# Patent

## Title
Coatings for implantable medical devices

## Abstract

Coatings for implantable medical devices comprising non-fouling moieties or polymers chemically bonded to the surface of the device via chelating structures, and methods of fabricating the coatings are disclosed.

## Background
REFERENCE TO RELATED APPLICATION
This is a divisional application of U.S. application Ser. No. 10/428,691 filed May 1, 2003, now U.S. Pat. No. 7,563,454, the teaching of which is incorporated herein in its entirety by reference.


BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to biologically compatible, non-fouling coatings for implantable medical devices such as stents.
2. Description of the State of the Art
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the lumen wall. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature.
A problem associated with the above procedure includes formation of intimal flaps or torn arterial linings which can collapse and occlude the conduit after the balloon is deflated. Moreover, thrombosis and restenosis of the artery may develop over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, a stent is implanted in the lumen to maintain the vascular patency. Examples in patent literature disclosing stents which have been applied in PTCA procedures include stents illustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor. Biological therapy can be achieved by medicating the stents. Medicated stents provide for the local administration of a therapeutic substance at the diseased site. In order to provide an efficacious concentration to the treated site, systemic administration of such medication often produces adverse or toxic side effects for the patient. Local delivery is a preferred method of treatment in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Local delivery thus produces fewer side effects and achieves more favorable results. One proposed method for medicating stents involves the use of a polymeric carrier coated onto the surface of a stent. A solution which includes a solvent, a polymer dissolved in the solvent, and a therapeutic substance dispersed in the blend is applied to the stent. The solvent is allowed to evaporate, leaving on the stent surface a coating of the polymer and the therapeutic substance impregnated in the polymer. Once the stent has been implanted at the treatment site, the therapeutic substance has a sustained release profile from the polymer.
As a result of the implantation of bare metal stents, a low incidence of stent thrombosis can occur, even when the anticoagulation therapy is administered before, during, and after stent implantation. Although thrombosis is only a low incidence problem for the average patient, patients having problems with blood hyper-coagulation, e.g., patients having small vessels, or those suffering from diabetes, are expected to benefit from less thrombogenic stents. Therefore, improved means of tethering anti-thrombogenic and non-thrombogenic moieties to stents is desirable.
In addition, once a bare metal stent is implanted, a thick, denatured layer of protein typically tends to accumulate on a stent surface as a result of the body's reaction to a foreign material. Such accumulation, or “fouling” of the stent surface, is undesirable from the point of view of the stent's long-term tissue compatibility. Surfaces treatments, which can reduce this chronic, foreign body reaction, to make the stent surface non-fouling or at least less fouling are, thus, beneficial. Therefore, improved means of tethering anti-fouling and non-fouling moieties to stents is also desirable.
Although local administration of therapeutic agents via stents has shown favorable results in reducing restenosis, improvements can be made to the coatings. One improvement is to have drug eluting stent coatings, and biologically compatible stent coatings that are firmly anchored to the stent surface. The embodiments of the present invention provide, among other advantages and improvements, a means of tethering biologically compatible or non-fouling polymers to bare metal stents. In addition, incorporating the compounds described in the present invention into a stent primer allows to have improved adhesion of the stent coatings to the stents.
SUMMARY
An implantable medical device is provided, the device comprising a compound a compound chemically coordinated with a surface of the device, wherein the compound includes a moiety capable of forming a chelate structure with a metal or a metal oxide, and a non-fouling moiety, conjugated to the moiety capable of forming a chelate structure. The moiety capable of forming a chelate structure includes a compound having the formula:




wherein each of R and R1, separately, is an electron-rich group, such as hydroxyl, mercapto, phosphine, alkylphosphine, primary amino, secondary amino, tertiary amino, and carboxyl groups, and X is a reactive group such as carboxyl, mercapto, sulfonate, aldehyde, alkyl carbonyl, vinyl, acrylate, methacrylate groups, and a halogen atom. One example of a moiety capable of forming a chelate structure includes a dihydroxyphenyl moiety. The dihydroxyphenyl moiety can be derived from a derivative of pyrocatechol such as 3,4-dihydroxybenzylamine or 3,4-dihydroxyphenyl-L-alanine. A non-fouling moiety can be derived from poly(ethylene glycol), poly(ethylene oxide), poly(vinyl pyrrolidone), hyaluronic acid and its derivatives, chondroitan sulfate, dextran and its derivatives, dextrin, heparin and its derivatives, hydroxyethyl cellulose, carboxymethyl cellulose, cellulosics, or poly(vinyl alcohol).

