Sustained delivery of therapeutic agents to an eye compartment

• US 9,937,130 B2
• Filed: 04/25/2016
• Issued: 04/10/2018
• Est. Priority Date: 02/25/2010
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: McDonnell, Peter J., Khan, Yasin A., Lai, Samuel K., Kashiwabuchi, Renata T., Behrens, Ashley, Hanes, Justin S.
• Primary Examiner(s): Sasan, Aradhana
• Application Number:
  US15/138,132
• Publication Number:
  US 20160235674A1
• Time in Patent Office: 715 Days
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• 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 47/6921 the form being a particulate, a powder, an adsorbate, a bead or a sphere
• CPC Class Codes: A61K 47/6931 the material constituting the nanoparticle being a polymer
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

Compositions and methods for treating eye disorders by administering a drug delivery system into an eye compartment of the patient, wherein the drug delivery system contains a particle containing a core; a coating associated with the particle, wherein the coating is covalently or non-covalently associated with the particle and presents a hydrophilic region to the environment around the particle; and a therapeutic agent are disclosed. The eye compartment can exhibit reduced inflammation or IOP after administration of the drug delivery systems to a patient than if a drug delivery system including an uncoated particle were administered to the patient.

Claims

1. A method for treating an eye disorder in a patient in need thereof, comprising administering by intravitreal injection into the vitreous chamber of the eye an effective amount of a drug delivery system which comprises:

(i) microparticles including a core which includes the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles, wherein the coating comprises molecules having a hydrophilic region and a hydrophobic region, wherein the hydrophilic region is polyethylene glycol; and

(iii) a therapeutically effective amount of an anti-angiogenic agent,

wherein the drug delivery system provides sustained release of the anti-angiogenic agent into the vitreous chamber over a period of time of at least three months; and

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure than if the particles were uncoated, for at least about 30 days post-administration.

2. The method of claim 1, wherein the diameter of the microparticles is about 50 microns or less.

3. The method of claim 1, wherein the diameter of the microparticles is about 30 microns or less.

4. The method of claim 1, wherein the coating molecule is a block-copolymer.

5. The method of claim 1, wherein the microparticles consist essentially of polylactide-co-glycolide.

6. The method of claim 1, wherein the disorder is macular degeneration.

7. The method of claim 1, wherein the disorder is age-related macular degeneration.

8. The method of claim 1, wherein the disorder is diabetic retinopathy.

9. The method of claim 1, wherein the disorder is corneal neovascularization.

10. The method of claim 1, wherein the anti-angiogenic agent is released from the drug delivery system into the vitreous chamber of the patient'"'"'s eye over a period of time of at least six months.

11. The method of claim 1, wherein the anti-angiogenic agent is an anti-vascular endothelial growth factor agent.

12. The method of claim 1, wherein the patient is a human.

13. The method of claim 1, wherein the drug delivery system is lyophilized and then reconstituted prior to administration by intravitreal injection.

14. The method of claim 1, wherein the drug delivery system is provided in a sterile suspension.

15. The method of claim 14, wherein the sterile suspension includes a suspending agent.

16. An injectable composition for administration to the vitreous chamber of the eye of a patient, comprising a drug delivery system that comprises:

(i) microparticles having a diameter of 30 μ

m or less including a core which includes the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles, wherein the coating is formed of molecules having a polyethylene glycol hydrophilic region and a hydrophobic region;

(iii) a therapeutically effective amount of an anti-angiogenic agent;

(iv) in a sterile suspension suitable for intravitreal delivery;

wherein the drug delivery system provides sustained release of the anti-angiogenic agent into the vitreous chamber of the eye of the patient over a period of time of at least three months and

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure than if the particles were uncoated, for at least about 30 days post-administration.

17. The injectable composition of claim 16, wherein the composition includes a suspending agent.

18. The injectable composition of claim 16, wherein the anti-angiogenic agent is an anti-vascular endothelial growth factor agent.

19. The injectable composition of claim 16, wherein the drug delivery system provides sustained release of the anti-angiogenic agent into the vitreous chamber of the eye over a period of time of at least six months.

20. The injectable composition of claim 16, wherein the patient is a human.

21. A drug delivery system for intravitreal injection into the vitreous chamber of the eye of a patient, comprising:

(i) microparticles having a diameter of 30 μ

m or less including a core which includes the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles, wherein the coating comprises molecules having a hydrophilic region and a hydrophobic region, wherein the hydrophilic region is polyethylene glycol;

(iii) a therapeutically effective amount of a anti-angiogenic agent;

(iv) in a sterile suspension; and

(v) a device containing a needle for intravitreal injection;

wherein the drug delivery system provides sustained release of the anti-angiogenic agent into the vitreous chamber of the eye patient'"'"'s over a period of time of at least three months and wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure than if the particles were uncoated for at least about 30 days post-administration.

