# Patent

## Title
Heparin prodrugs and drug delivery stents formed therefrom

## Abstract

A prodrug comprising a heparin and a drug is provided. The prodrug can be used to form a coating on a medical device. The prodrug can also be used with a polymeric material to form a coating on a medical device. The polymeric material can be a hydrophobic polymer, a hydrophilic polymer, a non-fouling polymer, or combinations thereof. The medical device can be implanted in a human being for the treatment of a disease such as atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, or combinations thereof.

## Background
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention generally relates to a prodrug formed of heparin and a drug and drug-delivery stents formed from a material having the prodrug.
2. Description of the Background
Blood has a property of being coagulated by the action of various components in blood when it has come into contact with foreign matters. Hence, there is a need for a high anticoagulant property in component materials for medical articles or instruments used on the part coming into contact with blood, as exemplified by artificial hearts, artificial cardiac valves, artificial blood vessels, blood vessel catheters, cannulas, pump-oxygenators, blood vessel by-pass tubes, intraaortic balloon pumps, transfusion instruments and extracorporeal circulation circuits.
Heparin has been commonly used to impart to anticoagulant properties the medical devices, but a systemic use of heparin may undesirably lead to the formation of a large number of bleeding nests. Methods have been developed to minimize side effects associated with the use of heparin with limited success (see, for example, U.S. Pat. Nos. 5,270,064 and 6,630,580). Meanwhile, problems associated with systemic administration of a drug have led to the development of methods for local delivery of the drug. Administration of a pharmacologically active drug directly to a patient may lead to some undesirable consequences because many therapeutic drugs have undesirable properties that may become pharmacological, pharmaceutical, or pharmacokinetic barriers in clinical drug applications.
Therefore, in the art of drug-delivery implantable medical devices, there is a need for minimizing the side effects associated with the use of heparin and a drug.
The present invention addresses such problems by providing a coating composition and a coating formed thereof including a prodrug formed of heparin and a drug.
SUMMARY OF THE INVENTION
Provided herein is a prodrug having heparin and a drug in which the drug and heparin form a hydrolytically or enzymatically unstable linkage. The prodrug can be an ester type prodrug in which the drug molecule and the heparin molecule can form an ester bond formed of the carboxyl group in the heparin molecule and hydroxyl group in the drug or vice versa. The prodrug can be a Schiff-base-type prodrug in which a drug having an amine group and heparin functionalized to have an aldehyde group form a Schiff base or vice versa. The prodrug can also be an acetal- or hemi-acetal-type prodrug in which hydroxyl groups on a drug and heparin functionalized to have an aldehyde group or vice versa form an acetal or hemi-acetal.
The prodrug molecule can be used to form a coating on an implantable device. The prodrug can also be attached to a polymer via the heparin molecule to form a polymer bearing the prodrug defined herein, which can then be coated onto an implantable device. Alternatively, the prodrug can be grafted onto a polymeric coating on an implantable device.
In one embodiment, the prodrug can be used alone to form a coating on a medical device. In another embodiment, the prodrug can be used with a polymeric material to form a coating on a medical device. The polymeric material can be a hydrophobic polymer, a hydrophilic polymer, a non-fouling polymer, or combinations thereof. The medical device can be implanted in a human being for the treatment of a disease such as atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, or combinations thereof.



BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 shows heparin's building blocks: glycosamine and iduronic acid.