An implantable medical device is provided, the device comprising a compound chemically coordinated with a surface of the device, wherein the compound includes a moiety capable of forming a chelate structure with a metal or a metal oxide, and a polymer conjugated to the moiety capable of forming a chelate structure. Examples of polymers which can be conjugated to the moiety capable of forming a chelate structure include poly(butyl methacrylate), poly(ethyl methacrylate), poly(methyl methacrylate), poly(vinyl alcohol), poly(ethylene-co-vinyl alcohol), poly(ethyl acetate-co-vinyl alcohol), poly(vinyl acetate), poly(ethylene-co-vinyl acetate), poly(styrene-co-ethylene), poly(styrene-co-tert-butylene), poly(vinylbutyral), poly(dimethyl siloxane), silicones, poly(tetrafluoroethylene), poly(vinyl fluoride), poly(vinylidene fluoride), poly(ethylene-co-tetrafluoroethylene), poly(vinylidene fluoride-co-hexafluoropropene), poly(styrene-block-co-ethylene-block-co-butylene), poly(styrene-block-co-butadiene-block-co-styrene), polyurethanes and polyamides.
A method for modifying an implantable medical device is also provided, the method comprises conjugating a moiety capable of forming a chelate structure to a non-fouling moiety to form the non-fouling adduct being capable of chelating, and bonding the non-fouling adduct to a surface of the device.
A method for modifying an implantable medical device is also provided, the method comprises conjugating a moiety capable of forming a chelate structure to a polymer to form a polymeric adduct, the polymeric adduct being capable of chelating, and bonding the polymeric adduct to a surface of the device.
A method for modifying an implantable medical device is also provided, the method comprises tethering a moiety capable of forming a chelate structure to a surface of the device, and bonding a first compound to the chelate structure. The first compound can include a substance having a non-fouling moiety or a polymer.


DETAILED DESCRIPTION
According to some embodiments of the present invention, stents having non-fouling properties are provided. According to other embodiments of the present invention, primers for stent coatings are provided, the primers including the chelating structures.
I. Stents Having Non-Fouling Properties.
According to one embodiment of the present invention, a stent coating can contain at least one non-fouling, biologically compatible moiety. The term “non-fouling” is defined as “resisting protein adhesion or deposition, or absorbing or attracting only a minimal amount of proteins, or less proteins than a compound not having a non-fouling moiety when placed in vivo or in simulated biological fluids.” The term “non-fouling moiety” is defined as a moiety carrying non-fouling properties.
To fabricate the coating having non-fouling properties, a one step or a two step process can be used. In the one step process, a chelating moiety can be chemically conjugated to a non-fouling moiety as a separate step to form a non-fouling adduct. The conjugation can be via covalent, ionic, or coordination bonds. The non-fouling adduct can then be brought into contact with the stent surface to form a bridge to the metal surface. The definition of a “chelating moiety” proposed by the International Union of Pure and Applied Chemistry (IUPAC) is used in the present application. The IUPAC defines a “chelate” as a molecular entity in which there is chelation. Chelation is defined by the IUPAC as the formation of bonds between two or more separate binding sites within the same ligand and a central atom.
In the two-step process, the first step includes forming a chelate structure by reacting the bare metal surface of the stent with the chelating moiety. The second step includes tethering a compound having non-fouling properties to the chelate structure using chemical functionality available on the chelating moiety.
An example of a suitable chelating moiety that can be used is a derivative of benzene having a reactive substitutent in position 1 of the benzene ring and two electron-rich (nucleophilic) substituents in an ortho configuration. The term “ortho configuration” refers to the two electron rich substituents being located in adjacent positions of the benzene ring, such as in positions 3 and 4, or positions 2 and 3 of the ring. The role of the electron rich substituents of the benzene ring is to chemically coordinate, or chelate, with metal and/or metal oxide atoms on the stent surface. The ortho configuration places the electron-rich substituents in positions where maximum interaction of the electron-rich substituents with coordination centers on the metal surface is expected.
A structure of the chelating-moiety can be illustrated by formula (I):




