Stent coated with a sustained-release drug delivery and method for use thereof

Abstract

An intraluminal medical device comprises a stent having a coating applied to at least part of an interior surface, an exterior surface, or both. The coating comprises a sustained release formulation of a combination of pharmaceutical compounds dispersed within a biologically tolerated polymer composition. The choice of the combination of pharmaceutical compounds are intended to reduce neointimal hyperplasia restenosis.

1 . A medical device comprising:
 (a) a substrate having a surface; and   (b) a coating adhered to the surface, said coating comprising a polymer matrix including an anti-neoplastic nucleoside analog, or prodrug thereof, dispersed or dissolved therein.   
     
     
         2 . The device of  claim 1 , wherein the nucleoside analog is a pyrimidine analog. 
     
     
         3 . The device of  claim 2 , wherein the pyrimidine analog is selected from the group consisting of 5-fluorouracil (5FU), 5′-deoxyfluorouridine, fluorouridine, 2′-deoxyfluorouridine, fluorocytosine, trifluoro-methyl-2′-deoxyuridine, arabinosyl cytosine, cyclocytidine, 5-aza-2′-deoxycytidine, arabinosyl-5-azacytosine, 6-azacytidine, N-phosphonoacetyl-L-asparticacid (PALA), pyrazofurin, 6-azauridine, azaribine, thymidine, and 3-deazauridine. 
     
     
         4 . The device of  claim 2 , wherein the pyrimidine analog is a 5-fluoropyrimidine or 5-fluoropyrimidine nucleoside analog. 
     
     
         5 . The device of  claim 1 , wherein the nucleoside analog is 5-fluorouracil (5FU) or a prodrug thereof. 
     
     
         6 . A medical device comprising:
 (a) a substrate having a surface; and   (b) a coating adhered to the surface, said coating comprising a polymer matrix including a steroid, or prodrug thereof, dispersed or dissolved therein, which steroid has a solubility less than 0.1 mg/mL in water at 25° C.   
     
     
         7 . The device of  claim 6 , wherein the steroid is a corticosteroid. 
     
     
         8 . The device of  claim 6 , wherein the steroid is triamcinolone or a prodrug thereof. 
     
     
         9 . The device of  claim 6  or  7 , wherein the steroid has a solubility less than 0.01 mg/mL in water at 25° C., dispersed or dissolved therein. 
     
     
         10 . The device of  claim 6  or  7 , wherein the steroid has a logP value at least 0.5 logP units more than the logP value for dexamethasone. 
     
     
         11 . (canceled) 
     
     
         12 . A medical device comprising:
 (a) a substrate having a surface; and,   (b) a coating adhered to the surface, said coating comprising a polymer matrix having a low solubility prodrug dispersed therein, wherein said low solubility prodrug is represented by the general formula of A::B, in which   A represents a drug moiety having a therapeutically active form for producing a clinical response in a patient;   :: represents an ionic bond between A and B that dissociates under physiological conditions to generate said therapeutically active form of A; and   B represents a moiety which, when ionically bonded to A, results in the prodrug having a lower solubility than the therapeutically active form of A.   
     
     
         13 . The device of  claim 12 , wherein the solubility of the therapeutically active form of A in water is greater than 1 mg/mL and the solubility of the prodrug in water at 25° C. is less than 1 mg/mL. 
     
     
         14 . The device of  claim 12 , which provides sustained release of the therapeutically active form of A for a period of at least 24 hours, and, over the period of release, the concentration of the prodrug eluting from polymer is less than 10% of the concentration of the therapeutically active form of A. 
     
     
         15 . The device of  claim 12 , wherein the therapeutically active form of A has a logP value at least 1 logp unit less than the logP value of the prodrug. 
     
     
         16 . The device of  claim 12 , wherein the solubility of the prodrug is less than 100 μg/ml in water at 25° C. 
     
     
         17 . The device of  claim 12 , wherein B is a hydrophobic aliphatic moiety. 
     
     
         18 . The device of  claim 12 , wherein B is a drug moiety having a therapeutically active form generated upon cleavage of said linker L or dissociation of said ionic bond. 
     
     
         19 . The device of  claim 18 , wherein A and B are the same drug moiety. 
     
     
         20 . The device of  claim 16 , wherein A and B are different drug moieties. 
     
