N: 3.47%, O: 11.92%, F: 31.98%. O: 21.55%, F: 0%. DSC
T.sub.g = -68.70.degree. C. T.sub.g = -67.37.degree. C. TGA 264.1
.degree.C., 20% mass loss 273.8.degree. C., 12% mass 411.4.degree.
C., 75% mass loss loss 406.9.degree. C., 84% mass loss Tensile
testing Stress at break = 1.4 MPa Stress at break = 1.2 Strain at
break = 32.3% MPa Strain at break = 36.5%
EXAMPLE 24
Hetero Cross-Linked Films of Blended Compound 2 and Compound 10,
Prepared by UV Cure
[0238] Compound 10 (1.9639 g), Compound 2 (2.0037 g), and HMP
(0.0221 g) were weighed in a 20 mL vial. DCM (5 g) was added to the
vial and the vial was vortexed until all components were well
dissolved. The solution appeared translucent and exhibited phase
separating. Diethyl ether (4 g) was then added to the vial, and the
vial was vortexed and allowed to sit at room temperature. Again,
phase separation occurred, The mixture was cast onto the desired
substrates such as Teflon molds, stainless steel discs, an aluminum
weighing pan and a KBr disc. DCM and diethyl ether solvents were
allowed to evaporate at room temperature for 1 hour or 24 hours
under an aluminum foil. After 1 hour, the stainless steel discs,
aluminum weighing pan and KBr disc containing liquid samples were
placed in the center of the UV box. Samples on all substrates
appeared clear with visual droplets. The box was purged with argon
gas for 10 minutes before the UV lamp was turned on for 5 minutes.
All substrates were removed from the box and cooled to room
temperature before carrying out film analysis. After 24 hours, the
UV cure procedure was repeated for samples cast on Teflon
molds.
EXAMPLE 25
Hetero Cross-Linked Films of Blended Compound 2 and Vinyl
Pyrrolidone, Prepared by UV Cure
[0239] Compound 2 (2.9929 g), vinyl pyrrolidone (0.9822 g), HMP
(0.0191 g) and MeOH (HPLC grade, 5 g) were weighed in to a 20 mL
vial. The vial was vortexed until all contents was well mixed. If
air bubbles appeared, the vial was allowed to sit at room
temperature until all bubbles dissipated before the mixture was
cast on Telfon molds, stainless steel substrates, an aluminum
weighing pan and a KBr disc. MeOH solvent was allowed to evaporate
at room temperature for 1 hour or 24 hours under an aluminum foil.
After 1 hour, the stainless steel discs, aluminum weighing pan and
KBr disc containing liquid samples were placed in the center of the
UV box. The box was purged with argon gas for 10 minutes before the
UV lamp was turned on for 5 minutes. All substrates were removed
from the box and cooled to room temperature before carrying out
film analysis. After 24 hours, the UV cure procedure was repeated
to samples cast on Teflon molds. Gel content, swell ratio, contact
angle measurements and TGA analysis were performed on films
prepared on the stainless steel substrates. The typical thickness
of these films was 0.4 mm. XPS analysis was performed on films cast
on aluminum weighing pans (0.03 mm thick). Gel extraction analysis:
85% gel, 180% swelling. Contact angle: 134.5.degree..+-.2.1. TGA: 2
onset points: (A) 293.2.degree. C., 25.9% mass loss, (B)
418.2.degree. C., 68.5% mass loss. FTIR analysis: the elimination
of the C.dbd.C group was monitored to observe the polymerization of
the materials prepared on the KBr disc. Tensile testing: stress at
break=7.3 MPa, strain at break=69.8%. XPS analysis (90.degree.): C:
47.65%, N: 3.45%, O: 10.53%, F: 38.42%.
EXAMPLE 26
Hetero Cross-Linked Films of Blended Compound 2 and HEMA, Prepared
by UV Cure
[0240] Compound 2 (0.4003 g), HEMA (0.1485 g) and HMP (0.0033 g)
were weighed in to a 20 mL vial. The vial was vortexed until
Compound 2 was completely dissolved. If air bubbles appeared, the
vial was allowed to sit at room temperature until all bubbles
dissipated, before the mixture was cast onto the desired substrates
(stainless steel discs, an aluminum weighing pan and a KBr disc).
The stainless steel substrates, weighing pans and KBr disc
containing liquid samples were placed in the center of the UV box.
The box was purged with argon gas for 10 minutes before the UV lamp
was turned on for 5 minutes. All substrates were removed from the
box and cooled to room temperature before carrying out film
analysis. Gel content, swell ratio, contact angle measurements and
TGA analysis were performed on films prepared on the stainless
steel substrates. The typical thickness of these films was 0.4 mm.
XPS analysis was performed on films cast on aluminum weighing pans
(0.03 mm thick). Gel extraction analysis: 90.3% gel, 192% swelling.
Contact angle: The water droplet spread quickly on the film surface
and detached from the needle in about 1 minute. The contact angle
of the detached droplet is about 65.degree..+-.2 (n=3). DSC:
T.sub.g=10.3.degree. C. TGA: 2 onset points: (A) 299.4.degree. C.,
27.8% mass loss, (B) 414.7.degree. C., 66.1% mass loss. IR: the
C.dbd.C group conversion was monitored by FTIR and performed on
films prepared on the KBr disc. XPS analysis (90.degree.): C:
50.94%, N: 3.38%, O: 11.41%, F: 34.27%.
EXAMPLE 27
Hetero Cross-Linked Films of Blended Compound 2 and Methacrylic
Acid, Prepared by UV Cure
[0241] Compound 2 (0.4047 g), MAA (0.1321 g) and HMP (0.0035
.sub.g) were weighed in to a 20 mL vial. The vial was vortexed
until Compound 2 was completely dissolved. If air bubbles appeared,
the vial was allowed to sit at room temperature until all bubbles
dissipated, before the mixture was cast onto desired substrates
(stainless steel discs, an aluminum weighing pan and a KBr disc).
