Extended release microparticles and suspensions thereof for medical therapy

1. A solid aggregating biodegradable microparticle comprising a prodrug of a therapeutically active compound, encapsulated in (a) poly(lactic-co-glycolic acid) (PLGA) and/or polylactic acid (PLA) and (b) poly(lactic-co-glycolic acid) (PLGA) covalently bound to polyethylene glycol (PEG) and/or polylactic acid (PLA) covalently bound to polyethylene glycol (PEG), and a surfactant, wherein the microparticle

(i) has a mean diameter between 20 μm and 40 μm;

(ii) has been surface-modified with a surface-treatment agent to partially degrade surface polymer at a temperature less than about 18° C. wherein the surface-treatment agent is selected from (a) an aqueous base/alcohol, (b) an aqueous acid/alcohol, (c) phosphate buffered saline/alcohol, or (d) water/alcohol;

(iii) aggregates in vivo to form at least one pellet of at least 500 μm in vivo that provides sustained drug delivery in vivo for at least three months; and

(v) wherein the prodrug is of the formula:

or a pharmaceutically acceptable salt thereof

wherein

y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

y′ is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. The solid aggregating microparticle of claim 1 , wherein the prodrug is selected from

or a pharmaceutically acceptable salt thereof.

3. The solid aggregating microparticle of claim 1 in a dosage form for a delivery route selected from the group consisting of intravitreal, intrastromal, intracameral, subtenon, sub-retinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, epi scleral, posterior juxtascleral, circumcorneal, and tear duct injections.

4. The solid aggregating microparticle of claim 1 , wherein the at least one pellet provides sustained drug delivery for at least 4 months.

5. The solid aggregating microparticle of claim 1 , wherein the microparticle comprises PLGA and PLGA-PEG.

6. The solid aggregating microparticle of claim 5 , wherein the ratio of PLGA/PLGA-PEG is about 99/1.

7. The solid aggregating microparticle of claim 1 , wherein the microparticle comprises PLA and PLGA-PEG.

8. The solid aggregating microparticle of claim 7 , wherein the ratio of PLA/PLGA-PEG is about 99/1.

9. The solid aggregating microparticle of claim 1 , wherein the microparticle comprises PLGA, PLA, and PLGA-PEG.

10. The solid aggregating microparticle of claim 9 , wherein the PLGA-PEG is in an amount from about 0.5 percent to about 10 percent.

11. The solid aggregating microparticle of claim 1 , wherein the microparticle comprises (i) PLGA; (ii) PLGA wherein the PLGA in (ii) has a different ratio of lactide to glycolide than the PLGA in (i); and, (iii) PLGA-PEG.

12. The solid aggregating microparticle of claim 7 , wherein the PLA is acid end-capped.

13. The solid aggregating microparticle of claim 7 , wherein the PLA is ester end-capped.

14. The solid aggregating microparticle of claim 5 , wherein the PLGA-PEG is PLGA45k-PEG5k.

15. The solid aggregating microparticle of claim 1 , wherein y is selected from 1, 2, 3, 4, 5, and 6.

16. The solid aggregating microparticle of claim 1 , wherein y is 1, 2, 3, 4, 5, or 6 and y′ is 1, 2, 3, 4, 5, or 6.

17. The solid aggregating microparticle of claim 16 , wherein y is 2, 3, or 4 and y′ is 2, 3, or 4.

18. The solid aggregating microparticle of claim 1 , wherein the alcohol is selected from ethanol, propanol, and 2-propanol.

19. The solid aggregating microparticle of claim 18 , wherein the alcohol is ethanol.

20. The solid aggregating microparticle of claim 1 , wherein the surface-treatment agent is an aqueous acid/alcohol and the aqueous acid is selected from hydrochloric acid, hydrobromic acid, and sulfuric acid.

21. The solid aggregating microparticle of claim 1 , wherein the surface-treatment agent is an aqueous base/alcohol.

22. The solid aggregating microparticle of claim 21 , wherein the aqueous base is a hydroxide base.

23. The solid aggregating microparticle of claim 22 , wherein the hydroxide base is selected from sodium hydroxide and potassium hydroxide.

