Particulate insulin-containing products and method of manufacture

• US 6,761,909 B1
• Filed: 12/21/1999
• Issued: 07/13/2004
• Est. Priority Date: 12/21/1999
• Status: Expired due to Term

• Current Assignee: Endo Pharmaceuticals Colorado, Inc.
• Original Assignee: Rxkinetix, Inc. (Endo International PLC)
• Inventors: Etter, Jeffrey B.
• Primary Examiner(s): Carlson, Karen Cochrane
• Assistant Examiner(s): LIU, SAMUEL W
• Application Number:
  US09/469,733
• Time in Patent Office: 1,666 Days
• Field of Search: 424/489, 424/499, 424/43, 424/45, 424/400, 424/501, 424/44-48, 424/490, 424/497, 514/2, 514/3, 514/4, 514/12, 530/303, 530/350, 530/304, 530/418, 426/425, 426/426, 426/330
• US Class Current: 424/489
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Abstract

Provided is a compressed anti-solvent technique for manufacture of insulin-containing powders for pulmonary delivery. The insulin is processed in a cosolvent system including two or more mutually soluble organic solvents. Also provided are powders manufacturable by the manufacture method, including powders of substantially pure insulin and powders including a biocompatible polymer for pulmonary sustained insulin release applications. Also provided are packaged products including insulin-containing powder in a container that is receivable by and operable with a dry powder inhaler to produce an aerosol including dispersed insulin-containing particles when the inhaler is actuated.

Claims

1. A method for making a particulate product containing insulin, the method comprising:

contacting a feed solution containing insulin with a compressed anti-solvent fluid to precipitate particles containing insulin, the feed solution including the insulin in a cosolvent system, the cosolvent system comprising a first organic solvent and a second organic solvent that are mutually soluble, the first organic solvent and the second organic solvent not being the same; and

separating the particles from the first organic solvent, the second organic solvent and the anti-solvent fluid;

wherein the contacting comprises extracting the first organic solvent and the second organic solvent into the anti-solvent fluid; and

wherein the first organic solvent and the second organic solvent are present in the cosolvent system at a volume ratio of the second organic solvent to the first or organic solvent of from 10;

90 to 99;

1.

2. The method of claim 1, wherein insulin is at least 10 times more soluble in the first organic solvent than in the second organic solvent.

3. The method of claim 1, wherein the first organic solvent and the second organic solvent are present in the cosolvent system at a volume ratio of the second organic solvent to the first organic solvent of larger than 30:

70.

4. The method of claim 1, wherein the first organic solvent and the second organic solvent are present in the cosolvent system at a volume ratio of the second organic solvent to the first organic solvent of from 50:

50 to 90;

10.

5. The method of claim 1, wherein the first organic solvent is selected from the group consisting of dimethyl sulfoxide and dimethyl formamide.

6. The method of claim 5, wherein the second organic solvent is an alcohol.

7. The method of claim 5, wherein the second organic solvent is a C1-C5 alkanol.

8. The method of claim 1, wherein the first organic solvent and the second organic solvent are present in the cosolvent system at a volume ratio of the second organic solvent to the first organic solvent of from 10:

90 to 90;

10.

9. The method of claim 8, wherein the concentration of insulin in the cosolvent system is smaller than 3 mg of insulin per milliliter of the feed solution.

10. The method of claim 8, wherein the concentration of insulin in the cosolvent system is in a range of from 0.3 to 3 mg of insulin per milliliter of the solution.

11. The method of claim 9, wherein the compressed anti-solvent fluid, during the contacting, is at a reduced pressure of larger than 0.9 and a reduced temperature of larger than 0.95, the reduced pressure being a ratio of pressure expressed in atmospheres of the compressed anti-solvent fluid during the contacting to the critical pressure expressed in atmospheres of the compressed anti-solvent fluid, and the reduced temperature being a ratio of temperature expressed in K of the compressed anti-solvent fluid during the contacting to the critical temperature expressed in K of the compressed anti-solvent fluid.

