System for sustained-release delivery of anti-inflammatory agents from a coated medical device

• US 20030158598A1
• Filed: 01/14/2003
• Published: 08/21/2003
• Est. Priority Date: 09/17/2001
• Status: Abandoned Application

• Current Assignee: Control Delivery Systems Inc. (EyePoint Pharmaceuticals, Inc.)
• Original Assignee: Control Delivery Systems Inc. (EyePoint Pharmaceuticals, Inc.)
• Inventors: Ashton, Paul, Chen, Jianbing
• Application Number:
  US10/345,064
• Publication Number:
  US 20030158598A1
• Time in Patent Office: Days
• US Class Current: 623/1.42
• 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

Abstract

The subject invention provides medical devices having a coating disposed on at least one surface, wherein the coating includes a polymer matrix and a low solubility anti-inflammatory corticosteroid formulation, or low solubility codrug or prodrug of an anti-inflammatory corticosteroid formulation.

Claims

1. A medical device comprising:

(a) a substrate having a surface; and

(b) a coating disposed on the surface, said coating comprising a polymer matrix including an anti-inflammatory corticosteroid, or a codrug or prodrug thereof, which corticosteroid is formulated in a form having a solubility less than 0.1 mg/mL in water at 25°

C.,

wherein the corticosteroid is released from said polymer matrix at a rate of release to produce an effective concentration of said corticosteroid in tissue or biological fluid in which the medical device is implanted.

6. The device of any of claims 1-4, wherein the corticosteroid is a glucocorticoid or prodrug thereof.

7. The device of claim 6, wherein the glucocorticoid is selected from 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, triamcinolone and rofleponide, or an acetylated derivative thereof.

8. The device of any of claims 1-4, wherein the corticosteroid is an acetylated triamcinolone, or a prodrug thereof.

9. The device of claim 8, wherein the glucocorticoid is triamcinolone acetonide or a prodrug thereof.

10. The device of any one of claims 1-5, wherein the polymer is non-bioerodible.

11. The device of any one of claims 1-5, wherein the polymer is bioerodible.

12. The device of claim 11, wherein the bioerodible polymer contains polyanhydride, polylactic acid, polyglycolic acid, polyorthoester or polyalkylcyanoacrylate, or derivatives or copolymers thereof.

29. The device of any of claims 1-5, wherein the corticosteroid has a logP value at least 0.5 logP units more than the logP value for dexamethasone.

30. The device of claim 29, wherein the steroid is triamcinolone acetonide or a prodrug thereof.

31. The device of any of claims 1-5, wherein the polymer reduces interactions, when implanted, between the corticosteroids in the polymer and proteinaceous components in surrounding biological fluid.

32. The device of any one of claims 1-5, wherein, when disposed in vivo, said coating provides sustained release of the corticosteroid for a period of at least 24 hours.

33. The device of claim 32, wherein said coating provides sustained release of a therapeutically effective amount of the corticosteroid for a period of at least 30 days.

34. The device of claim 32, wherein said coating provides sustained release of a therapeutically effective amount of the corticosteroid for a period of no more than 1 year.

35. The device of any one of claims 1-5, 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.

36. The device of any one of claim 1-5, wherein the substrate is selected from 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.

37. The device of any one of claims 1-5, which is a vascular stent.

38. The device of claim 37, which is an expandable stent, and said coating is flexible to accommodate compressed and expanded states of said expandable stent.

39. The device of any one of claims 1-5, wherein the weight of the coating attributable to the corticosteroid is in the range of about 0.05 mg to about 50 mg of drug per cm² of the surface coated with said polymer matrix.

40. The device of any one of claims 1-5, wherein the coating has a thickness is in the range of 5 micrometers to 100 micrometers.

41. A method for treating a mammalian organism to obtain a desired local or systemic physiological or pharmacological effect, comprising:

administering a pharmaceutically effective amount of a drug by placing in said mammal the device of any of claims 1-5 to a mammal.

42. A method for treating an intraluminal tissue of a patient, the method comprising the steps of:

(a) providing the stent of claim 37;

(b) positioning the stent at an appropriate intraluminal tissue site; and

(c) deploying the stent.

2. A medical device comprising:

(a) a substrate having a surface; and

(b) a coating disposed on the surface, said coating comprising a polymer matrix including a soluble anti-inflammatory corticosteroid, and one or more additives which decrease the rate of release of the corticosteroid into the biological fluid or tissue surrounding the device,

wherein the corticosteroid is released from said polymer matrix at a rate of release to produce an effective concentration of said corticosteroid in tissue or biological fluid in which the medical device is implanted.