22. The drug delivery system of claim 21, wherein the composition includes a suspending agent.

23. The drug delivery system of claim 21, wherein the anti-angiogenic agent is an anti-VEGF agent.

24. The drug delivery system of claim 21, wherein the drug delivery system provides sustained release of the anti-angiogenic agent into the vitreous chamber of the eye over a period of time of at least six months.

25. The drug delivery system of claim 21, wherein the patient is a human.

26. A method for treating macular degeneration in a human in need thereof, comprising administering by intravitreal injection into the vitreous chamber of the eye of a patient an effective amount of a drug delivery system which comprises:

(i) microparticles having a diameter of 30 μ

m or less including a core which consists essentially of the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles, wherein the coating comprises molecules having a polyethylene glycol hydrophilic region and a hydrophobic region,

(iii) a therapeutically effective amount of an anti-vascular endothelial growth factor agent,

wherein the drug delivery system provides sustained release of the anti-vascular endothelial growth factor agent into the vitreous chamber over a period of time of at least three months;

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure than if the particles were uncoated for at least about 30 days post-administration; and

wherein the drug delivery system is lyophilized and then reconstituted prior to administration by intravitreal injection in a sterile suspension that includes a suspending agent.

27. The method of claim 26, wherein the anti-angiogenic agent is released from the drug delivery system into the vitreous chamber over a period of time of at least six months.

28. The method of claim 26, wherein the patient is a human.

29. An injectable composition for administration to the vitreous chamber of the eye of a patient, comprising a drug delivery system that comprises:

(i) microparticles having a diameter of 30 μ

m or less including a core which includes the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticle;

wherein the coating comprises molecules having a polyethylene glycol hydrophilic region and a hydrophobic region;

(iii) a therapeutically effective amount of an anti-vascular endothelial growth factor agent;

(iv) in a sterile suspension suitable for intravitreal delivery that includes a suspending agent;

wherein the drug delivery system provides sustained release of anti-vascular endothelial growth factor agent into the vitreous chamber of the eye over a period of time of at least three months, and

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure than if the particles were uncoated for at least about 30 days post-administration.

30. The injectable composition of claim 29, wherein the drug delivery system provides sustained release of the anti-VEGF agent into the vitreous chamber of the eye over a period of time of at least six months.

31. The injectable composition of claim 29, wherein the microparticles consist essentially of polylactide-co-glycolide.

32. The injectable composition of claim 29, wherein the patient is a human.

33. An injectable system for intravitreal injection into the vitreous chamber of the eye of a patient, comprising a drug delivery system that comprises:

(i) microparticles having a diameter of 30 μ

m or less including a core which includes the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles;

wherein the coating is a molecule that has a polyethylene glycol hydrophilic region and a hydrophobic region;

(iii) a therapeutically effective amount of an anti-VEGF agent;

(iv) in a sterile suspension, wherein the sterile suspension includes a suspending agent; and

(v) a device containing a needle for intravitreal injection.

34. The injectable system of claim 33, wherein the microparticles consist essentially of polylactide-co-glycolide.

35. The injectable system of claim 33, wherein the patient is a human.

36. A method for treating an eye disorder in a patient in need thereof, comprising administering by intravitreal injection into the vitreous chamber of the eye an effective amount of a drug delivery system which comprises:

(i) microparticles including a core which includes the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles;

wherein the coating comprises molecules having a hydrophilic region and a hydrophobic region, and wherein the hydrophilic region is polyethylene glycol;

(iii) a therapeutically effective amount of an anti-angiogenic agent,

wherein the drug delivery system provides sustained release of the anti-angiogenic agent into the vitreous chamber over a period of time of at least three months; and

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure than if the particles were uncoated.

37. The method of claim 36, wherein the microparticles have a diameter of about 50 microns or less.

38. The method of claim 36, wherein the microparticles have a diameter of about 30 microns or less.

39. The method of claim 36, wherein the coating molecule is a block-copolymer.

40. The method of claim 36, wherein the microparticle consists essentially of polylactide-co-glycolide.

41. The method of claim 36, wherein the disorder is macular degeneration.

42. The method of claim 36, wherein the disorder is age-related macular degeneration.

43. The method of claim 36, wherein the disorder is diabetic retinopathy.

44. The method of claim 36, wherein the disorder is corneal neovascularization.

45. The method of claim 36, wherein the anti-angiogenic agent is released from the drug delivery system into the vitreous chamber of the patient'"'"'s eye over a period of time of at least six months.

46. The method of claim 36, wherein the anti-angiogenic agent is an anti-vascular endothelial growth factor agent.

47. The method of claim 36, wherein the patient is a human.

48. The method of claim 36, wherein the drug delivery system is lyophilized and then reconstituted prior to administration by intravitreal injection.