where R and R1 are electron-rich groups allowing to bind the compound (I) to metal surface of a stent to form the chelate structure. In compound (I), X is in position 1, R is in position 3, and R1 is in position 4 of the benzene ring; therefore, R and R1 are in an ortho configuration. Examples of R and R1 groups that can be used in practice of the present invention include hydroxyl, mercapto, phosphine (—PH2), alkylphosphine, primary amino, secondary amino, tertiary amino, and carboxyl. Groups R and R1 can be the same or different. For example, R can be hydroxyl and R1 can be amino group; R can be hydroxyl and R1 can be carboxyl group; or both R and R1 can be hydroxyls, etc.

In the compound represented by formula (I), group X is a reactive group. Group X can be used to conjugate a non-fouling moiety to compound (I) to form a non-fouling adduct. Examples of group X that can be used include an amino group, a carboxyl group, a mercapto group, a halogen atom, such as an iodine atom, a bromine atom, or a chlorine atom, a sulfonate group, an aldehyde group, an alkyl carbonyl group, a vinyl group, an acrylate group, and a methacrylate group.
When the bare metal surface of the stent is exposed to compound (I) or to a non-fouling adduct of compound (I) with a non-fouling moiety, a chelate structure is formed, thus binding compound (I) or the non-fouling adduct to the metal surface, which can also contain metal oxide. One way of treatment of the bare metal surface of the stent is soaking the stent in a solution of compound (I) or a non-fouling adduct which includes compound (I). The duration of the soaking can be between about 5 minutes and about 24 hours, for example, about 2 hours. The solution temperature can be ambient or slightly above. The excess amount of compound (I) or the non-fouling adduct which includes compound (I), can be then removed by rinsing the stent in a suitable solvent, such as deionized water.
The solvents that can be used to form the solutions of compound (I) or the non-fouling adduct which includes compound (I) include polar solvents, for example water or water/alcohol blends. The pH of the solution of compound (I) can be between about 6 and about 8. If in compound (I) both R and R1 are hydroxyl groups, the chelate structure can be illustrated as demonstrated by formula (II):




where M symbolizes a metal or a metal oxide.

In the synthetic process of attaching the non-fouling moiety to the chelating moiety, the non-fouling moiety can conjugate via the reactive group X. If the conjugating moiety is already bound to the metal surface, then the non-fouling moiety is attached to the chelate structure of formula (II).
In the step of conjugation, the reactive group X can be used for binding the non-fouling moiety. As a result, the non-fouling moiety can be tethered to the stent surface via the chelate structure (II). Examples of suitable compounds providing the non-fouling moiety include poly(ethylene glycol)(PEG), poly(ethylene oxide) (PEO), poly(vinyl pyrrolidone)(PVP), hyaluronic acid and its derivatives, chondroitan sulfate, dextran and its derivatives, dextrin, heparin and its derivatives, hydroxyethyl cellulose, carboxymethyl cellulose, cellulosics, and poly(vinyl alcohol).
Examples of compound (I) that are useful in practice of the present invention include substances where both R and R1 are hydroxyl groups, as shown by formula (III):




Substances shown by formula (III) are derivatives of pyrocatechol, where X can be methylamino group or L-alanine group. If X is methylamino group, compound (III) is 3,4-dihydroxybenzylamine (DHBA) shown by formula (IV), and if X is L-alanine group, compound (III) is 3,4-dihydroxyphenyl-L-alanine (DOPA) shown by formula (V):