     
         21 . The device of  claim 12 , wherein B, after cleavage from the prodrug, is a biologically or pharmacologically inert moiety. 
     
     
         22 . The device of  claim 12 , wherein A is selected from immune response modifiers, anti-proliferatives, anti-mitotic agents, anti-platelet agents, platinum coordination complexes, hormones, anticoagulants, fibrinolytic agents, anti-secretory agents, anti-migratory agents, immunosuppressives, angiogenic agents, angiotensin receptor blockers, nitric oxide donors, antisense oligionucleotides and combinations thereof, cell cycle inhibitors, corticosteroids, angiostatic steroids, anti-parasitic drugs, anti-glaucoma drugs, antibiotics, differentiation modulators, antiviral drugs, anticancer drugs and antiinflammatory drugs. 
     
     
         23 . The device of  claim 12 , wherein B is selected from immune response modifiers, anti-proliferatives, anti-mitotic agents, anti-platelet agents, platinum coordination complexes, hormones, anticoagulants, fibrinolytic agents, anti-secretory agents, anti-migratory agents, immunosuppressives, angiogenic agents, angiotensin receptor blockers, nitric oxide donors, antisense oligionucleotides and combinations thereof, cell cycle inhibitors, corticosteroids, angiostatic steroids, anti-parasitic drugs, anti-glaucoma drugs, antibiotics, differentiation modulators, antiviral drugs, anticancer drugs, and antiinflammatory drugs. 
     
     
         24 . The device of  claim 12 , wherein A is an antineoplastic agent and B is an antiinflammatory agent. 
     
     
         25 . The device of  claim 12 , wherein at least one of A or B is an antineoplastic agent. 
     
     
         26 . The device of  claim 24 , wherein said antineoplastic agent is selected from the group consisting of anthracyclines, vinca alkaloids, purine analogs, pyrimidine analogs, inhibitors of pyrimidine biosynthesis, and alkylating agents. 
     
     
         27 . The device of  claim 24 , wherein said antineoplastic agent is selected from the group consisting of 5-fluorouracil (5FU), 5′-deoxy-5-fluorouridine5-fluorouridine, 2′-deoxy-5-fluorouridine, fluorocytosine, 5-trifluoromethyl-2′-deoxyuridine, arabinoxyl cytosine, cyclocytidine, 5-aza-2′-deoxycytidine, arabinosyl 5-azacytosine, 6-azacytidine, N-phosphonoacetyl-L-aspartic acid, pyrazofurin, 6-azauridine, azaribine, and 3-deazauridine. 
     
     
         28 . The device of  claim 24 , wherein said antineoplastic agent is selected from the group consisting of cladribine, 6-mercaptopurine, pentostatin, 6-thioguanine, and fludarabin phosphate. 
     
     
         29 . The device of  claim 24 , wherein said antineoplastic agent is a pyrimidine analog. 
     
     
         30 . The device of  claim 28 , wherein said pyrimidine analog is selected from the group consisting of arabinosyl cytosine, cyclocytidine, 5-aza-2′-deoxycytidine, arabinosyl 5-azacytosine and 6-azacytidine. 
     
     
         31 . The device of  claim 29 , wherein the pyrimidine analog is selected from the group consisting of 5-fluorouracil (5FU), 5′-deoxyfluorouridine, fluorouridine, 2′-deoxyfluorouridine, fluorocytosine, trifluoro-methyl-2′-deoxyuridine, arabinosyl cytosine, cyclocytidine, 5-aza-2′-deoxycytidine, arabinosyl-5-azacytosine, 6-azacytidine, N-phosphonoacetyl-L-asparticacid (PALA), pyrazofurin, 6-azauridine, azaribine, thymidine and 3-deazauridine. 
     
     
         32 . The device of  claim 28 , wherein the pyrimidine analog is a 5-fluoropyrimidine or 5-fluoropyrimidine nucleoside analog. 
     
     
         33 . The device of  claim 32 , wherein the nucleoside analog is 5-fluorouracil (5FU) or a prodrug thereof. 
     
     
         34 . The device of  claim 12  or  24 , wherein at least one of A or B is steroid. 
     
     
         35 . The device of  claim 34 , wherein the steroid is a corticosteroid. 
     