DETAILED DESCRIPTION
Prodrugs Including Heparin
Many therapeutic drugs have undesirable properties that may become pharmacological, pharmaceutical, or pharmacokinetic barriers in clinical drug applications. Among the various approaches to minimize the undesirable drug properties while retaining the desirable therapeutic activity, a chemical approach using drug derivatization offers perhaps the highest flexibility and has been demonstrated as an important means of improving drug efficacy. The prodrug approach, a chemical approach using reversible derivatives, can be useful in the optimization of the clinical application of a drug. The prodrug approach gained attention as a technique for improving drug therapy in the early 1970s. Numerous prodrugs have been designed and developed since then to overcome pharmaceutical and pharmacokinetic barriers in clinical drug application, such as low oral drug absorption, lack of site specificity, chemical instability, toxicity, and poor patient acceptance (bad taste, odor, pain at injection site, etc.) (Stella V., Pro-drugs: an overview and definition. In: Higuchi T., Stella V., eds. Prodrugs As Novel Drug Delivery Systems. ACS Symposium Series. Washington, D.C.: American Chemical Society; 1975:1-115).
As used herein, the term “prodrug” refers to an agent rendered less active by a chemical or biological moiety, which metabolizes into or undergoes in vivo hydrolysis to form a drug or an active ingredient thereof. The term “prodrug” can be used interchangeably with terms such as “proagent”, “latentiated drugs,” “bioreversible derivatives,” and “congeners” (Harper N J. Drug latentiation. Prog Drug Res. 1962; 4:221-294; Roche E B. Design of Biopharmaceutical Properties through Prodrugs and Analogs. Washington, D.C.: American Pharmaceutical Association; 1977; Sinkula A A, Yalkowsky S H. Rationale for design of biologically reversible drug derivatives: prodrugs. J Pharm Sci. 1975; 64:181-210). Usually, the use of the term implies a covalent link between a drug and a chemical moiety, though some authors also use it to characterize some forms of salts of the active drug molecule. Although there is no strict universal definition for a prodrug itself, and the definition may vary from author to author, generally prodrugs can be defined as pharmacologically inert chemical derivatives that can be converted in vivo, enzymatically or nonenzymatically, to the active drug molecules to exert a therapeutic effect (Sinkula A A, Yalkowsky S H. Rationale for design of biologically reversible drug derivatives: prodrugs. J Pharm Sci. 1975; 64:181-210; Stella V J, Charman W N, Naringrekar V H. Prodrugs. Do they have advantages in clinical practice? Drugs. 29:455-473 (1985)).
In one embodiment, the prodrug described herein includes a drug and heparin that form a linkage that can be enzymatically or hydrolytically cleaved under in vivo conditions. In some embodiments, the linkage can be an ester group, a Schiff base, or an acetal or hemi-acetal.
In another embodiment, the prodrug described herein can include a drug, a polymer and heparin. Heparin is conjugated or linked to the polymer by a physical or chemical linkage. The drug can link or be attached to the heparin or the polymer. In some embodiments, the linkage between heparin and the polymer can be, for example, ionic bonding, hydrogen bonding, or a chemical bonding such as an ester group, a Schiff base, or an acetal or hemi-acetal. The linkage between the drug and the polymer can be, for example, an ester group, a Schiff base, or an acetal or hemi-acetal, and the linkage between the drug and heparin can be, for example, an ester group, a Schiff base, or an acetal or hemi-acetal.
Heparin
The term “heparin” refers to a heparin molecule, a heparin fragment such as pentasaccharide, a heparin derivative or a heparin complex. Heparin derivatives can be any functional or structural variation of heparin. Representative variations include alkali metal or alkaline-earth metal salts of heparin, such as sodium heparin (e.g., hepsal or pularin), potassium heparin (e.g., clarin), lithium heparin, calcium heparin (e.g., calciparine), magnesium heparin (e.g., cutlieparine), low molecular weight heparin (e.g., ardeparin sodium) with a molecular weight of from about 4,000 to about 5,000 Daltons and high affinity heparin (see, e.g., Scully, et al., Biochem. J. 262:651-658 (1989)). Other examples include heparin sulfate, heparinoids, heparin based compounds and heparin having a hydrophobic counter-ion such as tridodecylmethylammonium and benzalkonium.
Heparin contains both carboxyl groups and hydroxyl groups (FIG. 1). Carboxyl groups can form an ester linkage by reacting with hydroxyl reactive groups on a drug (see Scheme 1, below). Alternatively, the hydroxyl groups on heparin can also form an ester linkage by reacting with carboxyl groups on a drug (see Scheme 2, below).
In some other embodiments, the prodrug described herein can be formed of a functionalized heparin and a drug molecule. For example, Heparin-CHO can react with an amine group on a drug or vice versa to form a Schiff-base-type prodrug (see Scheme 3, below). Heparin-CHO can also react with hydroxyl groups on a drug or vice versa to form acetal or hemi-acetal type prodrugs (see Scheme 4, below).
Modification of Heparin
Heparin is a highly negatively charged molecule very soluble in water. It has some solubility in formamide, but is practically insoluble in other organic solvents. This lack of solubility in organic solvents limits its use in certain applications. The conventional method of improving the solubility of heparin in organic solvents can be achieved by complexing heparin with a positive charged organic moiety such as a quaternary ammonium salt, e.g. tridodecylmethylammoniumchloride and benzalkonium chloride. Some exemplary, useful hydrophobic quaternary ammonium compounds and methods of forming complexes of these compounds with heparin are described in U.S. Pat. Nos. 4,654,327, 4,871,357 and 5,047,020.
Heparin contains many reactive groups such as carboxyl, amine, and hydroxyl groups in its molecular structure. Partially oxidized heparin contains terminal aldehyde groups. Prior to or subsequent to forming the prodrug described above, in some embodiments, heparin can be physically or chemically (e.g. covalently) attached to hydrophilic and hydrophobic polymers by chemical reactions between the functional groups on heparin and the polymer. Heparin can also be copolymerized with other monomer(s) to form a polymer containing heparin. In some other embodiments, attachment of heparin can be accomplished by chemically (e.g. covalently) or physically coupling heparin onto a polymer-coated surface. Physical coupling includes, for example, ionic interaction or hydrogen bonding.
As used herein, the term “hydrophobic” refers to an attribute of a material that defines the degree of water affinity of the molecules of the material. Hydrophobicity and hydrophilicity are relative terms. Generally, hydrophobicity and hydrophilicity of a polymer can be gauged using the Hildebrand solubility parameter δ. The term “Hildebrand solubility parameter” refers to a parameter indicating the cohesive energy density of a substance. The δ parameter is determined as follows:

δ=(ΔE/V)1/2 

where δ is the solubility parameter, (cal/cm3)1/2;

ΔE is the energy of vaporization, cal/mole; and

V is the molar volume, cm3/mole.

If a blend of hydrophobic and hydrophilic polymer(s) is used, whichever polymer in the blend has a lower δ value compared to the δ value of the other polymer in the blend is designated as a hydrophobic polymer, and the polymer with a higher δ value is designated as a hydrophilic polymer. If more than two polymers are used in the blend, then each can be ranked in order of its δ value. In some embodiments, the defining boundary between hydrophobic and hydrophilic can be set at 10.5, (cal/cm3)1/2.
Any biocompatible polymer can be used to modify the hydrophilicity of heparin. Representative hydrophobic polymers include, but are not limited to, poly(ester amide), polystyrene-polyisobutylene-polystyrene block copolymer (SIS), polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide), poly(D,L-lactide), poly(lactides), polylactic acid (PLA), poly(lactide-co-glycolide), poly(glycolide), polyalkylene, polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(4-hyroxyhexanoate), mid-chain polyhydroxyalkanoate, poly (trimethylene carbonate), poly (ortho ester), polyphosphazenes, poly (phosphoester), poly(tyrosine derived arylates), poly(tyrosine derived carbonates), polydimethyloxanone (PDMS), polyvinylidene fluoride (PVDF), polyhexafluoropropylene (HFP), polydimethylsiloxane, poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP), poly (vinylidene fluoride-co-chlorotrifluoroethylene) (PVDF-CTFE), poly(methacrylates) such as poly(butyl methacrylate) (PBMA) or poly(methyl methacrylate) (PMMA), poly(vinyl acetate), poly(ethylene-co-vinyl acetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes), poly(ether-urethanes), poly(carbonate-urethanes), poly(silicone-urethanes), poly(urea-urethanes) or a combination thereof. Methods of derivatizing heparin with hydrophobic materials or polymers are described in, for example, U.S. Pat. Nos. 4,331,697; 5,069,899; 5,236,570; 5,270,046; 5,453,171; 5,741,881; 5,770,563; 5,855,618; 6,589,943 and 6,630,580.
Any hydrophobic counter ion can be used to modify the hydrophilicity of heparin. For example, hydrophobic quaternary ammonium compounds have been commonly used to form complexes with heparin that are soluble in organic solvents. Some exemplary useful hydrophobic quaternary ammonium compounds and methods of forming complexes of these compounds with heparin are described in U.S. Pat. Nos. 4,654,327, 4,871,357 and 5,047,020.
In some other embodiments, a hydrophilic polymer and/or a non-fouling polymer can be used to modify the hydrophilicity of heparin. Non-fouling or anti-fouling is defined as preventing, delaying or reducing the amount of formation of protein build-up caused by the body's reaction to foreign material. Representative hydrophilic polymers include, but are not limited to, polymers and co-polymers of PEG acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone (VP), carboxylic acid bearing monomers such as methacrylic acid (MA), acrylic acid (AA), hydroxyl bearing monomers such as HEMA, hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, and 3-trimethylsilylpropyl methacrylate (TMSPMA), poly(ethylene glycol) (PEG), poly(propylene glycol), SIS-PEG, polystyrene-PEG, polyisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG, PDMS-PEG, PVDF-PEG, PLURONICTM surfactants (polypropylene oxide-co-polyethylene glycol), poly(tetramethylene glycol), poly(L-lysine-ethylene glycol) (PLL-g-PEG), poly(L-g-lysine-hyaluronic acid) (PLL-g-HA), poly(L-lysine-g-phosphoryl choline) (PLL-g-PC), poly(L-lysine-g-vinylpyrrolidone) (PLL-g-PVP), poly(ethylimine-g-ethylene glycol) (PEI-g-PEG), poly(ethylimine-g-hyaluronic acid) (PEI-g-HA), poly(ethylimine-g-phosphoryl choline) (PEI-g-PC), and poly(ethylimine-g-vinylpyrrolidone) (PEI-g-PVP), PLL-co-HA, PLL-co-PC, PLL-co-PVP, PEI-co-PEG, PEI-co-HA, PEI-co-PC, and PEI-co-PVP, hydroxy functional poly(vinyl pyrrolidone), polyalkylene oxide, dextran, dextrin, sodium hyaluronate, hyaluronic acid, elastin, chitosan, acrylic sulfate, acrylic sulfonate, acrylic sulfamate, methacrylic sulfate, methacrylic sulfonate, methacrylic sulfamate and combination thereof. The non-fouling polymer can be, for example, poly(ethylene glycol), poly(alkylene oxide), hydroxyethylmethacrylate (HEMA) polymer and copolymers, poly(n-propylmethacrylamide), sulfonated polystyrene, hyaluronic acid, poly(vinyl alcohol), poly(N-vinyl-2-pyrrolidone), sulfonated dextran, phosphoryl choline, choline, or combinations thereof.
The heparin can be readily attached to a polymer or polymeric surface by forming a Schiff base between an amino group and an aldehyde group that heparin and the polymer may have, by forming an amide group between an amine group on a polymer and the carboxyl group on heparin via NHS(N-hydroxysuccinimide) activation (see, e.g., Staros, et al., Anal. Biochem. 156:220-222 (1986)), EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) activation (see, e.g., J. M. Tedder, A. Nechvatal, A. W. Murray, et al. Amino-acids and proteins. In: Basic organic chemistry. London: John Wiley & Sons, Chapter 6, pp. 305-342 (1972); D. Sehgal, I. K. Vijay, Anal. Biochem. 218:87 (1994)) or aziridine chemistry. Some representative methods of attaching heparin to a polymer or polymeric surface are described in U.S. application Ser. No. 10/857,141, filed on May 27, 2004, the teachings of which are incorporated herein by reference.