The primary amino group in DHBA or DOPA is chemically active and can be used for conjugating a non-fouling moiety with the molecule of DHBA or DOPA to form a non-fouling, biocompatible stent coating. For example, hyaluronic acid can be attached to the molecule of DHBA or DOPA (or the ethyl ester of DOPA) using the following synthetic scheme. Hyaluronan can be combined with an excess of the amine at pH approximately 6.8 in the presence of a soluble carbodiimide and 1-hydroxybenzotriazole in aqueous dimethylsulfoxide. A water soluble carbodiimide such as 1-ethyl-3(3-dimethylaminopropyl)carbodiimide, also known as carbodiimide or EDC, having the formula CH3—CH2—N═C═N—CH2—CH2—CH2—N(CH3)2 can be used. EDC is manufactured by Pierce Corp., of Rockford, Ill. 1-hydroxybenzotriazole can be obtained from Aldrich Chemical, of Milwaukee, Wis. By choosing an appropriate ratio between hyaluronan and DHBA or DOPA, those having ordinary skill in the art can attach more than one molecule of DHBA or DOPA to each molecule of hyaluronic acid, if desired.
In case PEG is selected as the non-fouling moiety, the amino group can be also utilized for conjugating PEG to a DHBA or DOPA-based chelate structure. To this end, PEG-succinimidyl propionate can be used. Those having ordinary skill in the art can determine particular chemical pathways for conjugating heparin, PVP and other non-fouling moieties described above.
II. Primers for Stent Coatings Including the Chelating Structures
In addition to enabling the inclusion of non-fouling moieties, group X can also be used to conjugate compound (I) to a polymer to form a macromolecular (polymeric) adduct. The polymeric adduct can be used as a primer for the stent coating. Such polymeric adduct is expected to have improved adhesion to the metal surface of the stent compared to the same polymer without the chelating moiety (I).
Those having ordinary skill in the art can graft compound (I) at multiple locations along the polymer backbone. Grafting along the polymer backbone can be expected to facilitate greater adhesive interaction with the metal surface. Alternatively, compound (I) can be attached to a terminus of the polymer. Examples of suitable polymers to which compound (I) can be conjugated include
(a) poly(methacrylates) and poly(acrylates), e.g., poly(butyl methacrylate), poly(ethyl methacrylate), or poly(methyl methacrylate);
(b) polymers derived from monomers having vinyl groups, e.g., poly(vinyl alcohol), poly(ethylene-co-vinyl alcohol), poly(ethyl acetate-co-vinyl alcohol), poly(vinyl acetate), poly(ethylene-co-vinyl acetate), poly(styrene-co-ethylene), poly(styrene-co-tert-butylene), or poly(vinylbutyral);
(c) silicon-containing polymers, e.g., poly(dimethyl siloxane) or silicones;
(d) fluorinated polymers, e.g., poly(tetrafluoroethylene), poly(vinyl fluoride), poly(vinylidene fluoride), poly(ethylene-co-tetrafluoroethylene), or poly(vinylidene fluoride-co-hexafluoropropene);
(e) block copolymers, e.g., poly(styrene-block-co-ethylene-block-co-butylene), or poly(styrene-block-co-butadiene-block-co-styrene); and
(f) polymers having functional groups, e.g., polyurethanes, or polyamides.
To form a polymeric adduct, the amino group of DHBA or DOPA can be utilized for conjugating a polymer to a chelating moiety. As one example of conjugating, DHBA or DOPA may be reacted with methacryloyl chloride to make the methacrylate derivative of DHBA or DOPA. The methacrylate derivative can then be copolymerized with other methacrylates, such as butyl methacrylate, to make a poly(butyl methacrylate) primer having the enhanced adhesive properties provided by DHBA or DOPA.
To fabricate a stent coating using a polymeric adduct described above, a polymer solution can be prepared by dissolving the polymeric adduct in a suitable solvent. The polymer solution can be applied onto a bare stent by a commonly used methods, such as spraying or dipping, and the solvent can then be allowed to evaporate, leaving on the stent surface a primer layer. An optional drug-polymer-layer (also referred to as “reservoir” or “reservoir layer”) serving as a reservoir for one or more therapeutic substances can be then fabricated. To make a reservoir layer, a composition comprising a solution of a suitable polymer and at least one therapeutic substance dispersed in the polymer solution can be prepared. The composition can then be applied over the primer layer, for example, by spraying, and the solvent can then be allowed to evaporate, leaving the reservoir layer disposed over the primer layer. An optional topcoat layer, which can be essentially free from any therapeutic substances can then be applied in a similar manner over the reservoir layer. The topcoat layer serves as a rate limiting membrane controlling the rate of release of the drug from the reservoir layer.
Examples of suitable polymers that can be used for fabricating the reservoir layer and/or the topcoat layer include poly(ethylene-co-vinyl alcohol), poly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene carbonate), poly(glycerol-sebacate), polyphosphoester, polyphosphoester urethane; poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), co-poly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates, polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid), polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinyl halide polymers and copolymers (such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidene halides (such as polyvinylidene fluoride and polyvinylidene chloride), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters (such as polyvinyl acetate), copolymers of vinyl monomers with each other and olefins (such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers), polyamides (such as Nylon 66 and polycaprolactam), alkyd resins, other polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins, other polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, soluble fluorinated polymers and carboxymethyl cellulose.
The therapeutic substance which can be used in the reservoir layer can include any substance capable of exerting a therapeutic or prophylactic effect for a patient. The therapeutic substance may include small molecule substances, peptides, proteins, oligonucleotides, and the like. The therapeutic substance could be designed, for example, to inhibit the activity of vascular smooth muscle cells. It can be directed at inhibiting abnormal or inappropriate migration and/or proliferation of smooth muscle cells to inhibit restenosis.
Examples of therapeutic substances that can be used for fabricating the optional reservoir layer include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich of Milwaukee, Wis., or COSMEGEN available from Merck). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I1, actinomycin X1, and actinomycin C1. The active agent can also fall under the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such antineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®, from Aventis S. A., Frankfurt, Germany) methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as ANGIOMAX (Biogen, Inc., Cambridge, Mass.). Examples of such cytostatic or antiproliferative agents include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co., Inc., Whitehouse Station, N.J.); calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, tacrolimus, dexamethasone, and rapamycin and structural derivatives or functional analogs thereof, such as 40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUS available from Novartis), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.
The embodiments of the present invention are described in connection with a stent, e.g., balloon expandable or self-expandable stents; however, other implantable medical devices can also be used. Examples of such implantable devices include stent-grafts, grafts (e.g., aortic grafts), artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, available from Guidant Corp. of Santa Clara, Calif.). The underlying structure of the device can be of virtually any design. The device can be made of a metallic material or an alloy such as, but not limited to, cobalt chromium alloy (ELGILOY), stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof. “MP35N” and “MP20N” are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co. of Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.
Some embodiments of the present invention can be further illustrated by the following examples.
EXAMPLE 1
A stent can be immersed in a buffered aqueous solution of DHBA for about 1 hour at ambient temperature to form a chelate structure (VI) on the stent. A phosphate buffer having pH about 7.4 can be used. The molar concentration of phosphate in the buffer solution can be about 10 mmol/l.




