Particulate drug-containing products and method of manufacture

• US 6,669,960 B2
• Filed: 12/18/2000
• Issued: 12/30/2003
• 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): Spear, James M.
• Assistant Examiner(s): DI NOLA BARON, LILIANA
• Application Number:
  US09/740,573
• Publication Number:
  US 20010036480A1
• Time in Patent Office: 1,107 Days
• Field of Search: 424/489, 424/499, 424/43, 424/45, 424/400, 514/2, 514/3
• 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 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• 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 drug-containing powders for pulmonary delivery. The drug 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 drug and powders including a biocompatible polymer for pulmonary sustained drug release applications. Also provided are packaged products including drug-containing powder in a container that is receivable by and operable with a dry powder inhaler to produce an aerosol including dispersed drug-containing particles when the inhaler is actuated.

Claims

1. A method for making a drug-containing particulate product, comprising:

contacting a drug-containing feed solution with a compressed anti-solvent fluid to precipitate drug-containing particles, the feed solution comprising the drug dissolved in mutually soluble solvents of a cosolvent system;

the mutually soluble solvents being mutually soluble when contacted with the compressed anti-solvent fluid during the contacting step and comprising at least a first organic solvent and a second organic solvent at a volume ratio of the second organic solvent to the first organic solvent in a range of from 10;

90 to 99;

1, the drug being at least an order of magnitude more soluble in the first organic solvent than the second organic solvent, and the second organic solvent being more readily extractable by the compressed anti-solvent fluid than the first organic solvent; and

separating the drug-containing particles from the anti-solvent fluid.

2. The method of claim 1, wherein the volume ratio a the second organic solvent to the first organic solvent is larger than 30:

70.

3. The method of claim 1, wherein the volume ratio of the second organic solvent to the first organic solvent is from 50:

50 to 90;

10.

4. The method of claim 1, wherein the first organic solvent is selected from the group consisting of DMSO and DMFA.

5. The method of claim 4, wherein the second organic solvent is an alcohol.

6. The method of claim 4, wherein the second organic solvent is a C1-C5 alkanol.

7. The method of claim 1, wherein the compressed anti-solvent, 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 during the contacting to the critical pressure expressed in atmospheres of the compressed anti-solvent, and the reduced temperature being a ratio of temperature expressed in K of the compressed anti-solvent during the contacting to the critical temperature expressed in K of the compressed anti-solvent.

8. The method of claim 7, wherein the reduced pressure of the compressed anti-solvent, during the contacting, is larger than 0.9.

9. The method of claim 7, wherein the compressed anti-solvent, during the contacting, is in a supercritical state.

10. The method of claim 7, wherein the compressed anti-solvent comprises compressed carbon dioxide.

11. The method of claim 1, wherein the compressed anti-solvent fluid consists essentially of only compressed carbon dioxide.

12. The method of claim 1, wherein the feed solution is substantially free of amphiphillic materials that improve solubility of the drug in the feed solution through hydrophobic ion pairing with the drug.

13. The method of claim 1, wherein, during the contacting step, the solution is introduced into a flow of the compressed anti-solvent fluid with a direction of flow of the solution being at an angle of from 45°

to 180°

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

14. The method of claim 1, wherein the cosolvent system includes water, if at all, in an amount of smaller than 5 weight percent.

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

16. The method of claim 1, wherein the drug is selected from the group consisting of a protein, a peptide and a genetic material.

17. The method of claim 1, wherein the drug is a protein.

18. The method of claim 1, wherein the drug is insulin.

19. The method of claim 1, wherein the concentration of the drug in the feed solution system is smaller than 0.3 mg of the drug per milliliter of the feed solution.

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 of larger than 1 square millimeter.

21. The method of claim 1, wherein the contacting step is conducted under conditions so that the particles have a tap density of larger than 0.1 gram per cubic centimeter.

22. The method of claim 1, wherein the first organic solvent comprises DMSO and the second organic solvent comprises at least one of chloroform, methanol, ethanol and isopropanol.

23. The method of claim 1, wherein the feed solution comprises dipalmitoylphosphatidylcholine and the particles comprise at least a portion of the dipalmitoylphosphatidylcholine.

24. A particulate product comprising the particles made according to the method of claim 1.

25. The method of claim 1, wherein the drug is dissolved in the cosolvent system at a concentration in a range of from 0.1 mg to 5 mg of the drug per milliliter of the cosolvent system.

26. The method of claim 1, wherein the drug is dissolved in the cosolvent system at a concentration in a range of from 0.1 mg to 3 mg of the drug per milliliter of the cosolvent system.

27. The method of claim 1, wherein the second organic solvent is more volatile than the first organic solvent.

28. The method of claim 4, wherein the second organic solvent comprises at least one of chloroform, methanol, ethanol and isopropanol.

29. The method of claim 1, wherein the first organic solvent is DMSO.

30. A particulate product comprising the particles made according to the method of claim 2.

31. A particulate product comprising the particles made according to the method of claim 3.

32. A particulate product comprising the particles made according to the method of claim 4.

33. A particulate product comprising the particles made according to the method of claim 5.

34. A particulate product comprising the particles made according to the method of claim 6.

35. A particulate product comprising the particles made according to the method of claim 7.

36. A particulate product comprising the particles made according to the method of claim 8.

37. A particulate product comprising the particles made according to the method of claim 9.

38. A particulate product comprising the particles made according to the method of claim 10.

39. A particulate product comprising the particles made according to the method of claim 11.

40. A particulate product comprising the particles made according to the method of claim 12.

41. A particulate product comprising the particles made according to the method of claim 13.

42. A particulate product comprising the particles made according to the method of claim 14.

43. A particulate product comprising the particles made according to the method of claim 15.

44. A particulate product comprising the particles made according to the method of claim 16.

45. A particulate product comprising the particles made according to the method of claim 17.

46. A particulate product comprising the particles made according to the method of claim 18.

47. A particulate product comprising the particles made according to the method of claim 19.

48. A particulate product comprising the particles made according to the method of claim 20.

49. A particulate product comprising the particles made according to the method of claim 21.

50. A particulate product comprising the particles made according to the method of claim 22.

51. A particulate product comprising the particles made according to the method of claim 23.

52. A particulate product comprising the particles made according to the method of claim 25.

53. A particulate product comprising the particles made according to the method of claim 26.

54. A particulate product comprising the particles made according to the method of claim 27.

55. A particulate product comprising the particles made according to the method of claim 28.

56. A particulate product comprising the particles made according to the method of claim 29.