The stainless steel substrates, aluminum weighing pan and KBr disc
containing liquid samples were placed in the center of the UV box.
The box was purged with an argon gas for 10 minutes before the UV
lamp was turned on for 5 minutes. All substrates were removed from
the box and cooled to room temperature before carrying out film
analysis. Gel content, swell ratio, contact angle measurements, DSC
and TGA analysis were performed on films prepared on stainless
steel substrates. The typical thickness of these films was 0.4 mm.
Gel extraction analysis: 91.4% gel, 175% swelling. Contact angle:
The water droplet spread on the film surface and detached from the
needle in about 5 minutes. The contact angle of the detached
droplet is about 74.degree..+-.1 (n=4). DSC: 1.sup.st heat:
negative heat flow at 23.5.degree. C. This represents a shift in
the T.sub.g of pure PTMO polymers (.about.-70.degree. C.) towards
that of pure MAA polymers (T.sub.g of .about.228.degree. C.). TGA:
2 onset points: (A) 234.9.degree. C., 30.2% mass loss, (B)
407.4.degree. C., 65.5% mass loss. IR: The C.dbd.C group conversion
was monitored by FTIR and performed on films prepared on KBr
discs.
EXAMPLE 28
Hetero Cross-Linked Films of Blended Compound 2 and Methyl
Methacrylate, Prepared by UV Cure
[0242] Compound 2 (3.0335 g), MMA (3.0182 g) and HMP (0.0200 g)
were weighed in to a 20 mL vial. The vial was vortexed until
Compound 2 was completely dissolved. If air bubbles appeared, the
vial was allowed to sit at room temperature until all bubbles
dissipated, before the mixture was cast onto the desired substrates
(Teflon molds, stainless steel substrates, an aluminum weighing pan
and a KBr disc). The Teflon molds, stainless steel substrates,
weighing pans and KBr disc containing liquid samples were placed in
the center of the UV box. The box was purged with an argon gas for
1 minute before the UV lamp was turned on for 5 minutes. All
substrates were removed from the box and cooled to room temperature
before carrying out film analysis. Gel content, swell ratio,
contact angle measurements and TGA analysis were performed on films
prepared on the stainless steel substrates. The typical thickness
of these films was 0.4 mm. XPS analysis was performed on films cast
on aluminum weighing pans (0.03 mm thick). Gel extraction analysis:
93.5% gel, 230% swelling. Contact angle: 132.9.degree..+-.2.2. TGA:
2 onset points: (A) 296.5.degree. C., 27.4% mass loss, (B)
411.4.degree. C., 69.5% mass loss. IR: the C.dbd.C group conversion
was monitored by FTIR and performed on films prepared on the KBr
discs. Tensile testing: stress at yield=9.2 MPa, stress at
break=13.6 MPa, strain at break=9.9%. XPS analysis (90.degree.): C:
47.5%, N:3.93%, O: 11.02%, F: 37.45%.
EXAMPLE 28'
Hetero Cross-Linked Films of Blended Compound 2 and TEGMA, Prepared
by UV Cure
[0243] Compound 2 (0.37500 g), TEGDMA (0.1250 g) and HMP (0.005 g)
were weighed in to a 20 mL vial. The vial was vortexed until
Compound 2 was completely dissolved. If air bubbles appeared, the
vial was allowed to sit at room temperature until all bubbles
dissipated, before the mixture was cast onto the desired substrates
(stainless steel substrates, an aluminum weighing pan and a KBr
disc). The stainless steel substrates, weighing pans and KBr disc
containing liquid samples were placed in the center of the UV box.
The box was purged with an argon gas for 1 minute before the UV
lamp was turned on for 5 minutes. All substrates were removed from
the box and cooled to room temperature before carrying out film
analysis. Gel content, swell ratio, contact angle measurements and
TGA analysis were performed on films prepared on stainless steel
substrates. The typical thickness of these films is 0.4 mm. XPS
analysis was performed on films cast on aluminum weighing pans
(0.03 mm thick). Gel extraction analysis: 89.8% gel, 140% swelling.
Contact angle: spread quickly. TGA: 246.5.degree. C., 97.35% mass
loss. IR: the C.dbd.C group conversion was monitored by FTIR
performed on films cast on KBr disks. XPS analysis (90.degree.):
C:49.07%, N: 3.14%, O: 12.56%, F: 35.22%.
EXAMPLE 29
Hetero Cross-Linked Films of Compound 2 and SIBS Polymer, Prepared
by UV Cure
[0244] SIBS solution (0.5 g/mL in toluene) was cast on stainless
steel substrates and an aluminum weighing pan. The toluene was
allowed to evaporate at room temperature overnight. In a 20 mL
vial, Compound 2, HMP, and MeOH (HPLC grade) were weighed. The vial
was vortexed until the components were completely well blended. If
air bubbles appeared, the vial was allowed to sit at room
temperature until all bubbles dissipated The Compound 2 solution
was transferred from the vial to a 50 mL HDPE spraying bottle. The
spraying bottle was used to deposit a thin layer of Compound 2 and
HMP on top of the SIBS film. MeOH solvent was allowed to evaporate
at room temperature for 1 hour under an aluminum foil. The
stainless steel substrates and weighing pans containing SIBS films
coated with Compound 2 and HMP were placed in the center of the UV
box. The box was purged with an argon gas for 5 minutes before the
UV lamp was turned on for 5 minutes. All substrates were removed
from the box and cooled to room temperature before carrying out
film analysis. Contact angle: 128.degree.. XPS analysis
(90.degree.): (SIBS) C: 98.90%, N: 0.18%, O: 0.45%, F: 0.47%.
(SIBS+Compound 2) C: 53.50%, N:3.95%, O:15.11%, F: 27.63%.