In a further embodiment, heparin can be derivatized with an unsaturated group such as acrylate, e.g., methacrylate, or vinyl alcohol using the chemistry described above. The heparin functionalized with an unsaturated group can be used in a free radical polymerization to graft or crosslink to a substrate or another formulation component such as a polymer.
Drugs
The drug can be any agent which is biologically active and capable of forming an ester bond with the carboxyl group or hydroxyl group of the heparin molecule or capable of forming a Schiff base or acetal or hemi-acetal with heparin functionalized to have an aldehyde group. In the alternative, the drug can have an aldehyde so as to react with the amino group of heparin-NH2 to form a Schiff base prodrug or an aldehyde or keto group so as to react with the hydroxyl group or groups on heparin to acetal or hemi-acetal prodrug. Most drugs have one of hydroxyl, carboxyl, amino, keto or aldehyde groups and thus can form the prodrugs described herein.
The drug can be, for example, a therapeutic, prophylactic, or diagnostic agent. As used herein, the drug includes a bioactive moiety, derivative, or metabolite of the drug.
Examples of suitable therapeutic and prophylactic agents capable of forming the prodrugs described herein include synthetic inorganic and organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, and DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activities. Nucleic acid sequences include genes, antisense molecules which bind to complementary DNA to inhibit transcription, and ribozymes. Other examples of drugs include antibodies, receptor ligands, and enzymes, adhesion peptides, oligosaccharides, blood clotting factors, inhibitors or clot dissolving agents such as streptokinase and tissue plasminogen activator, antigens for immunization, hormones and growth factors, oligonucleotides such as antisense oligonucleotides and ribozymes and retroviral vectors for use in gene therapy,
In one embodiment, the drug can be a drug for inhibiting the activity of vascular smooth muscle cells. More specifically, the drug can be aimed at inhibiting abnormal or inappropriate migration and/or proliferation of smooth muscle cells for the inhibition of restenosis. The drug can also include any substance capable of exerting a therapeutic or prophylactic effect in the practice of the present invention. For example, the drug can be a prohealing drug that imparts a benign neointimal response characterized by controlled proliferation of smooth muscle cells and controlled deposition of extracellular matrix with complete luminal coverage by phenotypically functional (similar to uninjured, healthy intima) and morphologically normal (similar to uninjured, healthy intima) endothelial cells. The drug can also fall under the genus of antineoplastic, cytostatic or anti-proliferative, 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 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 ä (Biogen, Inc., Cambridge, Mass.). Examples of 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.), actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I1, actinomycin X1, and actinomycin C1. Other drugs include 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, antibodies such as CD-34 antibody, abciximab (REOPRO), and progenitor cell capturing antibody, prohealing drugs that promotes controlled proliferation of muscle cells with a normal and physiologically benign composition and synthesis products, enzymes, anti-inflammatory agents, antivirals, anticancer drugs, anticoagulant agents, free radical scavengers, estradiol, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory, antibiotics, nitric oxide donors, super oxide dismutases, super oxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, ABT-578, clobetasol, cytostatic agents, aspirin, and a combination thereof.
The foregoing substances are listed by way of example and are not meant to be limiting. Other active agents which are currently available or that may be developed in the future are equally applicable.
The dosage or concentration of the drug required to produce a favorable therapeutic effect should be less than the level at which the drug produces toxic effects and greater than the level at which non-therapeutic results are obtained. The dosage or concentration of the drug can depend upon factors such as the particular circumstances of the patient, the nature of the trauma, the nature of the therapy desired, the time over which the ingredient administered resides at the vascular site, and, if other active agents are employed, the nature and type of the substance or combination of substances. Therapeutic effective dosages can be determined empirically, for example by infusing vessels from suitable animal model systems and using immunohistochemical, fluorescent or electron microscopy methods to detect the agent and its effects, or by conducting suitable in vitro studies. Standard pharmacological test procedures to determine dosages are understood by one of ordinary skill in the art.
Method of Forming A Prodrug
The carboxylic acid group of the heparin molecule can form an ester bond with a drug molecule via an established procedure in the art of organic synthesis (see, for example, Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, John Wiley & Sons, Inc., Copyright 1999). Generally, the prodrug described herein can be prepared according to Scheme 1, as described below.