Hyaluronic acid can be conjugated to the chelate structure (VI). Hyaluronic acid, also known as poly(β-glucuronic acid-[1→3])-co-β-N-acetylglucosamine-[1→4]) is a linear polysaccharide composed of disaccharide units of N-acetylglucosamine and D-glucoronic acid. In hyaluronic acid, uronic acid and the aminosugar are linked by alternating β-1,4 and β-1,3 glucosidic bonds. Hyaluronic acid has hydroxyl, hydroxymethyl, carboxyl, and amide groups.
A pathway for the process of conjugating hyaluronic acid to the chelate structure (VI) is expected to be a reaction of condensation of carboxyl, hydroxyl, or hydroxymethyl groups of hyaluronic acid with the primary amino group of the chelate structure (VI). The final product of conjugation is expected to contain primarily a compound of formula (III), where X is a product of conjugation of hyaluronic acid to the methylamino group.
To facilitate conjugation of hyaluronic acid to the chelate structure (VI), an appropriate coupling agent may be needed in presence of which the conjugation can be carried. Examples of suitable coupling agents include EDC. Hyaluronic acid can be conjugated to the chelate (VI) by addition of EDC and 1-hydroxybenzotriazole at a pH of about 6.8. The process of conjugation can be carried in aqueous dimethyl sulfoxide at ambient temperature for about 1 hour.
EXAMPLE 2
Poly(ethylene glycol) (PEG) can be conjugated to DHBA. For example, DHBA can be reacted with methoxylated PEG succinimidyl propionate (mPEG-SPA) available from Nektar (formerly Shearwater Corp.) of Huntsville Ala. The structure of mPEG-SPA includes a relatively labile N—O bond which is susceptible to nucleophilic substitution.
Since the succinimidyl group is an excellent electrophile and leaving group, it is expected to be attacked by the nucleophilic lone electron pair of the primary amino group of the chelate structure (VI). As a result, mPEG is conjugated to the chelate structure via an amide bond, and N-hydroxysuccinimide will be released as a by-product of the reaction. One possible path of conjugation can be as illustrated by the reaction scheme (VII):