     
         36 . The device of  claim 34 , wherein the steroid has a solubility less than 0.1 mg/mL in water at 25° C., dispersed or dissolved therein. 
     
     
         37 . The device of  claim 34 , wherein the steroid has a logP value at least 0.5 logP units more than the logP value for dexamethasone. 
     
     
         38 . The device of  claim 34 , wherein the steroid is triamcinolone or a prodrug thereof. 
     
     
         39 . The device of  claim 12 , wherein A is a fluorinated pyrimidine and B is a corticosteroid. 
     
     
         40 . The device of  claim 12 , wherein A is 5-fluorouracil and B is triamcinolone acetonide. 
     
     
         41 . The device of  claim 12 , wherein the linkage L is hydrolyzed in bodily fluid. 
     
     
         42 . The device of  claim 41 , wherein the linkage L includes one or more hydrolyzable groups selected from the group consisting of an ester, an amide, a carbamate, a carbonate, a cyclic ketal, a thioester, a thioamide, a thiocarbamate, a thiocarbonate, a xanthate and a phosphate ester. 
     
     
         43 . The device of  claim 12 , wherein the linkage L is enzymatically cleaved. 
     
     
         44 . The device of any of  claims 1 ,  2  or  12 , wherein the polymer is non-bioerodible. 
     
     
         45 . The device of  claim 44 , wherein the non-bioerodible polymer is selected from polyurethane, polysilicone, poly(ethylene-co-vinyl acetate), polyvinyl alcohol, and derivatives and copolymers thereof. 
     
     
         46 . The device of  claim 1 ,  2  or  12 , wherein the polymer is bioerodible. 
     
     
         47 . The device of  claim 46 , wherein the bioerodible polymer is selected from polyanhydride, polylactic acid, polyglycolic acid, polyorthoester, polyalkylcyanoacrylate and derivatives and copolymers thereof. 
     
     
         48 . The device of  claim 1 ,  2  or  12 , wherein the substrate is a surgical implement selected from a screw, a plate, a washer, a suture, a prosthesis anchor, a tack, a staple, an electrical lead, a valve, a membrane, an anastomosis device, a vertegral disk, a bone pin, a suture anchor, a hemostatic barrier, a clamp, a clip, a vascular implant, a tissue adhesive or sealant, a tissue scaffold, a bone substitute, an intraluminal device and a vascular support. 
     
     
         49 . The device of  claim 1 ,  2  or  12 , selected from the group consisting of catheters, implantable vascular access ports, blood storage bags, blood tubing, central venous catheters, arterial catheters, vascular grafts, intraaortic balloon pumps, heart valves, cardiovascular sutures, artificial hearts, a pacemaker, ventricular assist pumps, extracorporeal devices, blood filters, hemodialysis units, hemoperfusion units, plasmapheresis units, filters adapted for deployment in a blood vessel, intraocular lenses, shunts for hydrocephalus, dialysis grafts, colostomy bag attachment devices, ear drainage tubes, leads for pace makers and implantable defibrillators, and osteointegrated orthopedic devices. 
     
     
         50 . The device of  claim 1 ,  24 , or  12 , which is a vascular stent. 
     
     
         51 . The device of  claim 50 , which is an expandable stent, and said coating is flexible to accommodate compressed and expanded states of said expandable stent. 
     
     
         52 . The device of  claim 1 ,  2  or  12 , wherein the weight of the coating attributable to the drug is in the range of about 0.05 mg to about 10 mg of drug per cm2 of the surface coated with said polymer matrix. 
     
     
         53 . The device of  claim 1 ,  2  or  12 , wherein the coating has a thickness in the range of 5 micrometers to 100 micrometers The device of  claim 1 ,  2 ,  11  or  12 , wherein drug is present in an amount between 5% and 70% by weight of the coating. 
     
     
         54 . The device of  claim 1 ,  2  or  12 , wherein drug is present in an amount between 5% and 70% by weight of the coating. 
     
     
         55 . A stent having at least a portion which is insertable or implantable into the body of a patient, wherein the portion has a surface which is adapted for exposure to body tissue and wherein at least a part of the surface is covered with a coating for releasing at least one biologically active material, the coating comprising a polymer matrix having an antineoplastic nucleoside analog, or prodrug thereof, dispersed or dissolved therein. 
     