EXAMPLE 30
Hetero Cross-Linked Films of Compound 2 and EVA Polymer, Prepared
by UV Cure
[0245] EVA solution (0.5 g/mL in toluene) was cast on stainless
steel substrates and an aluminum weighing pan. The toluene was
allowed to evaporate at room temperature overnight. In a 20 mL
vial, Compound 2, HMP, and MeOH (HPLC grade) were weighed. The vial
was vortexed until the components were completely well blended. If
air bubbles appeared, the vial is allowed to sit at room
temperature until all bubbles dissipated. The Compound 2 solution
was transferred from the vial to a 50 mL HDPE spraying bottle. The
spraying bottle was used to deposit a thin layer of Compound 2 and
HMP on top of the EVA film. MeOH solvent was allowed to evaporate
at room temperature for 1 hour under an aluminum foil. The
stainless steel substrates and weighing pans containing EVA films
coated with Compound 2 and HMP were placed in the center of the UV
box. The box was purged with an argon gas for 5 minutes before the
UV lamp was turned on for 5 minutes. All substrates were removed
from the box and cooled to room temperature before carrying out
film analysis. Contact angle: 126.degree.. XPS analysis
(90.degree.): (EVA) C: 84.61%, N: 4.03%, O: 11.36%, F: 0%.
(EVA+Compound 2) C: 72.72%, N:4.08%, O: 12.59%, F: 10.21%.
EXAMPLE 31
Hetero Cross-Linked Films Prepared with a Mixture of Compound 2 and
Compound 6
[0246] Compound 2 (0.3 g) was dissolved in toluene (0.1 g/mL)
containing BPO (3 mg, 1 wt % of Compound 2 mass). Compound 6 (0.3g)
was dissolved in toluene (0.1 g/mL) containing BPO (3 mg, 1 wt % of
Compound 6 mass). These two solutions were mixed in a 50:50 ratio,
and 6 mL of this combined solution were cast into 4 cm.times.4 cm
PTFE wells. The PTFE casting plate was placed in a semi-enclosed
chamber at room temperature for 1 day. The film was then cured for
12 hours in an N.sub.2 purged 60.degree. C. oven. The resulting
film was clear, elastomeric, and non-tacky (FIG. 7). Gel extraction
analysis (acetone): 96% gel, 141% swelling. Contact angle analysis:
advancing angle: 116.degree.. XPS analysis (90.degree.): (top
surface: C: 51.4%, N: 2.5%, O: 14.8%, F: 31.1%.) (bottom surface:
C: 48.7%, N: 1.9%, O: 13.0%, F: 35.5%).
EXAMPLE 32
Hetero Cross-Linked Films Prepared with a Combination of Compound 6
and Compound 8
[0247] Compound 6 (0.3 g) was dissolved in toluene (0.1 g/mL)
containing BPO (3 mg, 1 wt % of Compound 6 mass). Compound 8 (0.3g)
was dissolved in toluene (0.1 g/mL) containing BPO (3 mg, 1 wt % of
Compound 8 mass). These two solutions were mixed in a 50:50 ratio,
and 6 mL of this combined solution were cast into 4 cm.times.4 cm
PTFE wells. The PTFE casting plate was placed in a semi-enclosed
chamber at room temperature for 1 day. The film was then cured for
12 hours in an N.sub.2 purged 60.degree. C. oven. The resulting
film was clear, elastomeric, resistant to tearing, and non-tacky
(FIG. 8). Gel extraction analysis (acetone): 96% gel, 154%
swelling. Contact angle analysis: advancing angle: 127.degree.. XPS
analysis (90.degree.): (top surface: C: 54.2%, N: 2.5%, O: 16.4%,
F: 26.8%.) (bottom surface: C: 49.2%, N: 1.8%, O: 12.2%, F:
36.1%).
EXAMPLE 33
Hetero Cross-Linked Films Prepared with a Combination of Compound 6
and a Vinyl Monomer (FEO1)
[0248] Compound 6 (0.3 g) was dissolved in toluene (0.1 g/mL)
containing BPO (3 mg, 1 wt % of Compound 6 mass). FEO1 (0.3 g) was
dissolved in toluene (0.1 g/mL) containing BPO (3 mg, 1 wt % of
FEO1 mass). These two solutions were mixed in a 50:50 ratio, and 6
mL of this combined solution were cast into 4 cm.times.4 cm PTFE
wells. The PTFE casting plate was placed in a semi-enclosed chamber
at room temperature for 1 day. The film was then cured for 12 hours
in an N.sub.2 purged 60.degree. C. oven. The resulting film was
clear, elastomeric, resistant to tearing, and non-tacky (FIG. 9).
Gel extraction analysis (acetone): 93% gel, 133% swelling. Contact
angle analysis: advancing angle: 104.degree.. XPS analysis
(90.degree.): (top surface: C: 47.8%, N: 1.0%, O: 13.4%, F: 36.2%.)
(bottom surface: C: 46.2%, N: 0.6%, O: 11.7%, F: 39.0%).
EXAMPLE 34
Hetero Cross-Linked Films Prepared with a Combination of Compound 6
and a Vinyl Monomer (HEMA)
[0249] Compound 6 (0.3 g) was dissolved in toluene (0.1 g/mL)
containing BPO (3 mg, 1 wt % of Compound 6 mass). HEMA (0.3g) was
dissolved in toluene (0.1 g/mL) containing BPO (3 mg, 1 wt % of
HEMA mass). These two solutions were mixed in a 50:50 ratio, and 6
mL of this combined solution were cast into 4 cm.times.4 cm PTFE
wells. The PTFE casting plate was placed in a semi-enclosed chamber
at room temperature for 1 day. The film was then cured for 12 hours
in an N.sub.2 purged 60.degree. C. oven. The resulting cured
material was tough and opaque (FIG. 10). Gel extraction analysis
(acetone): 93% gel, 153% swelling. XPS analysis (90.degree.): (top
surface: C: 53.4%, N: 2.5%, O: 16.2%, F: 27.2%.) (bottom surface:
C: 51.1%, N: 1.8%, O: 13.1%, F: 33.8%).