Those having ordinary skill in the art can choose appropriate conditions for carrying out reaction (VII). For example, the reaction can be conduct at a pH of about 8 in water or acetone/water blend, at ambient temperature for about 1 hour. An excess of mPEG-SPA can be used. After the reaction (VII) has been completed, the resulting adduct (VIII) can be purified by dialysis to remove N-hydroxysuccinimide and isolated by lyophilization or salt precipitation.
Adduct (VIII) can then be reacted with the stent. To react adduct (VIII) with the stent, the clean stent can be exposed to adduct (VIII) in a phosphate buffer having pH about 7.4 for about 1 hour at ambient temperature. The molar concentration of phosphate in the buffer solution can be about 10 mmol/l.
EXAMPLE 3
The chelate structure (VI) can be formed on a stent as described above. Heparin can then be conjugated to the chelate structure (VI). To conjugate heparin, first heparin can be partially degraded with nitrous acid, thus obtaining compound comprising a heparin-derived moiety having terminal aldehyde groups. This compound can be schematically shown as HEP-C(O)H, where HEP is a heparin moiety. The aldehyde groups are easily reacted with the primary amino groups of the chelate structure, as shown by the reaction scheme (IX), to form the Shiff's base (X) which includes imino groups:




The Shiff's base (X) can be reduced, for example, by reacting with sodiumborohydride, NaCNBH4, to form a structure where heparin is conjugated to the chelate structure (V).
Aldehyde terminated heparin used to conduct reaction (IX) may be obtained by combining heparin in an aqueous solution of 10% acetic acid and 0.25 mol/l aqueous solution of NaNO2 at room temperature for about 20 minutes. The solution can be neutralized to pH of about 5 with sodium hydroxide and dialyzed.
To conduct the reaction of reductive amination (IX), the chelated metal surface can be immersed in an aqueous solution of the HEP-C(O)H with sodium cyanoborohydride in absolute ethanol and with 1% aqueous acetic acid and incubated at a temperature of about 60° C. for about 1 hour.
EXAMPLE 4
A coating can be formed on a stent, the coating comprising a primer layer deposited over the bare stent and a drug polymer layer deposited over the primer layer. The primer layer includes a polymeric adduct. To obtain the polymeric adduct, 3,4-dihydroxybenzylmethacrylamide can be made synthetically first.
3,4-dihydroxybenzylmethacrylamide can be synthesized according to the following procedure. About 1 equivalent of 3,4-dihydroxybenzylamine can be combined with two equivalents of pyridine hydrobromide. Both components can be preliminarily dissolved in a suitable solvent to be selected by those having ordinary skill in the art, for example, in toluene. About 1 equivalent of methacryloyl chloride can then be added dropwise with stirring at room temperature to carry out reaction (XI):




After about two hours of continued stirring, 3,4-dihydroxybenzylmethacrylamide, the product of reaction (XI) can be isolated by extracting the organic phase with three portions of diethyl ether. The three ether fractions can be combined and extracted with two portions of water, followed by drying in a desiccator over anhydrous magnesium sulfate to obtain 3,4-dihydroxybenzylmethacrylamide.
1 equivalent of 3,4-dihydroxybenzylmethacrylamide can be combined with 19 equivalents of n-butylmethacrylate in 2-butanone. Under a blanket of nitrogen, a free radical copolymerization can be initiated by addition of about 0.15 mass % of benzoyl peroxide and allowing the reaction schematically shown as reaction (XII) to proceed at about 80° C. for about 12 hours to yield copolymer (XIII):