     
         56 . A stent having at least a portion which is insertable or implantable into the body of a patient, wherein the portion has a surface which is adapted for exposure to body tissue and wherein at least a part of the surface is covered with a coating for releasing at least one biologically active material, the coating comprising a polymer matrix having a steroid dispersed or dissolved therein, which steroid has a solubility less than 0.1 mg/mL in water at 25° C. 
     
     
         57 . (canceled) 
     
     
         58 . A stent having at least a portion which is insertable or implantable into the body of a patient, wherein the portion has a surface which is adapted for exposure to body tissue and wherein at least a part of the surface is covered with a coating for releasing at least one biologically active material, the coating comprising a polymer matrix having a low solubility prodrug dispersed therein, wherein said low solubility prodrug is represented by the general formula of A::B, in which
 A represents a drug moiety having a therapeutically active form for producing a clinical response in a patient;   :: represents an ionic bond between A and B that dissociates under physiological conditions to generate said therapeutically active form of A; and   B represents a moiety which, when ionically bonded to A, results in the prodrug having a lower solubility than the therapeutically active form of A.   
     
     
         59 . An intraluminal medical device coated with a sustained release system comprising a biologically tolerated polymer and a low-solubility prodrug dispersed in the polymer, said device having an interior surface and an exterior surface; said device having said system applied to at least a part of the interior surface, the exterior surface, or both. 
     
     
         60 . A method for treating an intraluminal tissue of a patient, the method comprising the steps of:
 (a) providing a stent having an interior surface and an exterior surface, said stent having a coating on at least a part of the interior surface, the exterior surface, or both; said coating comprising a low-solubility pharmaceutical prodrug dissolved or dispersed in a biologically-tolerated polymer;   (b) positioning the stent at an appropriate intraluminal tissue site; and   (c) deploying the stent.   
     
     
         61 . A medical device comprising:
 (a) a substrate having a surface;   (b) a pharmaceutically active agent dispersed adjacent to said surface; and   (c) a polymer matrix encapsulating said pharmaceutically active agent;   
       wherein said matrix further comprises a semi-permeable lattice having intermittent pores with cross sectional area sufficient to restrict the passage of moiety A but to allow the passage of moiety B. 
     
     
         62 . The device of  claim 61 , wherein said lattice is bioerodible. 
     
     
         63 . The device of  claim 61 , which provides sustained release of moiety A for a period of at least 24 hours, and, over the period of release, the concentration of moiety A in fluid outside the polymer is less than 10% of the concentration of moiety B in said fluid. 
     
     
         64 . The device of  claim 61 , wherein the substrate is a surgical implement selected from a screw, a plate, a washer, a suture, a prosthesis anchor, a tack, a staple, an electrical lead, a valve, a membrane, an anastomosis device, a vertegral disk, a bone pin, a suture anchor, a hemostatic barrier, a clamp, a clip, a vascular implant, a tissue adhesive or sealant, a tissue scaffold, a bone substitute, an intraluminal device and a vascular support. 
     
     
         65 . The device of  claim 61 , selected from the group consisting of catheters, implantable vascular access ports, blood storage bags, blood tubing, central venous catheters, arterial catheters, vascular grafts, intraaortic balloon pumps, heart valves, cardiovascular sutures, artificial hearts, a pacemaker, ventricular assist pumps, extracorporeal devices, blood filters, hemodialysis units, hemoperfusion units, plasmapheresis units, filters adapted for deployment in a blood vessel, intraocular lenses, shunts for hydrocephalus, dialysis grafts, colostomy bag attachment devices, ear drainage tubes, leads for pace makers and implantable defibrillators, and osteointegrated orthopedic devices. 
     
     
         66 . The device of  claim 61 , which is a vascular stent. 
     
     
         67 . A coating for a medical device comprising a polymer matrix and a prodrug, dispersed in the polymer, having a general formula of A-L-B in which
 A represents a drug moiety having a therapeutically active form for producing a clinical response in a patient;   L represents a covalent linker linking A and B to form a prodrug, said linker being cleaved under physiological conditions to generate said therapeutically active form of A; and   B represents a moiety which, when linked to A, results in the prodrug having a lower solubility than the therapeutically active form of A;   
       wherein the solubility of therapeutically active form of A in water is greater than 1 mg/ml and the solubility of the prodrug in water is less than 1 mg/ml. 
     
