US2005265960A1PendingUtilityA1
Polymers containing poly(ester amides) and agents for use with medical articles and methods of fabricating the same
Individually held — no corporate assignee on recordPriority: May 26, 2004Filed: May 26, 2004Published: Dec 1, 2005
Est. expiryMay 26, 2024(expired)· nominal 20-yr term from priority
Inventors:Stephen D. PacettiCharles D. ClaudeThierry GlauserJessica DesnoyerSyed Faiyaz Ahmed Hossainy
A61P 5/30A61P 41/00A61P 7/02C08G 69/44A61P 39/06A61L 31/10A61P 35/00
53
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Claims
Abstract
Polymers containing poly(ester amides) and agents for use with medical articles and methods of fabricating the same are disclosed. The medical article generally comprises an implantable substrate having a coating, and the coating contains a polymer comprising a polymeric product of a reaction comprising a polyol, a polycarboxylic acid, an amino acid and an agent.
Claims
exact text as granted — not AI-modified1 . A polymer represented by a formula:
wherein A comprises
B comprises
where R 1 and R 5 are optional and are independently selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
R 3 is selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
R 2 and R 4 are independently selected from a group consisting of hydrogen; substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
R 6 is selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained and branched aliphatic radicals;
L 1 is an optional linkage connecting said A to said B;
X is optionally an agent;
L 2 is optionally a linkage connecting X to said polymer;
n and m are integers not equal to 0;
provided that if (i) said R 1 , R 3 and R 5 are independently selected straight-chained or branched saturated aliphatic radicals having from 2-20 carbon atoms; (ii) said R 2 and R 4 are independently selected straight-chained or branched saturated aliphatic radicals having from 1-6 carbon atoms, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one unsaturated carbon-carbon bond, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one carbon-carbon triple bond, phenyl radicals, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; (iii) R 6 is a pentylene radical; and, (iv) said X is a straight-chained or branched saturated aliphatic radical having from 1-6 carbon atoms, a phenyl radical, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; and, (v) said m and n are integers not equal to 0; then, said L 2 cannot be
when the carbon of said L 2 is attached to either C 1 or C 5 of the pentylene radical, R 6 ;
provided further that if (i) said R 1 and R 5 are unsubstituted, straight-chained octyl radicals; (ii) said R 3 is an unsubstituted, straight-chained butyl radical; (iii) said R 2 and R 4 are unsubstituted t-butyl radicals; (iv) said R 6 is a pentylene radical; and (v) said X is TEMPO; then, said L 2 cannot be
when the carbon of said L 2 is attached to either C 1 or C 5 of the pentylene radical, R 6 , and the nitrogen of said L 2 is attached to C 1 of the TEMPO;
and provided further that if (i) said R 1 and R 5 are straight-chained-butyl or straight-chained-hexyl radicals; (ii) said R 3 is a straight-chained or branched saturated aliphatic radicals having from 2-20 carbon atoms; (iii) said R 2 and R 4 are independently selected straight-chained or branched saturated aliphatic radicals having from 1-6 carbon atoms, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one unsaturated carbon-carbon bond, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one carbon-carbon triple bond, phenyl radicals, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; (iv) said R 6 is a pentylene radical; (v) said X is TEMPO and L 2 is
or said X is rapamycin and said L 2 is
then, said R 1 and R 5 cannot be substituted with epoxy groups.
2 . The polymer of claim 1 , wherein said X is a biobeneficial agent selected from a group consisting of poly(alkylene glycols), poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid), poly(styrene sulfonate), sulfonated dextran; polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid, heparin and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations-thereof.
3 . The polymer of claim 1 , wherein the biobeneficial agent is hyaluronic acid, heparin, poly(ethylene glycol), or any derivatives, analogs, homologues, congeners, salts, copolymers or combinations thereof.
4 . The polymer of claim 1 , wherein said X is a bioactive agent selected from a group consisting of a free radical scavenger, a nitric oxide donor, rapamycin, everolimus, tacrolirnus, paclitaxel, docetaxel, estradiol, clobetasol, idoxifen, tazarotene and any prodrugs, metabolites, analogs, homologues, congeners, and any derivatives, salts and combinations thereof.