The product of copolymerization (XIII) can be isolated by precipitation with methanol and purified by repeated dissolution in 2-butanone followed by precipitation with methanol. Drying in vacuum at about 60° C. for about 12 hours completes the isolation of a polymeric adduct. The adduct is expected to include primarily poly(n-butylmethacrylate) terminated on one end with a derivative of 3,4-dihydroxybenzene. The adduct can be used as a primer for a stent coating.
A formulation of polymeric adduct (XIII) can be prepared, the formulation to include:
(a) about 2 mass % polymeric adduct (XIII); and
(b) a balance, a solvent blend comprising acetone and xylene in a mass ratio of about 1:1.
The formulation of polymeric adduct (XIII) can be applied to an 18 mm VISION stent (available from Guidant Corporation) to form a primer coating layer on the stent. A series of 10-second passes can be used, to deposit, for example, 10 μg of coating per spray pass. Between the spray passes, the stent can be dried for about 10 seconds using flowing air with a temperature of about 60° C. Ten spray passes can be applied, followed by baking the primer layer at about 140° C. for one hour. As a result, a primer layer can be formed having a solids content of about 100 μg. “Solids” means the amount of the dry residue deposited on the stent after all volatile organic compounds (e.g., the solvent) have been removed.
A drug-containing formulation can be prepared comprising:
(a) between about 0.1 mass % and about 15 mass %, for example, about 2.0 mass % of poly(vinylidene fluoride-co-hexafluoropropene) (VDF-HFP);
(b) between about 0.1 mass % and about 2 mass %, for example, about 1.6 mass % of EVEROPLIMUS; and
(c) a balance, a solvent blend comprising acetone and cyclohexanone in a mass ratio of about 1:1.
In a manner identical to the application of the primer layer, five spray passes can be performed, followed by baking the drug-polymer layer at about 50° C. for about 1 hour, to form the drug-polymer layer having a solids content between about 30 μg and 750 μg, for example, about 360 μg.
While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.

## Claims

1. An implantable medical device, comprising a compound chemically coordinated with a surface of the implantable medical device, wherein the compound includes:
(a) a moiety capable of forming a chelate structure with a metal or a metal oxide; and
(b) a polymer conjugated to the moiety capable of forming a chelate structure,
wherein the moiety capable of forming a chelate structure includes a compound having the formula:




wherein each of R and R1, separately, is an electron-rich group and X is a reactive group selected from amino, carboxyl, mercapto, sulfonate, aldehyde, alkyl carbonyl, vinyl, acrylate, methacrylate groups, and a halogen atom; and
wherein, when the electron-rich group is a hydroxyl group, only one of R and R1 is a hydroxyl group.

2. The device of claim 1, wherein the implantable medical device is a stent.

3. The device of claim 1, wherein one of R and R1 is selected from hydroxyl, mercapto, phosphine, alkylphosphine, primary amino, secondary amino, tertiary amino, and carboxyl groups and the other of R and R1 is selected from mercapto, phosphine, alkylphosphine, primary amino, secondary amino, tertiary amino, and carboxyl groups.

4. The device of claim 1, wherein the polymer comprises a poly(methacrylate), a poly(acrylate), a polymer derived from monomers having vinyl groups, a silicon-containing polymer, a fluorinated polymer, a block copolymer, or a polymer having functional groups.

5. The device of claim 4, wherein the fluorinated polymer is selected from the group consisting of poly(tetrafluoroethylene), poly(vinyl fluoride), poly(vinylidene fluoride), poly(ethylene-co-tetrafluoroethylene), and poly(vinylidene fluoride-co-hexafluoropropene).

6. A method for modifying an implantable medical device, the method comprising:
(a) conjugating a moiety capable of forming a chelate structure to a polymer to form a polymeric adduct, the polymeric adduct being capable of chelating; and
(b) forming a chelate structure between the polymeric adduct and a surface of the medical device wherein the moiety capable of forming a chelate structure includes a compound having the formula:




wherein each of R and R1, separately, is an electron-rich group and X is a reactive group selected from amino, carboxyl, mercapto, sulfonate, aldehyde, alkyl carbonyl, vinyl, acrylate, methacrylate groups, and a halogen atom; and
wherein, when the electron-rich group is a hydroxyl group, only one of R and R1 is a hydroxyl group.