12. The method of claim 11, wherein the compressed anti-solvent fluid, during the contacting step, is in a supercritical state.

13. The method of claim 11, wherein, in the feed solution, the insulin is dissolved in the cosolvent system.

14. The method of claim 13, wherein the feed solution includes a biocompatible polymer and the particles are multi-component particles including the insulin and the biocompatible polymer.

15. The method of claim 14, wherein, in the feed solution, both the insulin and the biocompatible polymer are dissolved in the cosolvent system.

16. The method of claim 1, wherein the compressed anti-solvent fluid, during the contacting, is at a reduced pressure of larger than 0.8 and a reduced temperature of larger than 0.95, the reduced pressure being a ratio of pressure expressed in atmospheres of the compressed anti-solvent fluid during the contacting to the critical pressure expressed in atmospheres of the compressed anti-solvent fluid, and the reduced temperature being a ratio of temperature expressed in K of the compressed anti-solvent fluid during the contacting to the critical temperature expressed in K of the compressed anti-solvent fluid.

17. The method of claim 16, wherein the compressed anti-solvent fluid, during the contacting, is at a reduced pressure of larger than 0.9.

18. The method of claim 16, wherein the compressed anti-solvent fluid, during the contacting, is in a supercritical state.

19. The method of claim 16, wherein the compressed anti-solvent fluid comprises compressed carbon dioxide.

20. The method of claim 1, wherein, during the contacting step, the solution is introduced into the compressed anti-solvent fluid through an opening having a cross-sectional area available for flow that is larger than 1 square millimeter.

21. The method of claim 20, wherein the solution, when introduced into the compressed anti-solvent fluid has a direction of flow that is at an angle of from 45°

to 180°

relative to the direction of flow of the compressed anti-solvent fluid.

22. The method of claim 1, wherein the cosolvent system comprises up to 5 weight percent water.

23. The method of claim 1, wherein the cosolvent system is free of water.

24. The method of claim 1, wherein the feed solution comprises colloidal particles of the insulin dispersed in the cosolvent system.

25. The method of claim 1, wherein the feed solution includes a biocompatible polymer and the particles are multi-component particles including the insulin and the biocompatible polymer.

26. The method of claim 25, wherein the insulin is more soluble in the first organic solvent than is the biocompatible polymer, and the biocompatible polymer is more soluble in the second organic solvent than the insulin.

27. The method of claim 25, wherein the biocompatible polymer is hydrophobic, the first organic solvent being a polar solvent for the insulin and the second organic solvent being a nonpolar solvent for the biocompatible polymer.

28. The method of claim 25, wherein the first organic solvent is miscible with water and the second organic solvent is immiscible with water.

29. The method of claim 25, wherein the second organic solvent is selected from the group consisting of methylene chloride, formaldehyde, dioxolane, chloroform, benzene, ethyl ether, toluene, xylene, 1,3-dioxane and tetrahydrofuran.

30. The method of claim 24, wherein the first organic solvent comprises an alcohol.

31. The method of claim 30, wherein the first organic solvent comprises a C1-C5-alkanol.

32. The method of claim 31, wherein the first organic solvent is selected from the group consisting of methanol, ethanol and isopropanol.

33. The method of claim 31, wherein the feed solution further comprises an acid dissolved in the cosolvent system.

34. The method of claim 33, wherein the acid comprises an inorganic acid.

35. The method of claim 33 wherein the acid comprises hydrochloric acid.

36. The method of claim 35, wherein the method comprises, prior to the contacting step, preparing the feed solution, comprising mixing a first solution having the insulin dissolved therein with a second solution having the biocompatible polymer dissolved therein, the first solution including the first organic solvent and the second solution including the second organic solvent.

37. The method of claim 36, wherein during the mixing step, the second solution is added to the first solution.

38. The method of claim 36, wherein the first solution comprises an acid to increase the solubility of the insulin in the first solution.