5 . The polymer of claim 4 , wherein the free radical scavenger is selected from a group consisting of 2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, free radical; 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate, free radical; 16-doxyl-stearic acid, free radical; superoxide dismutase mimic; and, any analogs, homologues, congeners, derivatives, salts and combinations thereof.
6 . The polymer of claim 4 , wherein the free radical scavenger is TEMPO or any analogs, homologues, congeners, derivatives, salts or combinations thereof.
7 . The polymer of claim 4 , wherein the nitric oxide donor is selected from the group consisting of S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazenium diolates and any analogs, homologues, congeners, derivatives, salts and combinations thereof.
8 . The polymer of claim 4 , wherein the bioactive agent is rapamycin, everolimus, tacrolimus, or any prodrug, metabolite, analog, congener, derivative, salt or combinations thereof.
9 . The polymer of claim 1 , wherein said L 2 is selected from a group consisting of anhydrides, ketals, acetals, orthoesters and all-aromatic carbonates.
10 . The polymer of claim 1 , wherein said polymer is represented by a formula:
wherein n, m and r are integers not equal to 0.
11 . The polymer of claim 1 , wherein said polymer is represented by the formula:
wherein n and m are integers not equal to 0.
12 . The polymer of claim 1 , wherein said polymer is represented by a formula:
wherein m and n are integers not equal to 0.
13 . A polymer represented by a formula:
wherein A comprises
B comprises
where R 1 and R 5 are optional and are independently selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
R 3 is selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
R 2 , R 4 , and R 7 are independently selected from a group consisting of hydrogen; substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
R 6 is selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained and branched aliphatic radicals;
L 1 is an optional linkage connecting said A to said B;
X is optionally an agent;
L 2 is optionally a linkage connecting X to said polymer; and
n and m are integers not equal to 0.
14 . The polymer of claim 13 , wherein said X is a biobeneficial agent selected from a group consisting of poly(alkylene glycols), poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid), poly(styrene sulfonate), sulfonated dextran; polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid, heparin and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
15 . The polymer of claim 14 , wherein the biobeneficial agent is hyaluronic acid, heparin, poly(ethylene glycol), or any derivatives, analogs, homologues, congeners, salts, copolymers or combinations thereof.
16 . The polymer of claim 13 , wherein said X is a bioactive agent selected from a group consisting of a free radical scavenger, a nitric oxide donor, rapamycin, everolimus, tacrolimus, paclitaxel, docetaxel, estradiol, clobetasol, idoxifen, tazarotene and any prodrugs, metabolites, analogs, homologues, congeners, derivatives, salts and combinations thereof.
17 . The polymer of claim 16 , wherein the free radical scavenger is selected from a group consisting of 2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, free radical; 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate, free radical; 16-doxyl-stearic acid, free radical; superoxide dismutase mimic; and, any analogs, homologues, congeners, derivatives, salts and combinations thereof.
18 . The polymer of claim 16 , wherein the free radical scavenger is TEMPO or any analogs, homologues, congeners, derivatives, salts or combinations thereof.
19 . The polymer of claim 16 , wherein the nitric oxide donor is selected from the group consisting of S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazenium diolates and any analogs, homologues, congeners, derivatives, salts and combinations thereof.
20 . The polymer of claim 16 ,.wherein the bioactive agent is rapamycin, everolimus, tacrolimus, or any prodrug, metabolite, analog, congener, derivative, salt or combinations thereof.
21 . The polymer of claim 13 , wherein said L 2 is selected from a group consisting of amides, esters, anhydrides, ketals, acetals, orthoesters and all-aromatic carbonates.
22 . The polymer of claim 13 , wherein said polymer is represented by a formula:
wherein n, m and r are integers not equal to 0.
23 . A polymer represented by a formula:
wherein A comprises
and B comprises
where R 1 and R 5 are optional and are independently selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
R 3 and R 8 are selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
R 2 , R 4 , R 7 and R 9 are independently selected from a group consisting of hydrogen; substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
L 1 is an optional linkage connecting said A to said B;
X is optionally an agent;
L 2 is optionally a linkage connecting X to said polymer; and
n and m are integers not equal to 0.