In Scheme 1, R represents a drug molecule or a derivative thereof. Heparin represents a heparin molecule or a moiety or derivative thereof. X represents a leaving group attached to the drug molecule. For example, X can be OH, a halo group, mesylate or tosyl group, and any other groups capable of leaving the drug molecule in forming the drug/heparin ester bond.

Alternatively, the prodrug can be made via a hydroxyl group in the heparin molecule and a carboxylic acid, as shown in Scheme 2.




In Scheme 2, R represents a drug molecule or a derivative thereof. Heparin represents a heparin molecule or a moiety or derivative thereof. X represents a leaving group attached to the carboxyl group of the drug molecule. For example, X can be H, a halo group, a carboxylate, mesylate or tosyl group, or any other group capable of leaving the drug molecule in forming the drug/heparin ester bond.

In some other embodiments, the prodrug described herein can be formed via an imine Schiff base by Heparin-CHO with an amine-containing drug (Scheme 3) or vice versa (Scheme 4). As shown in Scheme 3, the aldehyde group of Heparin-CHO can react with the amine group of an amine-containing drug to form an imine Schiff base, which is hydrolytically unstable and can release the amine-containing drug under in vivo conditions. Scheme 4 shows an alternative strategy for forming the prodrug by the reaction of the amino group of Heparin-NH2 with a keto group on the drug molecule to form an imine Schiff base linkage.








