IMPLANTS WITH A PHOSPHAZENE-CONTAINING COATING
The present disclosure relates to implants with a biocompatible coating having antithrombogenic properties and which also contains a pharmacologically active agent, as well as a process for their production.
1 . An implant comprising:
a) a substrate comprising an implant material,
b) a biocompatible matrix coating at least part of the surface of the substrate, and
c) at least one pharmacologically active agent associated with the biocompatible matrix;
wherein:
the biocompatible matrix comprises an antithrombogenic polymer having the formula
R 1 to R 6 are the same or different and are selected independently from an alkoxy, an alkylsulfonyl, a dialkylamino, an aryloxy, a heterocycloalkyl group having nitrogen as the heteroatom, a heteroaryl group having nitrogen as the heteroatom, or a halogenated derivative thereof, any of which independently having up to 20 carbon atoms; and
n may vary from about 40 to about 100,000.
2 . An implant according to claim 1 , wherein at least one of the groups R 1 to R 6 is an alkoxy group substituted with at least one fluorine atom.
3 . An implant according to claim 1 , wherein the antithrombogenic polymer is poly[bis(trifluoroethoxy)phosphazene].
4 . An implant according to claim 1 , wherein the pharmacologically active agent is selected from an antimitogenic agent, a cytostatic agent, a PDGF-inhibitor, a Raf-1 kinase inhibitor, a monoclonal antibody for integrin blockade of leukocytes, an antisense active agent, a superoxide dismutase, a radical trap, a steroid, a statin, a corticosteroid, an adenylate cyclase inhibitor, a somatostatin analogue, an antithrombin agent, a nitric oxide donor, a glycoprotein IIb/IIIa receptor antagonist, an antithrombotic agent, a prostaglandin analogue, a vascular endothelial growth factor (VEGF), or any combination thereof.
5 . An implant according to claim 1 , wherein the pharmacologically active agent is selected from rapamycin, paclitaxel, a tyrphostin, plasmid DNA, antisense-RNA, superoxide dismutase, probucol, cerivastatin, methotrexate, dexamethasone, methylprednisolone, forskolin, angiopeptin, argatroban, a urokinase derivative, abciximab, tirofiban, activated protein C, PEG-hirudin, trapidil, tacrolimus, genexol, or any combination thereof.
6 . An implant according to claim 1 , wherein the weight ratio of antithrombogenic polymer to pharmacologically active agent is from 1:0.0001 to 1:1.
7 . An implant according to claim 1 , further comprising an adhesion promoter situated between the substrate and the biocompatible matrix.
8 . An implant according to claim 7 , wherein the adhesion promoter is an amino-terminated silane.
9 . A method for making an implant, comprising:
a) providing a substrate comprising an implant material, a biocompatible matrix, and at least one pharmacologically active agent; and
b) either:
i) contacting the substrate with a mixture of the biocompatible matrix and the at least one pharmacologically active agent; or
ii) contacting the substrate with the biocompatible matrix to produce a primary polymer-coated substrate, following by contacting the primary polymer-coated substrate with the at least one pharmacologically active agent;
wherein:
the biocompatible matrix comprises an antithrombogenic polymer having the following formula (I) or a precursor to formula (I)
R 1 to R 6 are the same or different and are selected independently from an alkoxy, an alkylsulfonyl, a dialkylamino, an aryloxy, a heterocycloalkyl group having nitrogen as the heteroatom, a heteroaryl group having nitrogen as the heteroatom, or a halogenated derivative thereof, any of which independently having up to 20 carbon atoms; and
n may vary from about 40 to about 100,000.
10 . A method according to claim 9 , wherein the contacting step b) occurs in a solution comprising the biocompatible matrix, the at least one pharmacologically active agent, and at least one dipolar aprotic solvent.
11 . A method according to claim 10 , wherein the at least one dipolar aprotic solvent comprises ethyl acetate.
12 . A method according to claim 9 , further comprising contacting the substrate comprising an implant material of step a) with an adhesion promoter, prior to the contacting step b).
13 . A method according to claim 12 , wherein the adhesion promoter is an amino-terminated silane.
14 . A method according to claim 9 , wherein at least one of the groups R 1 to R 6 is an alkoxy group substituted with at least one fluorine atom.
15 . A method according to claim 9 , wherein the antithrombogenic polymer is poly[bis(trifluoroethoxy)phosphazene].
16 . A method according to claim 9 , wherein the pharmacologically active agent is selected from an antimitogenic agent, a cytostatic agent, a PDGF-inhibitor, a Raf-1 kinase inhibitor, a monoclonal antibody for integrin blockade of leukocytes, an antisense active agent, a superoxide dismutase, a radical trap, a steroid, a statin, a corticosteroid, an adenylate cyclase inhibitor, a somatostatin analogue, an antithrombin agent, a nitric oxide donor, a glycoprotein IIb/IIIa receptor antagonist, an antithrombotic agent, a prostaglandin analogue, a vascular endothelial growth factor (VEGF), or any combination thereof.
17 . A method according to claim 9 , wherein the pharmacologically active agent is selected from rapamycin, paclitaxel, a tyrphostin, plasmid DNA, antisense-RNA, superoxide dismutase, probucol, cerivastatin, methotrexate, dexamethasone, methylprednisolone, forskolin, angiopeptin, argatroban, a urokinase derivative, abciximab, tirofiban, activated protein C, PEG-hirudin, trapidil, tacrolimus, genexol, or any combination thereof.
18 . A method according to claim 9 , wherein the weight ratio of antithrombogenic polymer to pharmacologically active agent is from 1:0.0001 to 1:1.