24 . The polymer of claim 23 , wherein said X is a biobeneficial agent selected from a group consisting of poly(alkylene glycols), poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid), poly(styrene sulfonate), sulfonated dextran; polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid, heparin and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
25 . The polymer of claim 24 , wherein the biobeneficial agent is hyaluronic acid, heparin, poly(ethylene glycol), or any derivatives, analogs, homologues, congeners, salts, copolymers or combinations thereof.
26 . The polymer of claim 23 , wherein said X is a bioactive agent selected from a group consisting of a free radical scavenger, a nitric oxide donor, rapamycin, everolimus, tacrolimus, paclitaxel, docetaxel, estradiol, clobetasol, idoxifen, tazarotene and any prodrugs, metabolites, analogs, homologues, congeners, derivatives, salts and combinations thereof.
27 . The polymer of claim 26 , wherein the free radical scavenger is selected from a group consisting of 2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, free radical; 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate, free radical; 16-doxyl-stearic acid, free radical; superoxide dismutase mimic; and, any analogs, homologues, congeners, derivatives, salts and combinations thereof.
28 . The polymer of claim 26 , wherein the free radical scavenger is TEMPO or any analogs, homologues, congeners, derivatives, salts or combinations thereof.
29 . The polymer of claim 26 , wherein the nitric oxide donor is selected from the group consisting of S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazenium diolates and any analogs, homologues, congeners, derivatives, salts and combinations thereof.
30 . The polymer of claim 26 , wherein the bioactive agent is rapamycin, everolimus, tacrolimus, or any prodrug, metabolite, analog, congener, derivative, salt or combinations thereof.
31 . The polymer of claim 23 , wherein said L 2 is selected from a group consisting of amides, esters, anhydrides, ketals, acetals, orthoesters and all-aromatic carbonates.
32 . The polymer of claim 23 , wherein said polymer is represented by a formula:
wherein n and m are integers not equal to 0.
33 . A medical article comprising an implantable substrate comprising a coating, wherein said coating comprises a block-copolymer comprising at least one block of poly(ester amide) and at least one block of a polymeric agent.
34 . The medical article of claim 33 , wherein said polymeric agent is a biobeneficial agent selected from a group consisting of heparin, hyaluronic acid, poly(ethylene glycol), a graft copolymer of poly(L-lysine) and poly(ethylene glycol), and copolymers and combinations thereof.
35 . A polymer comprising a poly(ester amide) that is a polymeric product of a reaction comprising a polyol, a polycarboxylic acid, an amino acid, and an agent (X);
provided that said polymeric product is not where (i) R 1 , R 3 and R 5 are independently selected straight-chained or branched saturated aliphatic radicals having from 2-20 carbon atoms; (ii) R 2 and R 4 are independently selected straight-chained or branched saturated aliphatic radicals having from 1-6 carbon atoms, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one unsaturated carbon-carbon bond, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one carbon-carbon triple bond, phenyl radicals, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; and (iii) X is a straight-chained or branched saturated aliphatic radical having from 1-6 carbon atoms, a phenyl radical, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; and, (iv) m and n are integers not equal to 0; and provided further that said polymeric product is not where n and m are integers not equal to 0; and provided further that said polycarboxylic acid is not 2,3-epoxysuccinic acid, 3,4-epoxyadipic acid or a diepoxyadipic acid, where the amino acid chosen to link with said X is lysine, and said X is 4-amino-TEMPO or rapamycin.
36 . The polymer of claim 35 , wherein said X is a biobeneficial agent selected from a group consisting of poly(alkylene glycols), poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid), poly(styrene sulfonate), sulfonated dextran; polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid, heparin and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
37 . The polymer of claim 36 , wherein the biobeneficial agent is hyaluronic acid, heparin, poly(ethylene glycol), or any derivatives, analogs, homologues, congeners, salts, copolymers or combinations thereof.
38 . The polymer of claim 35 , wherein said X is a bioactive agent selected from a group consisting of a free radical scavenger, a nitric oxide donor, rapamycin, everolimus, tacrolimus, paclitaxel, docetaxel, estradiol, clobetasol, idoxifen, tazarotene and any prodrugs, metabolites, analogs, homologues, congeners, derivatives, salts and combinations thereof.
