Use of polymeric excipients for lyophilization or freezing of particles

Patent metadata

Field	Value
Publication number	US-10076501-B2
Application number	US-201715412897-A
Country	US
Kind code	B2
Filing date	Jan 23, 2017
Priority date	Dec 14, 2011
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

Abstract

Provided herein are use of polymeric excipients, specifically polyvinyl alcohols, optionally in conjunction with sugars, as cryoprotectants to prevent aggregation of PEG-containing particles. Also provided are PEG-containing particles comprising such polymeric excipients.

First claim

What is claimed is:

1. A method of preparing a lyophilized or frozen preparation of a composition comprising solid particles comprising a drug, wherein the solid particles are coated with polyethylene glycol (PEG), the method comprising adding polyvinyl alcohol (PVA) to an aqueous composition comprising the solid particles, and lyophilizing or freezing the aqueous composition;
wherein the drug has a solubility in water of less than about 1 mg/mL at about 25° C.

2. A method of preventing particle aggregation or particle size increase upon lyophilization and resuspension or freezing and thawing of an aqueous composition comprising solid particles comprising a drug, wherein the solid particles are coated with polyethylene glycol (PEG), the method comprising adding polyvinyl alcohol (PVA) to the aqueous particle composition prior to lyophilization or freezing;
wherein the drug has a solubility in water of less than about 1 mg/mL at about 25° C.

3. The method of claim 1 , wherein the concentration of PVA in the aqueous particle composition is between about 0.05% (w/v) to about 1% (w/v).

4. The method of claim 3 , wherein the concentration of PVA in the aqueous particle composition is about 0.1 to about 0.3%.

5. The method of claim 1 , wherein the PVA is about 3K to about 125K.

6. The method of claim 1 , wherein the PVA is at least about 50% hydrolyzed.

7. The method of claim 6 , wherein the PVA is at least about 75% hydrolyzed.

8. The method of claim 1 , wherein the weight ratio of the PVA to the particles in the resultant composition is less than about 0.2:1.

9. The method of claim 1 , wherein the concentration of the particles in the aqueous particle composition is about 1% to about 25% (w/v).

10. The method of claim 1 , wherein the particles comprise a polymeric core matrix coated with PEG.

11. The method of claim 1 , wherein the particles comprise PLA or PLGA.

12. The method of claim 1 , wherein the average particle size of the particles in the particle composition is no greater than about 200 nm.

13. The method of claim 1 , wherein the average size of the particles does not change by more than about 10% upon lyophilization and resuspension or freezing and thawing.

14. The method of claim 1 , further comprising adding a sugar to the aqueous particle composition prior to lyophilization or freezing.

15. The method of claim 14 , wherein the sugar is sucrose.

16. The method of claim 15 , wherein the concentration of sucrose in the aqueous particle composition is between about 5% to about 20%.

17. The method of claim 14 , wherein the sugar and the PVA are added sequentially into the particle composition.

18. The method of claim 1 , wherein the aqueous particle composition to which the PVA is added is free of PVA.

19. The method of claim 1 , wherein the PEG is covalently attached to the surface of the particles or tethered to the surface of the particles by hydrophobic or charge interactions.

20. The method of claim 1 , wherein the PEG is one of the structural components of the particles.

21. The method of claim 1 , wherein the drug is paclitaxel.

22. A pharmaceutical composition comprising solid particles comprising a drug, wherein the solid particles are coated with polyethylene glycol (PEG), wherein the composition further comprises polyvinyl alcohol (PVA), and wherein less than about 2% of the total PVA in the pharmaceutical composition is associated with the solid particles;
wherein the drug has a solubility in water of less than about 1 mg/mL at about 25° C.

23. The pharmaceutical composition of claim 22 , wherein the composition is lyophilized or frozen.

24. The pharmaceutical composition of claim 22 , wherein the composition is an aqueous suspension resuspended from a lyophilized or frozen composition.

25. The pharmaceutical composition of claim 22 , wherein the composition is an aqueous suspension.

26. The pharmaceutical composition of claim 22 , wherein the concentration of PVA in the particle composition is between about 0.05% to about 1%.

27. The pharmaceutical composition of claim 26 , wherein the concentration of PVA in the particle composition is about 0.1% to about 0.3%.

28. The pharmaceutical composition of claim 22 , wherein the PVA is about 3K to about 125K.

29. The pharmaceutical composition of claim 28 , wherein the PVA is about 13K or about 31 K.

30. The pharmaceutical composition of claim 22 , wherein the PVA is at least about 50% hydrolyzed.

31. The pharmaceutical composition of claim 30 , wherein the PVA is at least about 75% hydrolyzed.

32. The pharmaceutical composition of claim 22 , wherein the particles comprise a polymeric matrix core coated with PEG.

33. The pharmaceutical composition of claim 32 , wherein the particles comprise PLA or PLGA.

34. The pharmaceutical composition of claim 22 , wherein the average particle size of the particles in the particle composition is no greater than about 200 nm.

35. The pharmaceutical composition of claim 22 , further comprising a sugar.

36. The pharmaceutical composition of claim 35 , wherein the sugar is sucrose.

37. The pharmaceutical composition of claim 36 , wherein the concentration of sucrose in the particle composition is between about 5% to about 20%.

38. The pharmaceutical composition of claim 22 , wherein the PEG is covalently attached to the surface of the particles or tethered to the surface of the particles by hydrophobic or charge interactions.

39. The pharmaceutical composition of claim 22 , wherein the PEG is one of the structural components of the particles.

40. The pharmaceutical composition of claim 22 , wherein the weight ratio of the PVA to the particles in the composition is less than about 0.2:1.

41. The pharmaceutical composition of claim 22 , wherein the concentration of the particles in the aqueous particle composition is about 1% to about 25% (w/v).

42. The pharmaceutical composition of claim 22 , wherein the pharmaceutical composition is contained in sealed vial.

43. A pharmaceutical composition produced by the method of claim 1 .

44. The pharmaceutical composition of claim 22 , wherein the drug is paclitaxel.

45. The method of claim 14 , wherein the sugar and the PVA are added simultaneously into the particle composition.

46. A method of treating a cancer in an individual comprising administering an effective amount of the pharmaceutical composition of claim 22 to the individual.

Assignees

• Abraxis Bioscience Llc

Inventors

• Foss Willard
• Shinde Rajesh

Classifications

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title

• A61K9/107

  Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)} · CPC title

• A61K9/5031

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide) · CPC title

• A61K9/5192

  Processes · CPC title

• A61K9/0019

  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 title