     
         68 . A coating for a medical device comprising a polymer matrix and a prodrug, dispersed in the polymer, having a general formula of A::B in which
 A represents a drug moiety having a therapeutically active form for producing a clinical response in a patient;   :: represents a ionic bond between A and B that dissociates under physiological conditions to generate said therapeutically active form of A;   B represents a moiety which, when ionically bonded to A, results in the prodrug having a lower solubility than the therapeutically active form of A; and wherein the solubility of therapeutically active form of A in water is greater than 1 mg/ml and the solubility of the prodrug in water is less than 1 mg/ml.   
     
     
         69 . A coating for a medical device comprising a polymer matrix and a prodrug, dispersed in the polymer, having a general formula of A-L-B in which
 A represents a drug moiety having a therapeutically active form for producing a clinical response in a patient;   :: represents a ionic bond between A and B that dissociates under physiological conditions to generate said therapeutically active form of A;   B represents a moiety which, when ionically bonded to A, results in the prodrug having a lower solubility than the therapeutically active form of A; and wherein the solubility of therapeutically active form of A in water is greater than 1 mg/ml and the solubility of the prodrug in water is less than 1 mg/ml.   
     
     
         70 . A coating for a medical device comprising a polymer matrix and a prodrug, dispersed in the polymer, having a general formula of A::B in which
 A represents a drug moiety having a therapeutically active form for producing a clinical response in a patient;   :: represents a ionic bond between A and B that dissociates under physiological conditions to generate said therapeutically active form of A;   B represents a moiety which, when ionically bonded to A, results in the prodrug having a lower solubility than the therapeutically active form of A; and wherein, when disposed in biological fluid, said sustained release formulation provides sustained release of the therapeutically active form of A for a period of at least 24 hours, and, over the period of release, the concentration of the prodrug in fluid outside the polymer is less than 10% of the concentration of the therapeutically active form of A.   
     
     
         71 . The coating of any one of  claims 67 - 70 , wherein A and B are the same drug moiety. 
     
     
         72 . The coating of any one of  claims 67 - 70 , wherein A and B are different drug moieties. 
     
     
         73 . The coating of any one of  claims 67 - 70 , wherein B, after cleavage from the prodrug, is a biologically inert moiety. 
     
     
         74 . The coating of any one of  claims 67 - 70 , wherein A is selected from immune response modifiers, anti-proliferatives, anti-mitotic agents, anti-platelet agents, platinum coordination complexes, hormones, anticoagulants, fibrinolytic agents, anti-secretory agents, anti-migratory agents, immunosuppressives, angiogenic agents, angiotensin receptor blockers, nitric oxide donors, antisense oligionucleotides and combinations thereof, cell cycle inhibitors, corticosteroids, angiostatic steroids, anti-parasitic drugs, anti-glaucoma drugs, antibiotics, differentiation modulators, antiviral drugs, anticancer drugs, and anti-inflammatory drugs. 
     
     
         75 . The coating of any one of  claims 67 - 70 , wherein B is selected from immune response modifiers, anti-proliferatives, anti-mitotic agents, anti-platelet agents, platinum coordination complexes, hormones, anticoagulants, fibrinolytic agents, anti-secretory agents, anti-migratory agents, immunosuppressives, angiogenic agents, angiotensin receptor blockers, nitric oxide donors, antisense oligonucleotides and combinations thereof, cell cycle inhibitors, corticosteroids, angiostatic steroids, anti-parasitic drugs, anti-glaucoma drugs, antibiotics, differentiation modulators, antiviral drugs, anticancer drugs, and anti-inflammatory drugs. 
     
     
         76 . The coating of any one of  claims 67 - 70 , wherein the duration of release of the therapeutically active form of A from the polymer matrix is at least 24 hours. 
     
     
         77 . The coating of any one of  claims 67 - 70 , wherein A is 5-fluorouracil (5FU) and B is a steroid. 
     
     
         78 . The coating of any one of  claims 67 - 70 , wherein at least one of A or B is an antineoplastic agent. 
     
     
         79 . The coating of any one of  claims 67 - 70 , wherein said antineoplastic agent selected from the group consisting of anthracyclines, vinca alkaloids, purine analogs, pyrimidine analogs, inhibitors of pyrimidine biosynthesis, and alkylating agents. 
     