EXAMPLE 35
Hetero Cross-Linked Films Prepared with a Combination of Compound 2
and Compound 1
[0250] Compound 2 (0.1 g) was dissolved in toluene (0.1 g/mL)
containing BPO (1 mg, 1 wt % of Compound 2 mass). Compound 1-ester
(0.1 g) was dissolved in toluene (0.1 g/mL) containing BPO (1 mg, 1
wt % of Compound 1-ester mass). These two solutions were mixed in a
50:50 ratio, and 2 mL of this combined solution were cast into 2
cm.times.2 cm PTFE wells. The PTFE casting plate was placed in a
semi-enclosed chamber at room temperature for 1 day. The film was
then cured for 12 hours in an N.sub.2 purged 60.degree. C. oven.
The resulting cured material was homogeneous and firm. Gel
extraction analysis (acetone): 87% gel. XPS analysis (90.degree.):
top surface: C: 41.4%, N: 1.1%, O: 9.9%, F: 45.4%.
EXAMPLE 36
Homo Cross-Linked Films Prepared Using HEMA Monomer
[0251] HEMA (0.6 g) was dissolved in toluene (6 mL, 0.1 g/mL)
containing BPO (6 mg, 1 wt % of HEMA mass), and this solution was
cast into a 4 cm.times.4 cm PTFE well. The PTFE casting plate was
placed in a semi-enclosed chamber at room temperature for 1 day.
The film was then cured for 12 hours in an N.sub.2 purged
60.degree. C. oven. The resulting cured material was hard and
inconsistent in thickness. Gel extraction analysis (acetone):
>99% gel, 136% swelling.
EXAMPLE 37
Homo Cross-Linked Films Prepared Using FEO1 Monomer
[0252] FEO1 (0.6 g) was dissolved in toluene (6 mL, 0.1 g/mL)
containing BPO (6 mg, 1 wt % of FEO1 mass), and this solution was
cast into a 4 cm.times.4 cm PTFE well. The PTFE casting plate was
placed in a semi-enclosed chamber at room temperature for 1 day.
The film was then cured for 12 hours in an N.sub.2 purged
60.degree. C. oven. The resulting cured material was hard and
inconsistent in thickness. Gel extraction analysis (acetone): 84%
gel.
EXAMPLE 38
Hetero Cross-Linked Films Prepared Using a Blend of Compound 1 and
HEMA Monomer
[0253] Compound 1-ester (0.3 g) was dissolved in toluene (0.1 g/mL)
containing BPO (3 mg, 1 wt % of Compound 1-ester mass). HEMA (0.3g)
was dissolved in toluene (0.1 g/mL) containing BPO (3 mg, 1 wt % of
HEMA mass). These two solutions were mixed in a 50:50 ratio, and 6
mL of this combined solution were cast into 4 cm.times.4 cm PTFE
wells. The PTFE casting plate was placed in a semi-enclosed chamber
at room temperature for 1 day. The film was cured for 12 hours in
an N.sub.2 purged 60.degree. C. oven. The resulting cured material
was more firm than pure Compound 1 but shrank within the casting
form, and was too soft to handle as a film.
EXAMPLE 39
Hetero Cross-Linked Films Prepared Using a Blend of Compound 1 and
FEO1 Monomer
[0254] Compound 1-ester (0.3 g) was dissolved in toluene (0.1 g/mL)
containing BPO (3 mg, 1 wt % of Compound 1-ester mass). FEO1 (0.3g)
was dissolved in toluene (0.1 g/mL) containing BPO (3 mg, 1 wt % of
FEO1 mass). These two solutions were mixed in a 50:50 ratio, and 6
mL of this combined solution were cast into 4 cm.times.4 cm PTFE
wells. The PTFE casting plate was placed in a semi-enclosed chamber
at room temperature for 1 day. The film was then cured for 12 hours
in an N.sub.2 purged 60.degree. C. oven. The resulting cured
material was firm and even-looking within the casting form, but was
too soft to handle as a film.
Polymerization on a Stent Platform
EXAMPLE 40
Coating of Compound 2 on a Stent, Prepared by Spraying and Heat
Cure
[0255] Compound 2 (200 mg) was dissolved in toluene (4 mL, 0.05
g/mL), stirred for 90 minutes at room temperature and BPO (2 mg, 1
wt % of Compound 2 mass) was added and the mixture was stirred for
an additional 30 minutes. The solution blend was sprayed onto
stents using an EFD spray system, and the coatings were cured at
60.degree. C. in an N.sub.2 purged oven for 12 hours. SEM analysis
(FIG. 11) indicated that the stents were uniformly coated. In
addition, a Compound 2 coated stent was crimped on a balloon and
deployed at 10 psi. Coating remained intact (FIG. 12).
EXAMPLE 41
Coating of Compound 6 on a Stent, Prepared by Spraying and Heat
Cure
[0256] Compound 6 (200 mg) was dissolved in toluene (4 mL, 0.05
g/mL), stirred for 90 minutes at room temperature and BPO (2 mg, 1
wt % of Compound 6 mass) was added and the mixture was stirred for
an additional 30 minutes. The solution blend was sprayed onto
stents using an EFD spray system, and the coatings were cured at
60.degree. C. in an N.sub.2 purged oven for 12 hours. SEM analysis
(FIG. 13) indicated that the stents were uniformly coated. A
Compound 6 coated stent was extracted with toluene after curing for
24 hrs and SEM images suggested that the coating remained intact
after solvent extraction (FIG. 14). In addition, Compound 6 coated
stent was also extracted in PBS 7.4 buffer for 24 hrs and SEM
images suggested that the coating remained intact after buffer
extraction (FIG. 15).