In still some other embodiments, the prodrug described herein can be formed via an acetal or hemi-acetal by heparin-CHO with a hydroxyl group or hydroxyl groups on a drug (Scheme 5) or vice versa (Scheme 6). The acetal or hemi-acetal can undergo hydrolysis under in vivo conditions to release the drug. As shown in Scheme 5, the aldehyde group of heparin-CHO can react with the hydroxyl group or groups on a drug to form a prodrug with an acetal linkage or hemi-acetal linkage (Scheme 5). Alternatively, the hydroxyl group or groups can react with an aldehyde or keto group on a drug to form a prodrug with an acetal linkage or hemi-acetal linkage (Scheme 6).








In one embodiment, the hydroxyl group on the C40 position of everolimus can react with the carboxyl group on heparin to form an ester bond so as to form an everolimus/heparin prodrug.
In another embodiment, a drug can form a prodrug with heparin attached to a polymer such as poly(L-lysine-g-ethylene glycol)(PLL-PEG), which can be PLL-g-PEG or PLL-co-PEG. In this embodiment, the amino group in the PLL-PEG can react with a carboxyl group in heparin to form an amide bond via EDC activation and/or NHS activation, as described above. Alternatively, the amino group in the PLL-PEG can react with heparin-CHO to form a Schiff base. A drug such as paclitaxel, docetaxel, or everolimus can then be attached or linked to the heparin via one of the functionalities, such as an amino group, an aldehyde group, a carboxyl group or a hydroxyl group to form a prodrug as per the above description. In addition to heparin, the point of attachment for the drug can also be the PLL backbone via NH2 groups on PLL or PEG via a terminal hydroxyl group, an amino group or an aldehyde group of PEG. Using the same strategy, in some other embodiments, prodrugs can be formed by a drug and a polymer such as poly(L-lysine-hyaluronic acid) (PLL-HA), poly(L-lysine-phosphoryl choline) (PLL-PC), poly(L-lysine-vinylpyrrolidone) (PLL-PVP), poly(ethylimine-ethylene glycol) (PEI-PEG), poly(ethylimine-hyaluronic acid) (PEI-HA), poly(ethylimine-phosphoryl choline) (PEI-PC), and poly(ethylimine-vinylpyrrolidone) (PEI-PVP). These PLL or PEI based copolymers can be graft or block copolymers, e.g., PLL-g-PEG, PLL-g-HA, PLL-g-PC, PLL-g-PVP, PEI-g-PEG, PEI-g-HA, PEI-g-PC, PEI-g-PVP, PLL-co-HA, PLL-co-PC, PLL-co-PVP, PEI-co-PEG, PEI-co-HA, PEI-co-PC, and PEI-co-PVP. Note, in still some other embodiments, the primary amine —NH2 groups in PLL or PEI can be converted to NH3+ ions on the polymer under an acidic pH to bind or link with heparin.
Coatings Having A Prodrug
The prodrug can be used to form a coating on an implantable device. The prodrug can also be attached to a polymer via the heparin molecule to form a polymer bearing the prodrug defined herein, which can then be coated onto an implantable device. Alternatively, the prodrug can be attached or grafted onto a polymeric coating on an implantable device.
The prodrug provided herein can be used alone to form a coating on a medical device. The prodrug can also be used in combination with a polymeric material. The prodrug can be blended with a polymeric coating material or deposited as a coating on top of a polymeric coating which itself may optionally include a drug. The polymeric material can be any biocompatible polymer such as a hydrophobic polymer, a hydrophilic polymer, a non-fouling polymer, or a combination thereof. The polymeric material can be biodegradable, bioerodable, bioabsorable or biodurable.
In one embodiment, the coating material is a hydrophobic polymer. Representative hydrophobic polymers include, but are not limited to, polystyrene-polyisobutylene-polystyrene block copolymer (SIS), polystyrene, polyisobutylene, polycaprolactone (PCL), poly(L-lactide), poly(D,L-lactide), poly(lactides), polylactic acid (PLA), poly(lactide-co-glycolide), poly(glycolide), polyalkylene, polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(4-hyroxyhexanoate), mid-chain polyhydroxyalkanoate, poly (trimethylene carbonate), poly (ortho ester), polyphosphazenes, poly (phosphoester), poly(tyrosine derived arylates), poly(tyrosine derived carbonates), polydimethyloxanone (PDMS), polyvinylidene fluoride (PVDF), polyhexafluoropropylene (HFP), polydimethylsiloxane, poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP), poly (vinylidene fluoride-co-chlorotrifluoroethylene) (PVDF-CTFE), poly(butyl methacrylate), poly(methyl methacrylate), poly(methacrylates), poly(vinyl acetate), poly(ethylene-co-vinyl acetate), poly(ethylene-co-vinyl alcohol), poly(ester urethanes), poly(ether-urethanes), poly(carbonate-urethanes), poly(silicone-urethanes), poly(2-hydroxyethyl methacrylate), poly(urea-urethanes) and a combination thereof.
