Non-linear multiblock copolymer-drug conjugates for the delivery of active agents

• US 10,159,743 B2
• Filed: 03/12/2013
• Issued: 12/25/2018
• Est. Priority Date: 03/16/2012
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Fu, Jie, Campochiaro, Peter A., Hanes, Justin Scot
• Primary Examiner(s): Pipic, Alma
• Application Number:
  US13/797,531
• Publication Number:
  US 20130272994A1
• Time in Patent Office: 2,114 Days
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/6827 Ricin A
• CPC Class Codes: A61K 47/6927 the form being a solid microparticle having no hollow or gas-filled cores
• CPC Class Codes: A61K 47/6957 the form being a device or a kit, e.g. stents or microdevices
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

Non-linear multiblock copolymer-drug conjugates for the treatment and prevention of diseases and disorders of the eye are provided. The polymer-drug conjugates can form nanoparticles, microparticles, and implants that are capable of effectively delivering therapeutic levels of one or more active agents for an extended period of time. Administration to the eye of an active agent in the form of a non-linear multiblock copolymer-drug conjugate produces decreased side effects when compared to administration of the active agent alone. Also provided are methods of treating intraocular neovascular diseases, such as wet age-related macular degeneration as well as diseases and disorders of the eye associated with inflammation, such as uveitis.

Claims

1. A polymer conjugate defined by the following formula

(A-X_mYZ)_n

wherein

A is an ophthalmic drug for treatment of the posterior segment of the eye selected from the group consisting of brimonidine, apraclonidine, brinzolamide, acetazolamine, and dorzolamide;

Z represents, independently for each occurrence, a hydrophilic polymer segment selected from the group consisting of a poly(ethylene glycol) segment, a poly(propylene glycol) segment, and a copolymer thereof segment;

Y represents a multivalent branch point that is an organic, inorganic, or organometallic moiety;

X represents a hydrophobic polymer segment selected from the group consisting of a poly(lactic acid) segment, a poly(glycolic acid) segment, and a poly(lactic-co-glycolic acid) segment; and

m and n are independently 1, 2, 3, 4, or 5, and m+n is greater than 2.

2. The conjugate of claim 1, wherein Z is a copolymer of poly(ethylene glycol) and poly(propylene glycol).

3. The conjugate of claim 1, wherein Y is selected from the group consisting of:

4. A population of micro- and/or nanoparticles comprising the conjugate of any one of claims 1, 2, and 3.

5. A formulation comprising the polymer conjugate of any of claims 1, 2, and 3 and a pharmaceutically acceptable excipient.

6. A method of treating a disease or disorder comprising administering to the patient in need thereof an effective amount of the formulation of claim 5.

7. The method of claim 6, wherein the formulation is administered to the eye.

8. The conjugate of claim 1, wherein Y comprises at least two functional groups selected from the group consisting of carbonyl, aldehyde, carboxyl, ester, and amine.

9. The conjugate of claim 1, wherein Z is a poly(ethylene glycol) segment and X is a polylactic acid) segment.

10. The conjugate of claim 9, wherein A is brimonidine.

11. The conjugate of claim 9, wherein A is apraclonidine.

12. The conjugate of claim 9, wherein A is brinzolamide.

13. The conjugate of claim 9, wherein A is acetazolamine.

14. The conjugate of claim 9, wherein A is dorzolamide.

15. The conjugate of claim 1, wherein Z is a poly(ethylene glycol) segment and X is a poly(glycolic acid) segment.

16. The conjugate of claim 15, wherein A is brimonidine.

17. The conjugate of claim 15, wherein A is apraclonidine.

18. The conjugate of claim 15, wherein A is brinzolamide.

19. The conjugate of claim 15, wherein A is acetazolamine.

20. The conjugate of claim 15, wherein A is dorzolamide.

21. The conjugate of claim 1, wherein Z is a poly(ethylene glycol) segment and X is a polylactic-co-glycolic acid) segment.

22. The conjugate of claim 21, wherein A is brimonidine.

23. The conjugate of claim 21, wherein A is apraclonidine.

24. The conjugate of claim 21, wherein A is brinzolamide.

25. The conjugate of claim 21, wherein A is acetazolamine.

26. The conjugate of claim 21, wherein A is dorzolamide.

27. The conjugate of claim 1, wherein Z is a poly(propylene glycol) segment and X is a poly(lactic acid) segment.

28. The conjugate of claim 27, wherein A is brimonidine.

29. The conjugate of claim 27, wherein A is apraclonidine.

30. The conjugate of claim 27, wherein A is brinzolamide.

31. The conjugate of claim 27, wherein A is acetazolamine.

32. The conjugate of claim 27, wherein A is dorzolamide.

33. The conjugate of claim 1, wherein Z is a poly(propylene glycol) segment and X is a poly(glycolic acid) segment.

34. The conjugate of claim 33, wherein A is brimonidine.

35. The conjugate of claim 33, wherein A is apraclonidine.

36. The conjugate of claim 33, wherein A is brinzolamide.

37. The conjugate of claim 33, wherein A is acetazolamine.

38. The conjugate of claim 33, wherein A is dorzolamide.

39. The conjugate of claim 1, wherein Z is a poly(propylene glycol) segment and X is a poly(lactic-co-glycolic acid) segment.

40. The conjugate of claim 39, wherein A is brimonidine.

41. The conjugate of claim 39, wherein A is apraclonidine.

42. The conjugate of claim 39, wherein A is brinzolamide.

43. The conjugate of claim 39, wherein A is acetazolamine.

44. The conjugate of claim 39, wherein A is dorzolamide.

45. A formulation comprising the population of micro- and/or nanoparticles of claim 4 and a pharmaceutically acceptable excipient.