EXAMPLE 42
Coating of Compound 8 on a Stent, Prepared by Spraying and Heat
Cure
[0257] Compound 8 (200mg) was dissolved in toluene (4 mL, 0.05
g/mL), stirred for 90 minutes at room temperature and BPO (2 mg, 1
wt % of Compound 8 mass) was added and the mixture was stirred for
an additional 30 minutes. The solution blend was sprayed onto
stents using an EFD spray system, and the coatings were cured at
60.degree. C. in an N.sub.2 purged oven for 12 hours. SEM analysis
(FIG. 16) indicated that the stents were uniformly coated.
EXAMPLE 43
Coating of Compound 12 on a Stent, Prepared by Spraying and Heat
Cure (Toluene Solvent)
[0258] Compound 12 (200 mg) was dissolved in toluene (4 mL, 0.05
g/mL), stirred for 90 minutes at room temperature and BPO (2 mg, 1
wt % of Compound 12 mass) was added and the mixture was stirred for
an additional 30 minutes. The solution blend was sprayed onto
stents using an EFD spray system, and the coatings were cured at
60.degree. C. in an N.sub.2 purged oven for 12 hours. SEM analysis
(FIG. 17) indicated that the stents showed decent coating.
EXAMPLE 44
Coating of Compound 12 on a Stent, Prepared by Spraying and Heat
Cure (Toluene/THF Solvent)
[0259] Compound 12 (200 mg) was dissolved in 75:25 toluene:THF (4
mL, 0.05 g/mL), stirred for 90 minutes at room temperature and BPO
(2 mg, 1 wt % of Compound 12 mass) was added and the mixture was
stirred for an additional 30 minutes. The solution blend was
sprayed onto stents using an EFD spray system, and the coatings
were cured at 60.degree. C. in an N.sub.2 purged oven for 12 hours.
SEM analysis (FIG. 18) indicated that the stents were uniformly
coated.
EXAMPLE 45
Coating of a Mixture of Compound 2 and Compound 6 on a Stent,
Prepared by Spraying and Heat Cure
[0260] Compound 2 and Compound 6 (1:1, total 200 mg) were dissolved
in toluene (4 mL, 0.05 g/mL), stirred for 90 minutes at room
temperature and BPO (2 mg, 1 wt % of Compound 2 and Compound 6
combined mass) was added and the mixture was stirred for an
additional 30 minutes. The solution blend was sprayed onto stents
using an EFD spray system, and the coatings were cured at
60.degree. C. in an N.sub.2 purged oven for 12 hours. SEM analysis
(FIG. 19) indicated that the stents were uniformly coated.
EXAMPLE 46
Coating of a Mixture of Compound 6 and Compound 8 on a Stent,
Prepared by Spraying and Heat Cure
[0261] Compound 6 and Compound 8 (1:1, total 200 mg) were dissolved
in toluene (4 mL, 0.05 g/mL), stirred for 90 minutes at room
temperature and BPO (2 mg, 1 wt % of Compound 6 and Compound 8
combined mass) was added and the mixture was stirred for an
additional 30 minutes. The solution blend was sprayed onto stents
using an EFF spray system, and the coatings were cured at
60.degree. C. in an N.sub.2 purged oven for 12 hours. SEM analysis
(FIG. 20) indicated that the stents were uniformly coated.
EXAMPLE 47
Coating of a Mixture of Compound 6 and Paclitaxel on a Stent,
Prepared by Spraying and Heat Cure
[0262] Compound 6 (200 mg) was dissolved in 75:25 toluene:THF (4
mL, 0.05 g/mL), stirred for 90 minutes at room temperature and
Paclitaxel (17.6 mg, 8.8wt % of Compound 6 mass) and BPO (2 mg, 1
wt % of Compound 6 mass) was added and the mixture was stirred for
an additional 30 minutes. The solution blend was sprayed onto
stents using an EFD spray system, and the coatings were cured at
60.degree. C. in an N.sub.2 purged oven for 12 hours. SEM analysis
(FIG. 21) indicated that the stents were uniformly coated.
Biocompatibility Assays
EXAMPLE 48
MEM Elution Assay of Compound 2
[0263] Samples of film from Example 19 (1 cm.times.2 cm) were
weighed and incubated in MEM media for 24 hours. A counted aliquot
of L-929 mouse fibroblast culture was seeded into each MEM extract,
and stability of the cell population was evaluated after 24 hours
using a trypan blue exclusion method. By this cytotoxicity
evaluation method, the Compound 2 films were non-toxic.
EXAMPLE 49
Homo Cross-Linked Films of Compound 2 Prepared by Heat Cure,
Assessed for Inflammatory Cell Interaction
[0264] Compound 2 was dissolved in toluene (0.1 g/mL) containing
BPO initiator (1 wt % of Compound 2 mass). The toluene solution was
cast into 96 well polypropylene plates (6 wells per plate), and the
plates were placed in a semi-enclosed chamber at room temperature
for 1 day. The Compound 2 films were then cured for 12 hours in an
N.sub.2 purged 60.degree. C. oven, and vacuum dried. For comparison
purposes, films of SIBS were cast in a second 96 well plate: a 0.1
g/mL toluene solution of SIBS was cast in 6 wells, the plates were
placed in a semi-enclosed chamber at room temperature for 1 day,
dried in a 60.degree. C. oven for 1 day, and vacuum dried. Into the
plate containing SIBS were inserted 316 stainless steel inserts.
The plates were sterilized under a UV lamp for 1 hour, after which
each sample well was hydrated using 200 uL PBS. Approximately
2.5.times.10.sup.5 U937 monocyte-like cells were seeded onto each
sample in the presence of PMA, and were incubated at 37.degree. C.
in a humid incubator for three days. The adherent U937 macrophages
were enumerated using a CyQuant assay (FIG. 27). In a similar
experiment, the Compound 2 and SIBS films were prepared on
stainless steel inserts (FIG. 28).