39. The method of claim 35, wherein the second solution is prepared by dissolving the acid in the second organic solvent and then dissolving the insulin in the second organic solvent.

40. The method of claim 25, wherein the weight ratio of the insulin to the polymer in the feed solution is larger than 5:

95.

41. The method of claim 25, wherein the weight ratio of the insulin to the polymer in the feed solution is in a range of from 5:

95 to 50;

50.

42. The method of claim 25, wherein both of the first organic solvent and the second organic solvent are soluble in the compressed anti-solvent fluid, and during the contacting both of the first organic solvent and the second organic solvent are extracted into the compressed anti-solvent fluid.

43. The method of claim 25, wherein the compressed anti-solvent fluid, during the contacting step, is at a reduced pressure of larger than 0.5 relative to the critical pressure of the anti-solvent fluid, the reduced pressure being a ratio of pressure expressed in atmospheres of the compressed anti-solvent fluid during the contacting to the critical pressure expressed in atmospheres of the compressed anti-solvent fluid.

44. The method of claim 43, wherein the compressed anti-solvent fluid, during the contacting step, is at a reduced temperature of larger than 0.95 relative to the critical temperature of the anti-solvent fluid, the reduced temperature being a ratio of temperature expressed in K of the compressed anti-solvent fluid during the contacting to the critical temperature expressed in K of the compressed anti-solvent fluid.

45. The method of claim 44, wherein the compressed anti-solvent fluid, during the contacting step, is at a reduced pressure of larger than 0.8 relative to the critical pressure of the anti-solvent fluid.

46. The method of claim 25, wherein the compressed anti-solvent fluid, during the contacting step, is in a supercritical state.

47. The method of claim 25, wherein the compressed anti-solvent fluid comprises compressed carbon dioxide.

48. The method of claim 25, wherein the compressed anti-solvent fluid consists essentially of only compressed carbon dioxide.

49. The method of claim 25, wherein during the contacting step, the feed solution is introduced into a flowing stream of the compressed anti-solvent fluid, the direction of flow of the feed solution, when introduced into the flowing stream of the compressed anti-solvent fluid, is at an angle of from ₄₅°

to 180°

relative to the direction of flow of the compressed anti-solvent fluid.

50. The method of claim 25, wherein the multi-component particles have a degree of encapsulation of the insulin by the polymer of greater than 50 percent on a weight basis.

51. The method of claim 25, wherein the multi-component particles have a degree of encapsulation of the insulin by the polymer of greater than 70 percent on a weight basis.

52. The method of claim 25, wherein the biocompatible polymer includes a poly(lactic acid).

53. A method for making a particulate product containing insulin, the method comprising:

contacting, a feed solution containing insulin with a compressed anti-solvent fluid to precipitate particles containing insulin, the feed solution including the insulin in a cosolvent system, the cosolvent system comprising a first organic solvent and a second organic solvent that are mutually soluble, the first organic solvent and the second organic solvent not being the same; and

separating the particles from the first organic solvent, the second organic solvent and the anti-solvent fluid;

wherein the concentration of insulin in the cosolvent system is smaller than 3 mg of insulin per milliliter of the feed solution.

54. The method of claim 53, wherein the concentration of insulin in the cosolvent system is in a range of from 0.3 to 3 mg of insulin per milliliter of the solution.

55. A method for making a particulate product containing insulin, the method comprising:

contacting a feed solution containing insulin with a compressed anti-solvent fluid to precipitate particles containing insulin, the feed solution including the insulin in a cosolvent system, the cosolvent system comprising a first organic solvent and a second organic solvent that are mutually soluble, the first organic solvent and the second organic solvent not being the same; and

separating the particles from the first organic solvent, the second organic solvent and the anti-solvent fluid;

wherein the first organic solvent comprises a C1-C5 alkanol and the second organic solvent comprises methylene chloride.