In one embodiment, the coating material is a hydrophilic polymer, such as those previously described. In some embodiments, hydrophilic polymers include, but are not limited to, polymers and co-polymers of PEG acrylate (PEGA), PEG methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone (VP), carboxylic acid bearing monomers such as methacrylic acid (MA), acrylic acid (AA), hydroxyl bearing monomers such as HEMA, hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, and 3-trimethylsilylpropyl methacrylate (TMSPMA), poly(ethylene glycol) (PEG), poly(propylene glycol), SIS-PEG, polystyrene-PEG, polyisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG, PDMS-PEG, PVDF-PEG, PLURONICTM surfactants (polypropylene oxide-co-polyethylene glycol), poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone), polyalkylene oxide, dextran, dextrin, sodium hyaluronate, hyaluronic acid, elastin, chitosan, acrylic sulfate, acrylic sulfonate, acrylic sulfamate, methacrylic sulfate, methacrylic sulfonate, methacrylic sulfamate or combination thereof.
In another embodiment, the coating material is a non-fouling polymer such as, for example, poly(ethylene glycol), poly(alkylene oxide), hydroxyethylmethacrylate (HEMA) polymer and copolymers, poly(n-propylmethacrylamide), sulfonated polystyrene, hyaluronic acid (HA), poly(vinyl alcohol), poly(N-vinyl-2-pyrrolidone), sulfonated dextran, phospholipids such as phosphoryl choline (PC) and choline, or combinations thereof.
Examples of Implantable Device
As used herein, an implantable device may be any suitable medical substrate that can be implanted in a human or veterinary patient. Examples of such implantable devices include self-expandable stents, balloon-expandable stents, 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 Corporation, 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), high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “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., 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. Devices made from bioabsorbable or biostable polymers could also be used with the embodiments of the present invention.
Method of Use
In accordance with embodiments of the invention, a coating of the various described embodiments can be formed on an implantable device or prosthesis, e.g., a stent. For coatings including one or more active agents, the agent will retain on the medical device such as a stent during delivery and expansion of the device, and be released at a desired rate and for a predetermined duration of time at the site of implantation. Preferably, the medical device is a stent. A stent having the above-described coating is useful for a variety of medical procedures, including, by way of example, treatment of obstructions caused by tumors in bile ducts, esophagus, trachea/bronchi and other biological passageways. A stent having the above-described coating is particularly useful for treating occluded regions of blood vessels caused by abnormal or inappropriate migration and proliferation of smooth muscle cells, thrombosis, and restenosis. Stents may be placed in a wide array of blood vessels, both arteries and veins. Representative examples of sites include the iliac, renal, and coronary arteries.
For implantation of a stent, an angiogram is first performed to determine the appropriate positioning for stent therapy. An angiogram is typically accomplished by injecting a radiopaque contrasting agent through a catheter inserted into an artery or vein as an x-ray is taken. A guidewire is then advanced through the lesion or proposed site of treatment. Over the guidewire is passed a delivery catheter which allows a stent in its collapsed configuration to be inserted into the passageway. The delivery catheter is inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering the catheter through the vascular system under fluoroscopic guidance. A stent having the above-described coating may then be expanded at the desired area of treatment. A post-insertion angiogram may also be utilized to confirm appropriate positioning.
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. A prodrug comprising an ester of heparin and everolimus.

2. A composition comprising a prodrug of claim 1 and a pharmaceutical excipient.