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Claims for Patent: 6,495,164

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Claims for Patent: 6,495,164

Title: Preparation of injectable suspensions having improved injectability
Abstract:Injectable compositions having improved injectability. The injectable compositions include microparticles suspended in an aqueous injection vehicle having a viscosity of at least 20 cp at 20.degree. C. The increased viscosity of the injection vehicle that constitutes the fluid phase of the suspension significantly reduces in vivo injectability failures. The injectable compositions can be made by mixing dry microparticles with an aqueous injection vehicle to form a suspension, and then mixing the suspension with a viscosity enhancing agent to increase the viscosity of the fluid phase of the suspension to the desired level for improved injectability.
Inventor(s): Ramstack; J. Michael (Lebanon, OH), Riley; M. Gary I. (Cambridge, MA), Zale; Stephen E. (Hopkinton, MA), Hotz; Joyce M. (Cincinnati, OH), Johnson; Olufunmi L. (Cambridge, MA)
Assignee: Alkermes Controlled Therapeutics, Inc. I (Cambridge, MA)
Application Number:09/577,875
Patent Claims: 1. A composition suitable for injection through a needle into a host, comprising: microparticles comprising a polymeric binder, said microparticles having a mass median diameter of at least about 10 .mu.m; and an aqueous injection vehicle, wherein said microparticles are suspended in said injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein a fluid phase of said suspension has a viscosity greater than about 60 cp and less than about 600 cp at 20.degree. C., wherein the viscosity of said fluid phase of said suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.

2. The composition of claim 1, wherein said injection vehicle comprises a viscosity enhancing agent.

3. The composition of claim 2, wherein said viscosity enhancing agent comprises sodium carboxymethyl cellulose.

4. The composition of claim 2, wherein said injection vehicle further comprises a wetting agent.

5. The composition of claim 4, wherein said wetting agent is selected from the group consisting of polysorbate 20, polysorbate 40, and polysorbate 80.

6. The composition of claim 1, wherein said injection vehicle comprises a density enhancing agent.

7. The composition of claim 6, wherein said density enhancing agent comprises sorbitol.

8. The composition of claim 6, wherein said injection vehicle further comprises a wetting agent.

9. The composition of claim 8, wherein said wetting agent is selected from the group consisting of polysorbate 20, polysorbate 40, and polysorbate 80.

10. The composition of claim 1, wherein said injection vehicle comprises a tonicity adjusting agent.

11. The composition of claim 10, wherein said tonicity adjusting agent comprises sodium chloride.

12. The composition of claim 10, wherein said injection vehicle further comprises a wetting agent.

13. The composition of claim 12, wherein said wetting agent is selected from the group consisting of polysorbate 20, polysorbate 40, and polysorbate 80.

14. The composition of claim 1, wherein said injection vehicle comprises 1.5% by volume sodium carboxymethyl cellulose.

15. The composition of claim 1, wherein said injection vehicle comprises 3% by volume sodium carboxymethyl cellulose.

16. The composition of claim 1, wherein said microparticles further comprise an active agent encapsulated within said polymeric binder.

17. The composition of claim 16, wherein said polymeric binder is selected from the group consisting of poly(glycolic acid), poly-d,l-lactic acid; poly-l-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, polyphosphazines, albumin, casein, and waxes.

18. The composition of claim 16, wherein said polymeric binder is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 100:0 to about 50:50.

19. The composition of claim 18, wherein said active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.

20. The composition of claim 1, wherein the mass median diameter of said microparticles is less than about 250 .mu.m.

21. The composition of claim 1, wherein the mass median diameter of said microparticles is in the range of from about 20 .mu.m to about 150 .mu.m.

22. A method for preparing a composition suitable for injection through a needle into a host, comprising: (a) mixing dry microparticles with an aqueous injection vehicle to form a first suspension wherein the concentration of microparticles in the first suspension is greater than about 30 mg/ml; and (b) mixing the first suspension with a viscosity enhancing agent to form a second suspension, wherein the viscosity enhancing agent increases viscosity of a fluid phase of the second suspension to be in the range of from about 20 cp to about 600 cp at 20.degree. C., wherein the viscosity of the fluid phase of the second suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.

23. The method of claim 22, wherein the viscosity of the fluid phase of the second suspension after step (b) is from about 200 cp to about 600 cp at 20.degree. C.

24. The method of claim 23, wherein the viscosity of the aqueous injection vehicle prior to step (b) is less than about 60 cp at 20.degree. C.

25. The method of claim 22, wherein a viscosity of the viscosity enhancing agent is from about 1000 to about 2000 cp at 20.degree. C.

26. The method of claim 22, wherein the viscosity enhancing agent comprises sodium carboxymethyl cellulose.

27. The method of claim 22, wherein a volume of the viscosity enhancing agent mixed with the first suspension is approximately 10-25% of the volume of the first suspension.