EXAMPLE 50
Cone-and-Plate Assay of Homo Cross-Linked Films of Compound 2
[0265] Samples of Compound 2 film from Example 19 and 316 stainless
steel (4 cm.times.4 cm) were fixed into individual wells of a
cone-and-plate device. A 1.2 mL aliquot of whole blood suspension
containing .sup.51Cr labeled platelets (250 000 platelets/.mu.L)
and .sup.125I labeled fibrinogen was pipetted onto the films, and
cones were lowered into each well and immediately rotated at 200
rpm for 15 minutes. The films were then removed, rinsed, and
adherent platelets and fibrinogen quantified by a gamma counter
(FIG. 29).
EXAMPLE 51
MEM Elution Assay of Homo Cross-Linked Films of Compound 6
[0266] Samples of film from Example 20 (1 cm.times.2 cm) were
weighed and incubated in MEM media for 24 hours. A counted aliquot
of L-929 mouse fibroblast culture was seeded into each MEM extract,
and stability of the cell population was evaluated after 24 hours
using a trypan blue exclusion method. By this cytotoxicity
evaluation method, the Compound 6 films were non-toxic.
EXAMPLE 52
Homo Cross-Linked Films of Compound 6 Prepared by Heat Cure,
Assessed for Inflammatory Cell Interaction
[0267] Compound 6 was dissolved in toluene (0.1 g/mL) containing
BPO initiator (1 wt % of Compound 6 mass). The toluene solution was
cast into 96 well polypropylene plates (6 wells per plate), and the
plates were placed in a semi-enclosed chamber at room temperature
for 1 day. The Compound 6 films were then cured for 12 hours in an
N.sub.2 purged 60.degree. C. oven, and vacuum dried. For comparison
purposes, films of SIBS were cast in a second 96 well plate: a 0.1
g/mL toluene solution of SIBS was cast in 6 wells, the plates were
placed in a semi-enclosed chamber at room temperature for 1 day,
dried in a 60.degree. C. oven for 1 day, and vacuum dried. Into the
plate containing SIBS were also inserted 316 stainless steel
inserts. The plates were sterilized under a UV lamp for 1 hour,
after which each sample well was hydrated using 200 uL PBS.
Approximately 2.5.times.10.sup.5 U937 monocyte-like cells were
seeded onto each sample in the presence of PMA, and were incubated
at 37.degree. C. in a humid incubator for three days. The adherent
U937 macrophages were enumerated using a CyQuant assay (FIG. 27).
In a similar experiment, the Compound 6 and SIBS films were
prepared on stainless steel inserts (FIG. 28).
EXAMPLE 53
Cone-and-Plate Assay of Homo Cross-Linked Films of Compound 6
[0268] Samples of Compound 6 film from Example 20 and 316 stainless
steel (4 cm.times.4 cm) were fixed into individual wells of a
cone-and-plate device. A 1.2 mL aliquot of whole blood suspension
containing .sup.51Cr labeled platelets (250 000 platelets/.mu.L)
and .sup.125I labeled fibrinogen was pipetted onto the films, and
cones were lowered into each well and immediately rotated at 200
rpm for 15 minutes. The films were then removed, rinsed, and
adherent platelets and fibrinogen quantified by a gamma counter
(FIG. 29).
EXAMPLE 54
Homo Cross-Linked Films of Compound 8 Prepared by Heat Cure,
Assessed for Inflammatory Cell Interaction
[0269] Compound 8 was dissolved in toluene (0.1 g/mL) containing
BPO initiator (1 wt % of Compound 8 mass). The toluene solution was
cast into 96 well polypropylene plates (6 wells per plate), and the
plates were placed in a semi-enclosed chamber at room temperature
for 1 day. The Compound 8 films were then cured for 12 hours in an
N.sub.2 purged 60.degree. C. oven, and vacuum dried. For comparison
purposes, films of SIBS were cast in a second 96 well plate: a 0.1
g/mL toluene solution of SIBS was cast in 6 wells, the plates were
placed in a semi-enclosed chamber at room temperature for 1 day,
dried in a 60.degree. C. oven for 1 day, and vacuum dried. Into the
plate containing SIBS were also inserted 316 stainless steel
inserts. The plates were sterilized under a UV lamp for 1 hour,
after which each sample well was hydrated using 200 uL PBS.
Approximately 2.5.times.10.sup.5 U937 monocyte-like cells were
seeded onto each sample in the presence of PMA, and were incubated
at 37.degree. C. in a humid incubator for three days. The adherent
U937 macrophages were enumerated using a CyQuant assay (FIG. 27).
In a similar experiment, the Compound 8 and SIBS films were
prepared on stainless steel inserts (FIG. 28).
EXAMPLE 55
Homo Cross-Linked Films of Compound 12 Prepared by Heat Cure,
Assessed for Inflammatory Cell Interaction
[0270] Compound 12 was dissolved in toluene (0.1 g/mL) containing
BPO initiator (1 wt % of Compound 12 mass). The toluene solution
was cast into 96 well polypropylene plates (6 wells), and the
plates were placed in a semi-enclosed chamber at room temperature
for 1 day. The Compound 12 films were then cured for 12 hours in an
N.sub.2 purged 60.degree. C. oven, and vacuum dried. For comparison
purposes, films of SIBS were cast in a second 96 well plate: a 0.1
g/mL toluene solution of SIBS was cast in 6 wells, the plates were
placed in a semi-enclosed chamber at room temperature for 1 day,
dried in a 60.degree. C. oven for 1 day, and vacuum dried. Into the
plate containing SIBS were also inserted 316 stainless steel
inserts. The plates were sterilized under a UV lamp for 1 hour,
after which each sample well was hydrated using 200 uL PBS.
Approximately 2.5.times.10.sup.5 U937 monocyte-like cells were
seeded onto each sample in the presence of PMA, and were incubated
at 37.degree. C. in a humid incubator for three days. The adherent
U937 macrophages were enumerated using a CyQuant assay (FIG. 27).