3. A medical device comprising:

(a) a substrate having a surface; and

(b) a coating disposed on the surface, said coating comprising a polymer matrix including a prodrug, wherein said prodrug is represented by the general formula A-L-B, in which

A represents an anti-inflammatory corticosteroid or a prodrug thereof;

L represents a covalent bond or covalent linker linking A and B to form the prodrug, wherein the bond or linker is metabolized under physiological conditions; and

B represents a moiety which, when linked to A, results in a compound having an optimized solubility for sustained delivery in vivo from the coated device.

13. The device of any one of claims 3-4, wherein A and B are the same drug moiety.

14. The device of any one of claims 3-4, wherein A and B are different drug moieties.

15. The device of any one of claims 3-4, wherein B, after cleavage from the prodrug, is a biologically or pharmacologically inactive moiety.

16. The device of any one of claims 3-4, 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-glaucoma drugs, antibiotics, differentiation modulators, antiviral drugs, anticancer drugs, and anti-inflammatory drugs.

17. The device of any one of claims 3-4, wherein B is an anti-neoplastic agent.

18. The device of claim 17, wherein said anti-neoplastic agent is selected from the group consisting of anthracyclines, vinca alkaloids, purine analogs, pyrimidine analogs, inhibitors of pyrimidine biosynthesis, and alkylating agents.

19. The device of claim 17, wherein said anti-neoplastic agent is selected from arabinosyl cytosine, cyclocytidine, 5-aza-2′

-deoxycytidine, arabinosyl 5-azacytosine and 6-azacytidine.

20. The device of claim 17, wherein said anti-neoplastic agent is a fluorinated pyrimidine.

21. The device of claim 20, wherein the anti-neoplastic agent is selected from 5-fluorouracil (5-FU), 5′

-deoxy-5-fluorouridine, 5-fluorouridine, 2′

-deoxy-5-fluorouridine, fluorocytosine, 5-trifluoromethyl-2′

-deoxyuridine.

22. The device of claim 21, wherein the fluorinated pyrimidine is 5-fluorouracil (5-FU) or a prodrug thereof.

23. The device of claim 17, wherein said anti-neoplastic agent is selected from cladribine, 6-mercaptopurine, pentostatin, 6-thioguanine, and fludarabin phosphate, arabinoxyl cytosine, cyclocytidine, 5-aza-2′

-deoxycytidine, arabinosyl 5-azacytosine, 6-azacytidine, pyrazofurin, 6-azauridine, azaribine, thymidine, and 3-deazauridine

24. The device of any one of claims 3-4, wherein B is a non-steroidal anti-inflammatory.

25. The device of claim 24, wherein B is selected from diclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, nabumetone, naproxen and piroxicam.

26. The device of any of claims 3-4, wherein A is triamcinolone acetonide and B is 5-fluorouracil.

27. The device of claim 3, wherein the linkage L includes one or more hydrolyzable groups selected from 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.

28. The device of claim 3, wherein the linkage L is enzymatically cleaved.

4. A medical device comprising:

(a) a substrate having a surface; and

(b) a coating disposed on the surface, said coating comprising a polymer matrix including a low solubility prodrug, wherein said prodrug is represented by the general formula of A;

;

B, in which

A represents an anti-inflammatory steroid or a derivative thereof;

;

;

represents an ionic bond between A and B that dissociates under physiological conditions to generate said pharmaceutically active form of A; and

B represents a moiety which, when linked to A, results in a compound having an optimized solubility for sustained delivery in vivo from the coated device.

5. A medical device comprising:

(a) a substrate having a surface; and

(b) a coating disposed on the surface, said coating comprising a polymer matrix including triamcinolone acetonide.

43. A method of manufacturing a coating for a medical device, comprising admixing a polymer matrix and a pharmaceutically effective amount of an anti-inflammatory corticosteroid, or a codrug or prodrug thereof, which corticosteroid is formulated in a form having a solubility less than 0.1 mg/mL in water at 25°

C.

44. A use of a polymeric coating in the manufacture of a device to place in a patient for treatment of said patient with a sustained dosage regimen of an anti-inflammatory corticosteroid, which corticosteroid is formulated in a form having a solubility less than 0.1 mg/mL in water at 25°

C.