39 . The polymer of claim 38 , wherein the free radical scavenger is selected from a group consisting of 2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, free radical; 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate, free radical; 16-doxyl-stearic acid, free radical; superoxide dismutase mimic; and, any analogs, homologues, congeners, derivatives, salts and combinations thereof.
40 . The polymer of claim 38 , wherein the free radical scavenger is TEMPO or any analogs, homologues, congeners, derivatives, salts or combinations thereof.
41 . The polymer of claim 38 , wherein the nitric oxide donor is selected from the group consisting of S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazenium diolates and any analogs, homologues, congeners, derivatives, salts and combinations thereof.
42 . The polymer of claim 38 , wherein the bioactive agent is rapamycin, everolimus, tacrolimus, or any prodrug, metabolite, analog, congener, derivative, salt or combinations thereof.
43 . A coating for a medical article comprising the polymer of claim 1 .
44 . A coating for a medical article comprising the polymer of claim 13 .
45 . A coating for a medical article comprising the polymer of claim 23 .
46 . A coating for a medical article comprising the polymer of claim 35 .
47 . A medical article comprising the polymer of claim 1 .
48 . A medical article comprising the polymer of claim 13 .
49 . A medical article comprising the polymer of claim 23 .
50 . A medical article comprising the polymer of claim 35 .
51 . A stent comprising a coating, wherein said coating comprises a polymer represented by a formula:
wherein A comprises
B is selected from a group consisting of
where R 1 and R 5 are optional and are independently selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
R 3 and R 8 are independently selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
R 2 , R 4 , R 7 and R 9 are independently selected from a group consisting of hydrogen; substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals;
R 6 is selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained and branched aliphatic radicals;
L 1 is an optional linkage connecting said A to said B;
n and m are integers not equal to 0;
provided that B is not
where (i) said R 1 , R 3 and R 5 are independently selected straight-chained or branched saturated aliphatic radicals having from 2-20 carbon atoms; (ii) said R 2 and R 4 are independently selected straight-chained or branched saturated aliphatic radicals having from 1-6 carbon atoms, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one unsaturated carbon-carbon bond, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one carbon-carbon triple bond, phenyl radicals, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; and (iii) said R 6 is a carboxyl-substituted, pentylene radical;
and provided further that B is not
where (i) said R 1 and R 5 are epoxy-substituted, straight-chained-butyl or straight-chained-hexyl radicals; (ii) said R 3 is a straight-chained or branched saturated aliphatic radicals having from 2-20 carbon atoms; (iii) said R 2 and R 4 are independently selected straight-chained or branched saturated aliphatic radicals having from 1-6 carbon atoms, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one unsaturated carbon-carbon bond, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one carbon-carbon triple bond, phenyl radicals, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; and (iv) said R 6 is a carboxyl-substituted, pentylene radical.
52 . The stent of claim 51 , wherein said coating further comprises an agent that may be blended or connected to said coating.