28. The method of claim 22, further comprising before step (b): (c) withdrawing the first suspension into a first syringe.

29. The method of claim 28, wherein step (b) comprises: (i) providing a second syringe containing the viscosity enhancing agent; (ii) coupling the first syringe to the second syringe so that fluid can pass between the first and second syringes; and (iii) repeatedly passing the first suspension and the viscosity enhancing agent between the first and second syringes.

30. The method of claim 22, wherein the microparticles comprise a polymeric binder.

31. A composition suitable for injection through a needle into a host prepared by the method of claim 22.

32. A method of administering a composition to a host, comprising: injecting the composition of claim 31 into the host through a needle ranging in diameter from 18-22 gauge.

33. The composition of claim 31, wherein the viscosity of the fluid phase of the second suspension is greater than about 50 cp and less than about 60 cp at 20.degree. C.

34. The composition of claim 31, wherein the microparticles comprise an active agent and a polymeric binder.

35. The composition of claim 34, wherein the polymeric binder is poly (d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 85:15 to about 50:50.

36. The composition of claim 34, wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.

37. A method for administering a composition to a host, comprising: (a) mixing dry microparticles with an aqueous injection vehicle to form a first suspension wherein the concentration of microparticles in the first suspension is greater than about 30 mg/ml; (b) mixing the first suspension with a viscosity enhancing agent to form a second suspension, wherein the viscosity enhancing agent increases viscosity of a fluid phase of the second suspension to be in the range of from about 20 cp to about 600 cp at 20.degree. C.; and (c) injecting the second suspension into the host through a needle ranging in diameter from 18-22 gauge.

38. The method of claim 37, wherein the microparticles comprise a polymeric binder.

39. A method for administering a composition to a host, comprising: (a) mixing dry microparticles with an aqueous injection vehicle to form a suspension wherein the concentration of microparticles in the suspension is greater than about 30 mg/ml, wherein the aqueous injection vehicle prior to mixing has a viscosity at 20.degree. C. of less than about 60 cp; (b) changing the viscosity of a fluid phase of the suspension to be in the range of from about 20 cp to about 600 cp at 20.degree. C.; (c) withdrawing the suspension into a syringe; and (d) injecting the suspension from the syringe into the host through a needle ranging in diameter from 18-22 gauge.

40. The method of claim 39, wherein step (b) comprises: changing the temperature of the fluid phase of the suspension.

41. The method of claim 39, wherein step (c) is performed prior to step (b), and step (b) comprises: adding a viscosity enhancing agent to the suspension in the syringe to thereby increase the viscosity of the fluid phase of the suspension.

42. The method of claim 41, wherein the viscosity enhancing agent comprises sodium carboxymethyl cellulose.

43. The method of claim 39, wherein step (c) is performed prior to step (b).

44. A method of making a composition suitable for injection through a needle into a host, comprising: (a) providing microparticles comprising a polymeric binder, said microparticles having a mass median diameter of at least about 10 .mu.m; (b) providing an aqueous injection vehicle having a viscosity of at least 20 cp at 20.degree. C.; and (c) suspending the microparticles in the aqueous injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein the viscosity of a fluid phase of the suspension is in the range of from about 20 cp to about 600 cp at 20.degree. C., wherein the viscosity of the fluid phase of the suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.

45. A composition suitable for injection through a needle into a host prepared by the method of claim 44.

46. The composition of claim 45, wherein the microparticles further comprise an active agent.

47. The composition of claim 45, wherein the polymeric binder is poly (d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 100:0 to about 50:50.

48. The composition of claim 46, wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.

49. A method for preparing a composition suitable for injection through a needle into a host, comprising: (a) mixing dry microparticles with an aqueous injection vehicle that comprises a viscosity enhancing agent to form a suspension wherein the concentration of microparticles in the suspension is greater than about 30 mg/ml; (b) removing water from the suspension; and (c) reconstituting the suspension with a quantity of sterile water for injection to form an injectable suspension, wherein the quantity of sterile water for injection is sufficient to achieve a viscosity of a fluid phase of the injectable suspension in the range of from about 20 cp to about 600 cp at 20.degree. C. to provide injectability of the injectable suspension through a needle ranging in diameter from 18-22 gauge.

50. The method of claim 49, wherein the viscosity of the fluid phase of the injectable suspension after step (c) is from about 200 cp to about 600 cp at 20.degree. C.

51. The method of claim 49, wherein a viscosity of the viscosity enhancing agent is from about 1000 cp to about 2000 cp at 20.degree. C.

52. The method of claim 49, wherein the viscosity enhancing agent comprises sodium carboxymethyl cellulose.

53. The method of claim 49, wherein step (b) is carried out by vacuum drying.
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