In a similar experiment, the Compound 12 and SIBS films were
prepared on stainless steel inserts (FIG. 28).
Drug Inclusion and Release
[0271] Compounds from Section 1 provide a polymeric platform with
functional groups suitable for the immobilization and inclusion of
active agents. Compounds 6, 7, and 8 have functional groups for
covalent interaction with active agents. Films or stent coatings
including active agents are prepared according to Section 2 and 3
methods.
EXAMPLE 56
Films of Compound 2 and Aspirin (90:10), UV Cure
[0272] Compound 2 (1.6481 g), ASA (0.1841 g), HMP (0.0088 g) and
MeOH (HPLC grade, 4.01 g) were weighed in to a 20 mL vial. The vial
was vortexed until all components were well mixed. If air bubbles
appeared, the vial was allowed to sit at room temperature until all
bubbles dissipated, before the mixture was cast onto desired
substrates (stainless steel discs, an aluminum weighing pan and a
KBr disc). The MeOH was evaporated off at room temperature for 1
and 24 hours under aluminum foil. After 1 hour, the stainless steel
substrates, aluminum weighing pan and KBr disc containing liquid
samples were placed in the center of the UV box. The box was purged
with an argon gas for 10 minutes before the UV lamp was turned on
for 2 minutes. All substrates were removed from the box and cooled
to room temperature before carrying out film analysis. After 24
hours, the UV cure procedure was repeated for samples cast on
Teflon substrates. Gel content, swell ratio, contact angle
measurements, DSC and TGA analysis were performed on films prepared
on stainless steel substrates. The typical thickness of these films
was 0.4 mm. XPS analysis was performed on films cast on aluminum
weighing pans (0.03 mm thick). Gel content: 82%, swelling=180%.
Contact angle: 131.8.degree..+-.2.0. DSC: negative heat flow at
-64.degree. C. (associated with the T.sub.g of PTMO). TGA: 2 onset
points: (A) 234.9.degree. C., 30.2% mass loss, (B) 407.4.degree.
C., 65.5% mass loss. IR: the C.dbd.C group conversion is monitored
by FTIR and performed on films prepared on KBr discs. XPS: C:
50.68%, N: 3.02%, O: 12.00%, F: 34.31%. Aspirin release was
examined for films cast in Teflon molds (FIG. 22).
EXAMPLE 57
Films of Compound 2 and Aspirin (75:25), UV Cure
[0273] Compound 2 (100 mg), HMP (1 mg) and ASA (33 mg) were
dissolved in DMSO as a 2.5 g/mL solution. The solution was cast
into a 4 mL glass vial and the material was cured under UV light
for 2 minutes. The resulting clear elastomeric film was incubated
in PBS solutions for 24 hours at 37.degree. C., with measurement of
ASA release made at 1, 2, 3, 4, 7 and 24 hours by UV
spectrophotometer measurement (FIG. 23).
EXAMPLE 58
Films of Compound 2 and Ibuprofen (75:25), Heat Cure
[0274] Ibuprofen was mixed with Compound 2 (25 wt % of total mass)
in toluene (0.1 gram/mL) containing BPO (1 wt %), and cured at
60.degree. C. under N.sub.2. The release of ibuprofen from the
cured film was measured over 96 hours in PBS solution at 37.degree.
C. by UV spectrophotometer measurement (FIG. 24).
EXAMPLE 59
Films of Compound 2 and Ciprofloxacin-HEMA (Compound 17)
##STR00029## ##STR00030##
[0276] N-trityl ciprofloxacin, EDC, and DMAP (in a stoichiometory
of 1:8:0.5 molar ratio) were dissolved in anhydrous DCM. 10% excess
HEMA relative to the mole of COOH groups was then added into the
reaction system. The reaction mixture was stirred at room
temperature under N.sub.2 for 7 days. After rotary evaporated the
solvent, the solid residual was extracted by diethyl ether at room
temperature. The crude product of this reaction was roughly dried
and then was dissolved in DCM. TFAc (10 vol % of DCM) was added in
the solution, stirred at room temperature for 14 hours. The solvent
was removed by rotary evaporation at room temperature. The solid
crude product was stirred in diethyl ether and filtered three
times. The precipitated product (Compound 17) was dried under
vacuum at room temperature. .sup.19F NMR (300 MHz, DMSO): found one
multiple peak at -120.8 ppm. .sup.1H NMR (300 MHz, CDCl.sub.3)
found: .delta. (ppm): 8.44 (s, FC.sub.cipCH), 7.80 (b,
FC.sub.cipCCH), 7.5 (b, OC.sub.cipCHN), 6.10 (s,
HCH.dbd.C.sub.HEMA), 5.70 (s, HCH.dbd.C.sub.HEMA), 4.40 (s,
OCH.sub.2CH.sub.2O.sub.HEMA), 3.45 (br,
N.sub.cipCHCH.sub.2CH.sub.2), 2.80 (s, .sub.HEMACCH.sub.3), 1.77
(s, .sub.cipNCH.sub.2CH.sub.2N), 1.25 (m,
.sub.cipNCH.sub.2CH.sub.2NH), 1.25 (m,
.sub.cipNCH.sub.2CH.sub.2NH), 1.12 (t, .sub.cipNH).
[0277] Compound 17 (0.050 g), Compound 2 (0.500 g), BPO (0.0055 g)
and pyridine (2 ml) were transferred to a 20 mL vial. The vial was
vortexed until the components were completely well blended. The
mixture was cast onto the desired substrates including stainless
steel discs and an aluminum weighing pan. Pyridine solvent was
allowed to evaporate at room temperature for 17 hours under an
aluminum foil in a fume hood. The stainless steel substrates and
aluminum weighing pan containing liquid samples were placed in an
oven. The oven was purged with N.sub.2 for three times before the
heat was turned on to 110.degree. C. for 17 hours. During this
time, a gentle stream of N.sub.2 was kept on positive flow through
the oven. After 17 hours curing at 110.degree. C., samples were
cooled to room temperature under N.sub.2, and removed from the oven
for analysis. Gel content, swell ratio, contact angle measurements,
DSC and TGA analyses were performed on films prepared on stainless
steel substrates. XPS analysis was performed on films cast on
aluminum weighing pans (0.03 mm thick). Gel extraction (acetone):
86.2% gel, 220% swelling. Contact angle: 109.degree.. XPS analysis
(90.degree.): C:54.77%, N: 4.15%, O: 15.14%, F: 24.85%. DSC:
negative heat flow at -69.degree. C. (associated with the T.sub.g
of the PTMO). TGA: 2 onset points: (A) 227.degree. C., 19% mass
loss, (B) 392.degree. C., 76% mass loss.
