Aggregating microparticles for medical therapy

• US 10,441,548 B2
• Filed: 11/11/2016
• Issued: 10/15/2019
• Est. Priority Date: 11/12/2015
• Status: Active Grant

• Current Assignee: Graybug Vision, Inc.
• Original Assignee: Graybug Vision, Inc.
• Inventors: Yu, Yun, Kays, Joshua, Yang, Ming, Cleland, Jeffrey L.
• Primary Examiner(s): Park, H. Sarah
• Application Number:
  US15/349,985
• Publication Number:
  US 20170135960A1
• Time in Patent Office: 1,068 Days
• CPC Class Codes: A61K 31/382 having six-membered rings, e.g. thioxanthenes thiothixene A61K31/496
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/542 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• 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 9/5026 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 9/5089 Processes
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics

Abstract

The present invention is a surface treated drug-loaded solid (e.g., non-porous) microparticle that aggregates in vivo to form a consolidated larger particle for medical therapy. In one embodiment, the particles are used for ocular therapy. Processes for producing the surface treated microparticle and injectable formulations which include the surface treated microparticle are also provided. When used in the eye, long-term consistent intraocular delivery can be achieved without disrupting vision and minimizing undesirable inflammatory responses.

Claims

1. Surface-modified solid aggregating microparticles comprising at least one biodegradable polymer, a surfactant, and a therapeutic agent that is encapsulated in the biodegradable polymer wherein the microparticles have a mean diameter between 10 μ

m and 60 μ

m that;

(i) have a solid core with less than 10% porosity by ratio of void space to total volume;

(ii) contain from about 0.001 percent to about 1 percent surfactant and have been surface-modified to contain less surfactant than a microparticle prior to the surface modification wherein the surface has been modified at a temperature less than about 18°

C.; and

(iii) are capable of aggregating in vivo to form at least one pellet of at least 500 μ

m in vivo capable of sustained drug delivery in vivo for at least one month.

2. The surface modified solid aggregating microparticles of claim 1 suitable for injection.

3. The surface modified solid aggregating microparticles of claim 1 suitable for a delivery route selected from the group consisting of intravitreal, intrastromal, intracameral, subtenon, sub-retinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleral, circumcorneal, and tear duct injections.

4. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least two months.

5. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least three months.

6. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least four months.

7. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least five months.

8. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least six months.

9. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of sustained drug delivery for at least seven months.

10. The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a pH between about 6 and about 8.

11. The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a pH between about 6.5 and about 7.5.

12. The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a temperature of less than 16°

C.

13. The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a temperature of less than 10°

C.

14. The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a temperature of less than 8°

C.

15. The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out at a temperature of less than 5°

C.

16. The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 8 percent porosity.

17. The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 7 percent porosity.

18. The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 6 percent porosity.

19. The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 5 percent porosity.

20. The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 4 percent porosity.

21. The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 3 percent porosity.

22. The surface-modified solid aggregating microparticles of claim 1, wherein the solid core comprises a biodegradable polymer with less than 2 percent porosity.

23. The surface-modified solid aggregating microparticles of claim 1, wherein the therapeutic agent is a pharmaceutical drug.

24. The surface-modified solid aggregating microparticles of claim 1, wherein the therapeutic agent is a biologic drug.

25. The surface-modified solid aggregating microparticles of claim 1, wherein the therapeutic agent is sunitinib, or its pharmaceutically acceptable salt.

26. The surface-modified solid aggregating microparticles of claim 1, wherein the therapeutic agent is a tyrosine kinase inhibitor.

27. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a mean diameter between about 20 and 30 μ

m.

28. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a mean diameter between about 20 and 50 μ

m.

29. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a mean diameter between about 25 and 35 μ

m.

30. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a mean diameter between about 20 and 40 μ

m.

31. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a mean diameter between about 25 and 40 μ

m.

32. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 600 μ

m.

33. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter at least 700 μ

m.

34. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 1 mm.

35. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 1.5 mm.

36. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 2 mm.

37. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 3 mm.

38. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 4 mm.

39. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet has a diameter of at least 5 mm.

40. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of releasing not more than about 10 percent by weight of the therapeutic agent in vivo over a 24 hour period.

41. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of releasing not more than about 15 percent by weight of the therapeutic agent in vivo over a 24 hour period.

42. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of releasing not more than about 10 percent by weight of the therapeutic agent in vivo over a 12 hour period.

43. The surface-modified solid aggregating microparticles of claim 1, wherein the at least one pellet is capable of releasing not more than about 15 percent by weight of the therapeutic agent in vivo over a 12 hour period.

44. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a drug loading of 1-40 percent by weight.

45. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a drug loading of 5-25 percent by weight.

46. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a drug loading of 5-15 percent by weight.

47. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles have a drug loading of 0.1-5 percent by weight.

48. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise poly(lactide-co-glycolide).

49. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise poly(lactide-co-glycolide) covalently linked to polyethylene glycol.

50. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise more than one biodegradable polymer.

51. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise both poly(lactide-co-glycolide) and poly(lactide-co-glycolide) covalently linked to polyethylene glycol.

52. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise poly(lactic acid).

53. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise poly(lactic acid) covalently linked to polyethylene glycol.

54. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise both poly(lactic acid) and poly(lactic acid) covalently linked to polyethylene glycol.

55. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise both poly(lactic acid) and poly(lactide-co-glycolide) covalently linked to polyethylene glycol.

56. The surface-modified solid aggregating microparticles of claim 1 wherein the surfactant comprises polyvinyl alcohol.

57. An injectable material that comprises the microparticles of claim 1 in a pharmaceutically acceptable carrier for administration in vivo.

58. The injectable material of claim 57, further comprising a compound that inhibits aggregation of microparticles prior to injection.

59. The injectable material of claim 58 wherein the compound is a sugar.

60. The injectable material of claim 59 wherein the sugar is mannitol.

61. The injectable material of claim 57, further comprising a viscosity enhancer.

62. The injectable material of claim 61, wherein the viscosity enhancer comprises hyaluronic acid.

63. The injectable material of claim 61, wherein the viscosity enhancer comprises sodium hyaluronate.

64. The injectable material of claim 57, wherein the injectable material has a range of concentration of the surface-modified solid aggregating microparticles of about 100-600 mg/ml.

65. The injectable material of claim 57, wherein the injectable material has a range of concentration of the surface-modified solid aggregating microparticles of about 500 or less mg/ml.

66. The injectable material of claim 57, wherein the injectable material has a range of concentration of the surface-modified solid aggregating microparticles of about 300 or less mg/ml.

67. The injectable material of claim 57, wherein the injectable material has a range of concentration of the surface-modified solid aggregating microparticles of about 200 or less mg/ml.

68. The injectable material of claim 57, wherein the injectable material has a range of concentration of the surface-modified solid aggregating microparticles of about 150 or less mg/ml.

69. The surface-modified solid aggregating microparticles of claim 1, wherein the surface modification is carried out on wet microparticles.

70. The surface-modified solid aggregating microparticles of claim 1, wherein the surface treated microparticles are capable of releasing a therapeutic agent over a longer period of time compared to non-surface treated microparticles.

71. The surface-modified solid aggregating microparticles of claim 1, wherein the surface-modified solid aggregating microparticles are more hydrophobic than the microparticles prior to the surface modification.

72. The surface-modified solid aggregating microparticles of claim 1, wherein the surface-modified solid aggregating microparticles are less inflammatory than non-surface treated microparticles.

73. The surface-modified solid aggregating microparticles of claim 1, wherein the therapeutic agent is sunitinib malate.

74. The surface-modified solid aggregating microparticles of claim 73, wherein the microparticles comprise both poly(lactide-co-glycolide) and poly(lactide-co-glycolide) covalently linked to polyethylene glycol.

75. The surface-modified solid aggregating microparticles of claim 74, wherein the microparticles have a mean diameter between about 20 and 30 μ

m.

76. The surface-modified solid aggregating microparticles of claim 74, wherein the microparticles have a mean diameter between about 20 and 40 μ

m.

77. The surface-modified solid aggregating microparticles of claim 74, wherein the surfactant comprises polyvinyl alcohol.

78. The surface-modified solid aggregating microparticles of claim 1, wherein the microparticles comprise poly(lactide-co-glycolide), poly(lactic acid), and poly(lactide-co-glycolide) covalently linked to polyethylene glycol.