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

• US 20030108588A1
• Filed: 09/17/2002
• Published: 06/12/2003
• Est. Priority Date: 09/17/2001
• Status: Active Grant

• Current Assignee: pSivida US, Inc
• Original Assignee: PSivida Inc.
• Inventors: Ashton, Paul, Chen, Jianbing
• Granted Patent: US 7,279,175 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61L 17/005 containing a biologically active substance, e.g. a medicament or a biocide
• CPC Class Codes: A61L 2300/222 Steroids, e.g. corticosteroids
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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.

Claims

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.

44. The device of any of claims 1, 2, 11 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, 11 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, 11 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, 11 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, 2, 11 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, 11 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, 11 or 12, wherein the coating has a thickness is in the range of 5 micrometers to 100 micrometers.

54. 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.

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. 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 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.

13. The device of claim 11 or 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 11 or 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 11 or 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 11 or 12, wherein the solubility of the prodrug is less than 100 μ

g/ml in water at 25°

C.

17. The device of claim 11 or 12, wherein B is a hydrophobic aliphatic moiety.

18. The device of claim 11 or 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 11 or 12, wherein B, after cleavage from the prodrug, is a biologically or pharmacologically inert moiety.

22. The device of claim 11 or 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 anti-inflammatory drugs.

23. The device of claim 11 or 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 anti-inflammatory drugs.

24. The device of claim 11 or 12, wherein A is an antineoplastic agent and B is an anti-inflammatory agent.

25. The device of claim 11 or 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-fluorouridine 5-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 11, 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 11 or 12, wherein A is a fluorinated pyrimidine and B is a corticosteroid.

40. The device of claim 11 or 12, wherein A is 5-fluorouracil and B is triamcinolone acetonide.

41. The device of claim 11 or 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 11 or 12, wherein the linkage L is enzymatically cleaved.

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.

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. 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 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.

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.

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 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.

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-fluorouridine 5-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 anti-inflammatory.

87. The coating of claim 85, wherein 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, flumethasone, 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 ED₅₀ for producing said clinical response at least 10 times greater than the ED₅₀ 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).

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;

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, 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.

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.

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.