7. The method of claim 6, wherein the implantable medical device is a stent.

8. The method of claim 6, wherein one of R and R1 is selected from hydroxyl, mercapto, phosphine, alkylphosphine, primary amino, secondary amino, tertiary amino, and carboxyl groups and the other of R and R1 is selected from mercapto, phosphine, alkylphosphine, primary amino, secondary amino, tertiary amino, and carboxyl groups.

9. The method of claim 6, wherein the polymer is selected from a group consisting of poly(butyl methacrylate), poly(ethyl methacrylate), poly(methyl methacrylate), poly(vinyl alcohol), poly(ethylene-co-vinyl alcohol), poly(ethyl acetate-co-vinyl alcohol), poly(vinyl acetate), poly(ethylene-co-vinyl acetate), poly(styrene-co-ethylene), poly(styrene-co-tert-butylene), poly(vinylbutyral), poly(dimethyl siloxane), silicones, poly(tetrafluoroethylene), poly(vinyl fluoride), poly(vinylidene fluoride), poly(ethylene-co-tetrafluoroethylene), poly(vinylidene fluoride-co-hexafluoropropene), poly(styrene-block-co-ethylene-block-co-butylene), poly(styrene-block-co-butadiene-block-co-styrene), polyurethanes and polyamides.

10. A method for modifying an implantable medical device, the method comprising:
(a) tethering a moiety capable of forming a chelate structure to a surface of the implantable device; and
(b) bonding a first compound to the chelate structure,
wherein the moiety capable of forming a chelate structure includes a compound having the formula




wherein each of R and R1, separately, is an electron-rich group and X is a reactive group selected from amino, carboxyl, mercapto, sulfonate, aldehyde, alkyl carbonyl, vinyl, acrylate, methacrylate groups, and a halogen atom; and
wherein, when the electron-rich group is a hydroxyl group, only one of R and R1 is a hydroxyl group.

11. The method of claim 10, wherein the implantable medical device is a stent.

12. The method of claim 10, wherein one of R and R1 is selected from hydroxyl, mercapto, phosphine, alkylphosphine, primary amino, secondary amino, tertiary amino, and carboxyl groups and the other of R and R1 is selected from mercapto, phosphine, alkylphosphine, primary amino, secondary amino, tertiary amino, and carboxyl groups.

13. The method of claim 10, wherein the first compound includes a substance having a non-fouling moiety or a polymer.

14. The method of claim 13, wherein the polymer comprises a poly(methacrylate), a poly(acrylate), a polymer derived from monomers having vinyl groups, a silicon-containing polymer, a fluorinated polymer, a block copolymer, or a polymer having functional groups.

15. The method of claim 14, wherein the fluorinated polymer is selected from the group consisting of poly(tetrafluoroethylene), poly(vinyl fluoride), poly(vinylidene fluoride), poly(ethylene-co-tetrafluoroethylene), and poly(vinylidene fluoride-co-hexafluoropropene).

16. A method for modifying an implantable medical device, the method comprising:
(a) conjugating a moiety capable of forming a chelate structure to a polymer to form a polymeric adduct, the polymeric adduct being capable of chelating; and
(b) forming a chelate structure between the polymeric adduct and a surface of the medical device wherein the moiety capable of forming a chelate structure includes a compound having the formula:




wherein each of R and R1, separately, is an electron-rich group and X is a reactive group selected from carboxyl, mercapto, sulfonate, aldehyde, vinyl, acrylate, methacrylate groups, and a halogen atom;
and wherein, when the electron-rich group is a hydroxyl group, only one of R and R1 is a hydroxyl group.

17. A method for modifying an implantable medical device, the method comprising:
(a) tethering a moiety capable of forming a chelate structure to a surface of the implantable device; and
(b) bonding a first compound to the chelate structure,
wherein the moiety capable of forming a chelate structure includes a compound having the formula




wherein each of R and R1, separately, is an electron-rich group and X is a reactive group selected from carboxyl, mercapto, sulfonate, aldehyde, vinyl, acrylate, methacrylate groups, and a halogen atom;
and wherein, when the electron-rich group is a hydroxyl group, only one of R and R1 is a hydroxyl group.