EXAMPLE 60
Films of Compound 2 and Hydrocortisone-MA (Compound 18)
##STR00031##
[0279] Hydrocortisone (2.5 g, 6.90 mmol) was transferred to a
flame-dried 250 mL reaction flask equipped with a stir bar. The
flask was capped by a rubber septum and filled with N.sub.2
provided by a balloon. Anhydrous DCM (100 mL) was transferred to
the flask via a syringe. Hydrocortisone did not dissolve in DCM
completely, forming a milky suspension. TEA (1.10 ml, 7.89 mmol)
was transferred to the reaction flask by a syringe. A solution of
acryloyl chloride (0.65 g, 7.18 mmol in 10 ml of dry DCM) was added
dropwise to the reaction flask via a syringe. The addition took
about 10 minutes. As the solution of acryloyl chloride was added,
the suspension became less milky. The reaction flask was kept
stirring for 16 hours at room temperature. About 80 mL of DCM was
removed by rotary evaporator to give a milky suspension. Flash
column chromatography of the milky suspension using DCM as the
eluent yielded pure hydrocortisone-containing acrylate, Compound
18. R.sub.f of Compound 18 in diethyl ether containing 2 wt %
ethanol as the inhibitor: 0.46. .sup.1H NMR (300 MHz, CDCl.sub.3)
found: .delta. (ppm) 6.49 (1H, dd, --OCCHCH.sub.2), 6.23 (1H, dd,
--OCHCH.sub.2), 5.92 (1H, dd, --CHCH.sub.2), 5.68 (1H, s,
C.sup.4.sub.HCH), 5.13 (1H, d, OCCH.sub.2O--), 4.94 (1H, d,
OCCH.sub.2O--), 4.48 (1H, b, C.sup.11.sub.HCHOH), 2.87 (1H, m,
C.sup.11.sub.HCHOH), 2.60-0.94 (25H, m, C.sup.1.sub.HCH.sub.2,
C.sup.2.sub.HCH.sub.2, C.sup.6.sub.HCH.sub.2,
C.sup.7.sub.HCH.sub.2, C.sup.8.sub.HCH, C.sup.9.sub.HCH,
C.sup.12.sub.HCH.sub.2, C.sup.14.sub.HH, C.sup.15.sub.HCH.sub.2,
C.sup.16.sub.HCH.sub.2, C.sup.18.sub.HCH.sub.3,
C.sup.19.sub.HCH.sub.3.
[0280] Compound 18 (0.050 g), Compound 2 (0.500 g), BPO (0.0055 g)
and pyridine (2 ml) were transferred to a 20 mL vial. The vial was
vortexed until the components were completely well blended. The
mixture was cast onto the desired substrates including stainless
steel discs and an aluminum weighing pan. Pyridine solvent was
allowed to evaporate at room temperature for 17 hours under an
aluminum foil in a fume hood. The stainless steel substrates and
aluminum weighing pan containing liquid samples were placed in an
oven. The oven was purged with N.sub.2 for three times before the
heat was turned on to 110.degree. C. for 17 hours. During this
time, a gentle stream of N.sub.2 was kept on positive flow through
the oven. After 17 hours curing at 110.degree. C., samples were
cooled to room temperature under an N.sub.2 environment, and
removed from the oven for analysis. Gel content, swell ratio,
contact angle measurements, DSC and TGA analyses were performed on
films prepared on stainless steel substrates. XPS analysis was
performed on films cast on aluminum weighing pans (0.03 mm thick).
Gel extraction (acetone): 96.8% gel, 161% swelling. Contact angle:
109.degree.. XPS analysis (90.degree.): C:50.94%, N: 3.38%, O:
11.41%, F: 34.27%. DSC: negative heat flow at -68.7.degree. C.
(associated with the T.sub.g of the PTMO). TGA: 2 onset points: (A)
251.degree. C., 17% mass loss, (B) 409.degree. C., 78% mass
loss.
EXAMPLE 61
Films of Compound 6 and Hydrocortisone (99:1), Heat Cure
[0281] Hydrocortisone was mixed with Compound 6 (1 wt % of total
mass) in toluene (0.1 gram/mL) containing initiator (1 wt %), and
cured at 60.degree. C. under N.sub.2. The release of hydrocortisone
from the cured film was measured over 24 hours in PBS solution at
37.degree. C. by HPLC measurement (FIG. 25). A stent was coated
using the same casting solution and cure method (FIG. 26).
EXAMPLE 62
Films of Compound 6 and Dexamethasone (99:1), Heat Cure
[0282] Dexamethasone was mixed with Compound 6 (1 wt % of total
mass) in toluene (0.1 gram/mL) containing initiator (1 wt %), and
cured at 60.degree. C. under N.sub.2. The release of dexamethasone
from the cured film was measured over 24 hours in PBS solution at
37.degree. C. by HPLC measurement (FIG. 25).
Other Embodiments
[0283] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each independent publication or patent
application was specifically and individually indicated to be
incorporated by reference.
[0284] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure that come
within known or customary practice within the art to which the
invention pertains and may be applied to the essential features
hereinbefore set forth, and follows in the scope of the claims.
[0285] Other embodiments are within the claims.
* * * * *