     
         80 . The coating of any one of  claims 67 - 70 , wherein said antineoplastic drug is a fluorinated pyrimidine. 
     
     
         81 . The coating of any one of  claims 67 - 70 , wherein said antineoplastic drug is selected from the group consisting of 5-fluorouracil (5FU), 5′-deoxy-5-fluorouridine5-fluorouridine, 2′-deoxy-5-fluorouridine, fluorocytosine, 5-trifluoromethyl-2′-deoxyuridine, arabinoxyl cytosine, cyclocytidine, 5-aza-2′-deoxycytidine, arabinosyl 5-azacytosine, 6-azacytidine, N-phosphonoacetyl-L-aspartic acid, pyrazofurin, 6-azauridine, azaribine, and 3-deazauridine. 
     
     
         82 . The coating of any one of  claims 67 - 70 , wherein said antineoplastic drug is a pyrimidine nucleoside analog selected from the group consisting of arabinosyl cytosine, cyclocytidine, 5-aza-2′-deoxycytidine, arabinosyl 5-azacytosine, and 6-azacytidine. 
     
     
         83 . The coating of any one of  claims 67 - 70 , wherein said antineoplastic drug is selected from the group consisting of cladribine, 6-mercaptopurine, pentostatin, 6-thioguanine, and fludarabin phosphate. 
     
     
         84 . The coating of any one of  claims 67 - 70 , wherein the therapeutically active form of A is 5-fluorouracil. 
     
     
         85 . The coating of any one of  claims 67 - 70 , wherein at least one of A or B is an anti-inflammatory agent. 
     
     
         86 . The coating of  claim 85 , wherein said anti-inflammatory agent is a non-steroidal antiinflammatory. 
     
     
         87 . The coating of  claim 85 , wherein said anti-inflammatory agent is a glucocorticoid. 
     
     
         88 . The coating of  claim 87 , wherein said glucocorticoid is selected from the group consisting of aclometasone, beclomethasone, betamethasone, budesonide, clobetasol, clobetasone, cortisone, desonide, desoximetasone, diflorosane, fiumethasone, flunisolide, fluocinolone acetonide, fluocinolone, fluocortolone, fluprednidene, flurandrenolide, fluticasone, hydrocortisone, methylprednisolone aceponate, mometasone furdate, prednisolone, prednisone and rofleponide. 
     
     
         89 . The coating of any one of  claims 67 - 70 , wherein the therapeutically active form of B is selected from fluocinolone acetonide, triamcinolone acetonide, diclofenac, and naproxen. 
     
     
         90 . The coating of any one of  claims 67 - 70 , wherein the prodrug, in its linked form, has an ED 50  for producing said clinical response at least 10 times greater than the ED 50  of the therapeutically active form of A. 
     
     
         91 . The coating of any one of  claims 67 - 70 , wherein the polymer is non-bioerodible. 
     
     
         92 . The coating of any one of  claims 67 - 70 , wherein the polymer is bioerodible. 
     
     
         93 . The coating of any one of  claims 67 - 70 , wherein A is 5-fluorouracil (5FU) or triamcinolone (TA). 
     
     
         94 . A medical device comprising:
 (a) a substrate having a porous surface; and   (b) a pharmaceutically active agent carried by said surface;   (c) a polymer matrix encapsulating said pharmaceutically active agent;   
       wherein said matrix further comprises a semi-permeable lattice having intermittent pores with cross sectional area sufficient to restrict the passage of moiety A but to allow the passage of moiety B. 
     
     
         95 . The device of  claim 94 , wherein said lattice is bioerodible. 
     
     
         96 . The device of  claim 94 , which provides sustained release of moiety A for a period of at least 24 hours, and, over the period of release, the concentration of moiety A in fluid outside the polymer is less than 10% of the concentration of moiety B in said fluid. 
     
     
         97 . The device of  claim 94 , wherein the substrate is a surgical implement selected from a screw, a plate, a washer, a suture, a prosthesis anchor, a tack, a staple, an electrical lead, a valve, a membrane, an anastomosis device, a vertegral disk, a bone pin, a suture anchor, a hemostatic barrier, a clamp, a clip, a vascular implant, a tissue adhesive or sealant, a tissue scaffold, a bone substitute, an intraluminal device and a vascular support.