Copolymers having zwitterionic moieties and dihydroxyphenyl moieties and medical devices coated with the copolymers
Copolymers are manufactured to include a zwitterionic monomer (e.g., methacryloyloxyethyl phosphorylcholine monomer), a dihydroxyphenyl derivatized monomer, and optionally one or more additional monomers. The dihydroxyphenyl derivatized monomer gives the copolymers excellent adhesion properties. Optional monomers include a cationic amino monomer, a hydrocarbon monomer, and/or a hydrophilic monomer. The copolymers are biocompatible and can be used with medical devices.
1. A medical device comprising a supporting structure having a coating associated therewith, the coating comprising a polymer having the formula,
in which,
R 1 -R 4 are independently a methacryl, acryl, styryl, acrylamido, methacrylamido, sulfovinyl, amido, ester, ethyl, or propyl;
R 5 is a hydrocarbon chain, cycloaliphatic group, ester group, amide group, thiol, sulfone, carbonate, saccharide, PEG, or combination thereof;
R 6 includes a zwitterion group, a linker being a chain of 2-12 carbon atoms, and an ester or amide attachment to the methacryl group;
wherein the zwitterion group has a formula selected from the group consisting of
(I)
wherein the moieties A 2 and A 3 , which are the same or different, are —O—, —S—, —NH— or a valence bond, W + is a group comprising an ammonium, phosphonium or sulphonium cationic group and a group linking the anionic and cationic moieties which in one embodiment is a C 1-12 -alkanediyl group;
(II) -A 4 -R 3 —N + (R 4 ) 2 —R 5 —V − , wherein A 4 is a valence bond, —O—, —S—, or —NH—; V is a carboxylate or phosphate diester (monovalently charged) anion; R 3 is a valence bond (together with A 4 ) or alkanediyl, —C(O)alkylene- or —C(O)NH alkylene; the groups R 4 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms or the groups R 4 together with the nitrogen to which the are attached form a heterocyclic ring of 5 to 7 atoms; and R 5 is an alkyanediyl of 1 to 20 carbon atoms, of 1 to 10 carbon atoms, or of 1 to 6 carbon atoms; and
(III)
wherein A 5 is a valence bond, —O—, —S—, or —NH—; R 16 is a vlanece bond (optionally together with A 5 ) or alkanediyl, —C(O)alkylene- or —C(O)NH alkylene; the groups R 17 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms or the groups R 4 together with the nitrogen to which the are attached form a heterocyclic ring of 5 to 7 atoms; and R 5 is an alkyanediyl of 1 to 20 carbon atoms, of 1 to 10 carbon atoms, or of 1 to 6 carbon atoms;
R 7 is a methyl, ethyl, or hydrogen group;
n is in a range from about 0.005 to about 0.5;
o is in a range from about 0.005 to about 0.4;
p optionally included in a range from 0.005 to 0.25;
q is in a range from about 0.005 to about 0.98; and
r is optionally included in a range from about 0.005 to about 0.4.
2. The medical device as in claim 1 , in which n+o+p+q+r=1.
3. The medical device as in claim 1 , in which the 3,4-dihydroxyphenyl group is substituted with a 2,3-dihydroxyphenyl group.
4. The medical device as in claim 1 , in which the zwitterion group is selected from the group consisting of phosphorylcholine, phosphoryl ethanolamine, phosphatidyl ethanolamine, phosphoethanolamine, phosphatidyl serine, and combinations thereof.
5. The medical device as in claim 1 , in which the glass transition temperature of the polymer when hydrated is in a range from about −30° C. to about 37° C.
6. The medical device as in claim 1 , in which the glass transition temperature of the polymer when dry is in a range from about −30° C. to about 100° C.