53 . A method for fabricating a medical article comprising an implantable substrate, wherein said method comprises:
(a) preparing a polymer represented by a formula: wherein A comprises B comprises where R 1 and R 5 are optional and are independently selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals; R 3 is selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals; R 2 and R 4 are independently selected from a group consisting of hydrogen; substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals; R 6 is selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained and branched aliphatic radicals; L 1 is an optional linkage connecting said A to said B; X is optionally an agent; L 2 is optionally a linkage connecting X to said polymer; n and m are integers not equal to 0; provided that if (i) said R 1 , R 3 and R 5 are independently selected straight-chained or branched saturated aliphatic radicals having from 2-20 carbon atoms; (ii) said R 2 and R 4 are independently selected straight-chained or branched saturated aliphatic radicals having from 1-6 carbon atoms, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one unsaturated carbon-carbon bond, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one carbon-carbon triple bond, phenyl radicals, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; (iii) said R 6 is a pentylene radical; and, (iv) said X is a straight-chained or branched saturated aliphatic radical having from 1-6 carbon atoms, a phenyl radical, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; and, (v) said m and n are integers not equal to 0; then, said L 2 cannot be when the carbon of said L 2 is attached to either C 1 or C 5 of the pentylene radical, R 6 ; provided further that if (i) said R 1 and R 5 are unsubstituted, straight-chained octyl radicals; (ii) said R 3 is an unsubstituted, straight-chained butyl radical; (iii) said R 2 and R 4 are unsubstituted t-butyl radicals; (iv) said R 6 is a pentylene radical; and (v) said X is TEMPO; then, said L 2 cannot be where the carbon of said L 2 is attached to either C 1 or C 5 of the pentylene radical, R 6 , and the nitrogen of said L 2 is attached to C 1 of the TEMPO; and provided further that if (i) said R 1 and R 5 are straight-chained-butyl or straight-chained-hexyl radicals; (ii) said R 3 is a straight-chained or branched saturated aliphatic radicals having from 2-20 carbon atoms; (iii) said R 2 and R 4 are independently selected straight-chained or branched saturated aliphatic radicals having from 1-6 carbon atoms, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one unsaturated carbon-carbon bond, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one carbon-carbon triple bond, phenyl radicals, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; (iv) said R 6 is a pentylene radical; (v) said X is TEMPO and L 2 is where the carbon of said L 2 is attached to either C 1 or C 5 of the pentylene radical, R 6 , and the nitrogen of said L 2 is attached to C 1 of the TEMPO, or said X is rapamycin and said L 2 is when the carbon of said L 2 is attached to either C 1 or C 5 of the pentylene radical, R 6 ; then, said R 1 and R 5 cannot be substituted with epoxy groups; and (b) forming a coating comprising the polymer on at least a portion of an implantable substrate.
54 . The method of claim 53 , wherein said medical article is a stent.
55 . The method of claim 53 , wherein said X is a biobeneficial agent selected from a group consisting of poly(alkylene glycols), poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid), poly(styrene sulfonate), sulfonated dextran; polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid, heparin and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
56 . The method of claim 55 , wherein the biobeneficial agent is hyaluronic acid, heparin, poly(ethylene glycol), or any derivatives, analogs, homologues, congeners, salts, copolymers or combinations thereof.
57 . The method of claim 53 , wherein said X is a bioactive agent selected from a group consisting of a free radical scavenger, a nitric oxide donor, rapamycin, everolimus, tacrolimus, paclitaxel, docetaxel, estradiol, clobetasol, idoxifen, tazarotene and any prodrugs, metabolites, analogs, homologues, congeners, derivatives, salts and combinations thereof.
58 . The method of claim 57 , wherein the free radical scavenger is selected from a group consisting of 2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, free radical; 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate, free radical; 16-doxyl-stearic acid, free radical; superoxide dismutase mimic; and, any analogs, homologues, congeners, derivatives, salts and combinations thereof.
59 . The method of claim 57 , wherein the free radical scavenger is TEMPO or any analogs, homologues, congeners, derivatives, salts or combinations thereof.
60 . The method of claim 57 , wherein the nitric oxide donor is selected from the group consisting of S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazenium diolates and any analogs, homologues, congeners, derivatives, salts and combinations thereof.
61 . The method of claim 57 , wherein the bioactive agent is rapamycin, everolimus, tacrolimus, or any prodrug, metabolite, analog, congener, derivative, salt or combinations thereof.
62 . The method of claim 53 , wherein said L 2 is selected from a group consisting of amides, esters, anhydrides, ketals, acetals, orthoesters and all-aromatic carbonates.
63 . The method of claim 53 , wherein the polymer is represented by a formula:
wherein n, m and r are integers not equal to 0.
64 . The method of claim 53 , wherein the polymer is represented by a formula:
wherein n and m are integers not equal to 0.
65 . The method of claim 53 , wherein the polymer is represented by a formula:
wherein n and m are integers not equal to zero.