49. The method of claim 36, wherein the drug delivery system is provided in a sterile suspension.

50. The method of claim 49, wherein the sterile suspension includes a suspending agent.

51. An injectable composition for administration to the vitreous chamber of the eye of a patient, comprising a drug delivery system that comprises:

(i) microparticles having a diameter of 30 μ

m or less including a core which includes the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles;

wherein the coating comprises molecules having a polyethylene glycol hydrophilic region and a hydrophobic region;

(iii) a therapeutically effective amount of an anti-angiogenic agent;

(iv) in a sterile suspension suitable for intravitreal delivery;

wherein the drug delivery system provides sustained release of the anti-angiogenic agent into the vitreous chamber of the eye of the patient over a period of time of at least three months.

52. The injectable composition of claim 51, wherein the composition includes a suspending agent.

53. The injectable composition of claim 51, wherein the anti-angiogenic agent is an anti-vascular endothelial growth factor agent.

54. The injectable composition of claim 51, wherein the drug delivery system provides sustained release of the anti-angiogenic agent into the vitreous chamber of the eye over a period of time of at least six months.

55. The injectable composition of claim 51, wherein the microparticles consist essentially of polylactide-co-glycolide.

56. The injectable composition of claim 51, wherein the patient is a human.

57. An injectable system for intravitreal injection into the vitreous chamber of the eye of a patient, comprising a drug delivery system that comprises:

microparticles having a diameter of 30 μ

m or less including a core which includes the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles;

wherein the coating comprises molecules having a polyethylene glycol hydrophilic region and a hydrophobic region;

(iii) a therapeutically effective amount of an anti-angiogenic agent;

(iv) in a sterile suspension; and

(v) a device containing a needle for intravitreal injection,

wherein the system provides sustained release of the anti-angiogenic agent into the vitreous chamber of the eye patient'"'"'s over a period of time of at least three months and

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure than if the particles were uncoated.

58. The injectable system of claim 57, wherein the microparticles consist essentially of polylactide-co-glycolide.

59. The injectable system of claim 57, wherein the patient is a human.

60. The injectable system of claim 57, wherein the composition includes a suspending agent.

61. The injectable system of claim 57, wherein the anti-angiogenic agent is an anti-vascular endothelial growth factor agent.

62. A method for treating macular degeneration in a human in need thereof, comprising administering by intravitreal injection into the vitreous chamber of the eye of a patient an effective amount of a drug delivery system which comprises:

(i) microparticles having a diameter of 30 μ

m or less including a core which consists essentially of the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles;

wherein the coating comprises molecules having a polyethylene glycol hydrophilic region and a hydrophobic region;

(iii) a therapeutically effective amount of anti-vascular endothelial growth factor agent,

wherein the drug delivery system provides sustained release of the anti-vascular endothelial growth factor agent into the vitreous chamber over a period of time of at least three months;

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure than if the particles were uncoated; and

wherein the drug delivery system is lyophilized and then reconstituted prior to administration by intravitreal injection in a sterile suspension that includes a suspending agent.

63. The method of claim 62, wherein the anti-vascular endothelial growth factor agent is released from the drug delivery system into the vitreous chamber over a period of time of at least six months.

64. The method of claim 62, wherein the patient is a human.

65. An injectable composition for administration to the vitreous chamber of the eye of a patient, comprising a drug delivery system that comprises:

(i) microparticles having a diameter of 30 μ

m or less including a core which includes the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles;

wherein the coating comprises molecules having a polyethylene glycol hydrophilic region and a hydrophobic region;

(iii) a therapeutically effective amount of an anti-vascular endothelial growth factor agent;

(iv) in a sterile suspension suitable for intravitreal delivery that includes a suspending agent;

wherein the drug delivery system provides sustained release of the anti-VEGF agent into the vitreous chamber of the eye over a period of time of at least three months and

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure than if the particles were uncoated.

66. The injectable composition of claim 65, wherein the drug delivery system provides sustained release of the anti-angiogenic agent into the vitreous chamber of the eye over a period of time of at least six months.

67. The injectable composition of claim 65, wherein the patient is a human.

68. An injectable system for intravitreal injection into the vitreous chamber of the eye of a patient, comprising a drug delivery system that comprises:

microparticles having a diameter of 30 μ

m or less including a core which includes the biodegradable polymer polylactide-co-glycolide;

(ii) a coating non-covalently associated with the microparticles;

wherein the coating comprises molecules having a polyethylene glycol hydrophilic region and a hydrophobic region;

(iii) a therapeutically effective amount of an anti-vascular endothelial growth factor agent;

(iv) in a sterile suspension, wherein the sterile suspension includes a suspending agent; and

(x) a device containing a needle for intravitreal injection.

69. The injectable system of claim 68, wherein the patient is a human.