24. The solid aggregating microparticle of claim 21 , wherein the alcohol is ethanol.

25. The solid aggregating microparticle of claim 21 , wherein the surface-treatment agent is ethanol and sodium hydroxide.

26. The solid aggregating microparticle of claim 1 , wherein at least one pellet provides sustained drug delivery for at least 5 months.

27. The solid aggregating microparticle of claim 1 , wherein at least one pellet provides sustained drug delivery for at least 6 months.

28. The solid aggregating microparticle of claim 2 , wherein the prodrug is

or a pharmaceutically acceptable salt thereof.

29. The solid aggregating microparticle of claim 2 , wherein the prodrug is

or a pharmaceutically acceptable salt thereof.

30. The solid aggregating microparticle of claim 1 , wherein the prodrug is

or a pharmaceutically acceptable salt thereof.

31. The solid aggregating microparticle of claim 1 with a mean diameter between 25 μm and 40 μm.

32. The solid aggregating microparticle of claim 28 with a mean diameter between 25 μm and 40 μm.

33. The solid aggregating microparticle of claim 29 with a mean diameter between 25 μm and 40 μm.

34. The solid aggregating microparticle of claim 30 with a mean diameter between 25 μm and 40 μm.

35. The solid aggregating microparticle of claim 28 , wherein the microparticle comprises PLGA and PLGA-PEG.

36. The solid aggregating microparticle of claim 29 , wherein the microparticle comprises PLGA and PLGA-PEG.

37. The solid aggregating microparticle of claim 30 , wherein the microparticle comprises PLGA and PLGA-PEG.

38. The solid aggregating microparticle of claim 35 , wherein the ratio of PLGA/PLGA-PEG is about 99/1.

39. The solid aggregating microparticle of claim 36 , wherein the ratio of PLGA/PLGA-PEG is about 99/1.

40. The solid aggregating microparticle of claim 35 , wherein the PLGA-PEG is PLGA45k-PEG5k.

41. The solid aggregating microparticle of claim 36 , wherein the PLGA-PEG is PLGA45k-PEG5k.

42. The solid aggregating microparticle of claim 28 , wherein the at least one pellet provides sustained drug delivery for at least 4 months.

43. The solid aggregating microparticle of claim 29 , wherein the at least one pellet provides sustained drug delivery for at least 4 months.

44. The solid aggregating microparticle of claim 30 , wherein at least one pellet provides sustained drug delivery for at least 4 months.

45. The solid aggregating microparticle of claim 28 , wherein the surface-treatment agent is an aqueous base/alcohol.

46. The solid aggregating microparticle of claim 29 , wherein the surface-treatment agent is an aqueous base/alcohol.

47. The solid aggregating microparticle of claim 30 , wherein the surface-treatment agent is an aqueous base/alcohol.

48. The solid aggregating microparticle of claim 45 , wherein the alcohol is selected from ethanol, propanol, and 2-propanol.

49. The solid aggregating microparticle of claim 46 , wherein the alcohol is selected from ethanol, propanol, and 2-propanol.

50. The solid aggregating microparticle of claim 48 , wherein the alcohol is ethanol.

51. The solid aggregating microparticle of claim 49 , wherein the alcohol is ethanol.

52. The solid aggregating microparticle of claim 45 , wherein the aqueous base is a hydroxide base.

53. The solid aggregating microparticle of claim 46 , wherein the aqueous base is a hydroxide base.

54. The solid aggregating microparticle of claim 52 , wherein the hydroxide base is selected from sodium hydroxide and potassium hydroxide.

55. The solid aggregating microparticle of claim 53 , wherein the hydroxide base is selected from sodium hydroxide and potassium hydroxide.

56. The solid aggregating microparticle of claim 45 , wherein the surface-treatment agent is ethanol and sodium hydroxide.

57. The solid aggregating microparticle of claim 46 , wherein the surface-treatment agent is ethanol and sodium hydroxide.