66 . A method for fabricating a medical article comprising:
(a) preparing a polymer represented by a formula: wherein A comprises B comprises where R 1 and R 5 are optional and are independently selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals; R 3 is selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals; R 2 , R 4 , and R 7 are independently selected from a group consisting of hydrogen; substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals; R 6 is selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained and branched aliphatic radicals; L 1 is an optional linkage connecting said A to said B; X is optionally an agent; L 2 is optionally a linkage connecting X to said polymer; n and m are integers not equal to 0; and (b) forming a coating comprising the polymer on at least a portion of an implantable substrate.
67 . The method of claim 66 , wherein said medical article is a stent.
68 . The method of claim 66 , wherein said X is a biobeneficial agent selected from a group consisting of poly(alkylene glycols), poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid), poly(styrene sulfonate), sulfonated dextran; polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid, heparin and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
69 . The method of claim 68 , wherein the biobeneficial agent is hyaluronic acid, heparin, poly(ethylene glycol), or any derivatives, analogs, homologues, congeners, salts, copolymers or combinations thereof.
70 . The method of claim 66 , wherein said X is a bioactive agent selected from a group consisting of a free radical scavenger, a nitric oxide donor, rapamycin, everolimus, tacrolimus, paclitaxel, docetaxel, estradiol, clobetasol, idoxifen, tazarotene and any prodrugs, metabolites, analogs, homologues, congeners, derivatives, salts and combinations thereof.
71 . The method of claim 70 , wherein the free radical scavenger is selected from a group consisting of 2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, free radical; 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate, free radical; 16-doxyl-stearic acid, free radical; superoxide dismutase mimic; and, any analogs, homologues, congeners, derivatives, salts and combinations thereof.
72 . The method of claim 70 , wherein the free radical scavenger is TEMPO or any analogs, homologues, congeners, derivatives, salts or combinations thereof.
73 . The method of claim 70 , wherein the nitric oxide donor is selected from the group consisting of S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazenium diolates and any analogs, homologues, congeners, derivatives, salts and combinations thereof.
74 . The method of claim 70 , wherein the bioactive agent is rapamycin, everolimus, tacrolimus, or any prodrug, metabolite, analog, congener, derivative, salt or combinations thereof.
75 . The method of claim 66 , wherein said L 2 is selected from a group consisting of amides, esters, anhydrides, ketals, acetals, orthoesters and all-aromatic carbonates.
76 . The method of claim 66 , wherein the polymer is represented by a formula:
wherein n, m and r are integers not equal to zero.
77 . A method for fabricating a medical article comprising:
(a) preparing a polymer represented by a formula: wherein A comprises B comprises where R 1 and R 5 are optional and are independently selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals; R 3 and R 8 are selected from a group consisting of substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals; R 2 , R 4 , R 7 and R 9 are independently selected from a group consisting of hydrogen; substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated and unsaturated aliphatic radicals; and substituted, unsubstituted, and hetero-aromatic radicals; L 1 is an optional linkage connecting said A to said B; X is optionally an agent; L 2 is optionally a linkage connecting X to said polymer; n and m are integers not equal to 0; and (b) forming a coating comprising the polymer on at least a portion of an implantable substrate.
78 . The method of claim 77 , wherein said medical article is a stent.
79 . The method of claim 77 , wherein said X is a biobeneficial agent selected from a group consisting of poly(alkylene glycols), poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid), poly(styrene sulfonate), sulfonated dextran; polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid, heparin and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
80 . The method of claim 79 , wherein the biobeneficial agent is hyaluronic acid, heparin, poly(ethylene glycol), or any derivatives, analogs, homologues, congeners, salts, copolymers or combinations thereof.
81 . The method of claim 77 , wherein said X is a bioactive agent selected from a group consisting of a free radical scavenger, a nitric oxide donor, rapamycin, everolimus, tacrolimus, paclitaxel, docetaxel, estradiol, clobetasol, idoxifen, tazarotene and any prodrugs, metabolites, analogs, homologues, congeners, derivatives, salts and combinations thereof.
82 . The method of claim 81 , wherein the free radical scavenger is selected from a group consisting of 2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, free radical; 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate, free radical; 16-doxyl-stearic acid, free radical; superoxide dismutase mimic; and, any analogs, homologues, congeners, derivatives, salts and combinations thereof.