7. The medical device as in claim 1 , in which the polymer is substantially free of cross-linking.
8. The medical device as in claim 1 , in which the polymer having the formula,
in which,
R 6 includes a zwitterion group, a linker being a chain of 2-12 carbon atoms, and an ester or amide attachment to the methacryl group;
n is in a range from about 0.01 to about 0.50;
o is in a range from about 0.01 to about 0.4; and
q is in a range from about 0.1 to about 0.98;
n+o+q=1.
9. The medical device as in claim 8 , in which R 6 is selected from the group consisting of phosphorylcholine, phosphoryl ethanolamine, phosphatidyl ethanolamine, phosphoethanolamine, phosphatidyl serine, and combinations thereof.
10. The medical device as in claim 1 , in which the polymer having the formula,
in which,
n is in a range from about 0.005 to about 0.5;
o is in a range from about 0.005 to about 0.4;
p is in a range from about 0.005 to about 0.25;
q is in a range from about 0.1 to about 0.98; and
n+o+p+q=1.
11. The medical device as in claim 1 , in which the polymer having the formula,
in which,
n is in a range from about 0.005 to about 0.5;
o is in a range from about 0.005 to about 0.4;
q is in a range from about 0.005 to about 0.98; and
n+o+q=1.
12. The medical device as in claim 1 , in which the molecular weight of the polymer is in a range from about 20 kpa to about 800 kpa.
13. The medical device as in claim 1 , in which the molecular weight of the polymer is in a range from about 2 kpa to about 200 kpa.
14. The medical device as in claim 1 , in which the biocompatible coating further comprising a polymer selected from the group consisting of poly(vinyl pyrrolidinone), poly(n-butyl methacrylate), poly(n-butyl methacrylate) copolymers, methacrylate polymers, acrylate polymers, and/or a terpolymers of hexyl methacrylate, vinyl acetate, and vinyl pyrrolidinone.
15. The medical device as in claim 1 , wherein the zwitterion has formula
wherein the moieties A 2 and A 3 , which are the same or different, are —O—, —S—, —NH— or a valence bond, W + is a group comprising an ammonium, phosphonium or sulphonium cationic group and a group linking the anionic and cationic moieties which in one embodiment is a C 1-12 -alkanediyl group.
16. The medical device as in claim 15 , wherein the W + is a (CH) 2 + N(R 2 ) 3 , where R 2 are the same or different and each is hydrogen or C 1-4 alkyl, and m is from 1 to 4.
17. The medical device as in claim 1 , wherein the zwitterion has formula
-A 4 -R 3 —N + (R 4 ) 2 —R 5 —V − , wherein A 4 is a valence bond, —O—, —S—, or —NH—; V is a carboxylate or phosphate diester (monovalently charged) anion; R 3 is a valence bond (together with A 4 ) or alkanediyl, —C(O)alkylene- or —C(O)NH alkylene; the groups R 4 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms or the groups R 4 together with the nitrogen to which the are attached form a heterocyclic ring of 5 to 7 atoms; and R 5 is an alkyanediyl of 1 to 20 carbon atoms, of 1 to 10 carbon atoms, or of 1 to 6 carbon atoms.
18. The medical device as in claim 1 , wherein the zwitterion has formula
wherein A 5 is a valence bond, —O—, —S—, or —NH—; R 16 is a vlanece bond (optionally together with A 5 ) or alkanediyl, —C(O)alkylene- or —C(O)NH alkylene; the groups R 17 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms or the groups R 4 together with the nitrogen to which the are attached form a heterocyclic ring of 5 to 7 atoms; and R 5 is an alkyanediyl of 1 to 20 carbon atoms, of 1 to 10 carbon atoms, or of 1 to 6 carbon atoms.
19. The medical device as in claim 1 , which is an implantable device selected from the group consisting of coronary stents, peripheral stents, catheters, arteriovenous grafts, by-pass grafts, pacemaker, and defibrillator leads, anastomotic clips, arterial closure devices, patent foramen ovale closure devices, and drug delivery balloons.
20. The medical device as in claim 1 , which is a stent.