83 . The method of claim 81 , wherein the free radical scavenger is TEMPO or any analogs, homologues, congeners, derivatives, salts or combinations thereof.
84 . The method of claim 81 , wherein the nitric oxide donor is selected from the group consisting of S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazenium diolates and any analogs, homologues, congeners, derivatives, salts and combinations thereof.
85 . The method of claim 81 , wherein the bioactive agent is rapamycin, everolimus, tacrolimus, or any prodrug, metabolite, analog, congener, derivative, salt or combinations thereof.
86 . The method of claim 77 , wherein said L 2 is selected from a group consisting of amides, esters, anhydrides, ketals, acetals, orthoesters and all-aromatic carbonates.
87 . The method of claim 77 , wherein the polymer is represented by a formula:
wherein n and m are integers not equal to zero.
88 . A method for fabricating a medical article comprising:
(a) preparing a polymer comprising a poly(ester amide), wherein said preparing comprises combining a polyol, a polycarboxylic acid, an amino acid, and an agent (X); provided that said polymer is not where (i) R 1 , R 3 and R 5 are independently selected straight-chained or branched saturated aliphatic radicals having from 2-20 carbon atoms; (ii) R 2 and R 4 are independently selected straight-chained or branched saturated aliphatic radicals having from 1-6 carbon atoms, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one unsaturated carbon-carbon bond, straight-chained or branched aliphatic radicals having from 2-6 carbon atoms and at least one carbon-carbon triple bond, phenyl radicals, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; and (iii) X is a straight-chained or branched saturated aliphatic radical having from 1-6 carbon atoms, a phenyl radical, an ortho-fused bicyclic carbocyclic radical having 6-10 carbon atoms and at least one aromatic ring, or hydrogen; and, (iv) m and n are integers not equal to 0; provided further that said polymer is not where n and m are integers not equal to 0; provided further that said polycarboxylic acid is not 2,3-epoxysuccinic acid, 3,4-epoxyadipic acid or a diepoxyadipic acid, where the amino acid chosen to link with said X is lysine, and said X is 4-amino-TEMPO or rapamycin; and (b) forming a coating comprising the polymer on at least a portion of an implantable substrate.
89 . The method of claim 88 , wherein said preparing further comprises producing a poly(ester amide) with all amino end-groups for conjugating to said agent.
90 . The method of claim 88 , wherein said preparing further comprises producing a poly(ester amide) with all carboxyl end-groups for conjugating to said agent.
91 . The method of claim 88 , wherein said medical article comprises a stent.
92 . The method of claim 88 , wherein said X is a biobeneficial agent selected from a group consisting of poly(alkylene glycols), poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid), poly(styrene sulfonate)i sulfonated dextran; polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid, heparin and any derivatives, analogs, homologues, congeners, salts, copolymers and combinations thereof.
93 . The method of claim 92 , wherein the biobeneficial agent is hyaluronic acid, heparin, poly(ethylene glycol), or any derivatives, analogs, homologues, congeners, salts, copolymers or combinations thereof.
94 . The method of claim 88 , wherein said X is a bioactive agent selected from a group consisting of a free radical scavenger, a nitric oxide donor, rapamycin, everolimus, tacrolimus, paclitaxel, docetaxel, estradiol, clobetasol, idoxifen, tazarotene and any prodrugs, metabolites, analogs, homologues, congeners, derivatives, salts and combinations thereof.
95 . The method of claim 94 , wherein the free radical scavenger is selected from a group consisting of 2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, free radical; 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate, free radical; 16-doxyl-stearic acid, free radical; superoxide dismutase mimic; and, any analogs, homologues, congeners, derivatives, salts and combinations thereof.
96 . The method of claim 94 , wherein the free radical scavenger is TEMPO or any analogs, homologues, congeners, derivatives, salts or combinations thereof.
97 . The method of claim 94 , wherein the nitric oxide donor is selected from the group consisting of S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazenium diolates and any analogs, homologues, congeners, derivatives, salts and combinations thereof.
98 . The method of claim 94 , wherein the bioactive agent is rapamycin, everolimus, tacrolimus, or any prodrug, metabolite, analog, congener, derivative, salt or combinations thereof.Join the waitlist — get patent alerts
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