Microprecipitation of nanoparticulate pharmaceutical agents

• US 5,560,932 A
• Filed: 01/10/1995
• Issued: 10/01/1996
• Est. Priority Date: 01/10/1995
• Status: Expired due to Term

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Nano Systems, Inc.
• Inventors: Karpinski, Piotr H., McIntire, Gregory L., Bagchi, Pranab
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/370,955
• Time in Patent Office: 630 Days
• Field of Search: 424/9.5, 424/489, 424/488, 424/490, 424/9.4
• US Class Current: 424/489
• CPC Class Codes: A61K 49/049 Surface-modified nanoparticles, e.g. immune-nanoparticles
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: Y10S 977/881 Microscopy or spectroscopy, e.g. sem, tem
• CPC Class Codes: Y10S 977/927 Diagnostic contrast agent

Abstract

This invention describes the preparation of nanoparticulate pharmaceutical agent dispersion via a process that comprises the dissolution of the said pharmaceutical agent in an alkaline solution and then neutralizing the said solution with an acid in the presence of a suitable surface-modifying, surface-active agent to form a fine particle dispersion of the said pharmaceutical agent. This can be preferably followed by steps of diafiltration clean-up of the dispersion and then concentration of it to a desired level. This process of dispersion preparation leads to microcrystalline particles of Z-average diameters smaller than 400 nm as measured by photon correlation spectroscopy. Various modification of precipitation schemes are described, many of which are suitable for large-scale manufacture of these agent dispersions.

Claims

1. A process of forming nanoparticulate dispersions of pharmaceutical agents comprising:

first step of dissolution of the pharmaceutical agent in aqueous base,

a second step of adding to it an aqueous solution of one or more surface modifiers and

a third step of neutralizing the formed alkaline solution with an acid to form a dispersion.

2. The process of claim 1 wherein the pharmaceutical agent is selected from:

therapeutic agent and

diagnostic agent.

3. The process of claim 1 wherein the nanoparticulate dispersion is characterized by a Z-average particle diameter less than 400 nm as measured by photon correlation spectroscopy.

4. The process of claim 1 wherein the base is selected from any one or a combination of the following:

NaOH

KOH

CsOH

trialkyl amines and

pyridine.

5. The process of claim 1 wherein the neutralizing acid is selected from:

a weak acid and

a strong acid.

6. The process of claim 1 wherein the neutralizing acid is selected from one of the following:

HCl

HNO₃

HClO₄

H₂ SO₄

formic acid

propionic acid

acetic acid and

butyric acid.

7. The process of claim 1 wherein the surface modifier is a mixture selected from the following:

an anionic surfactant

a nonionic surfactant

a polymeric molecule and

an oligomeric molecule.

8. The process of claim 1 wherein the clean up and concentration of the dispersion is achieved by one of the methods selected from the following:

diafiltration

dialysis and

evaporation.

9. The process of claim 1 wherein the nanoparticulate dispersion is characterized by a Z-average particle diameter less than 300 nm a measured by photon correlation spectroscopy.

10. The process of claim 1 wherein the pharmaceutical agent is a X-ray contrast agent.

11. The process of claim 1 wherein the nanoparticulate pharmaceutical agent is concentrated to contain anywhere between 2 to 20% of the agent.

12. The method of claim 1 practiced in any mode selected from the following:

a batch process,

a semicontinuous batch process and

a continuous process.

27. The process of claim 1 wherein the surface modifier is base degradable.

13. A process of preparing an aqueous dispersion of a pharmaceutical agent comprising:

continuously providing a first solution comprising water and surface modifier or a mixture thereof,

continuously providing a second solution comprising a pharmaceutical agent in aqueous base to mix with the first flow, and

immediately neutralizing with an acid solution to precipitate nanoparticulate dispersion of said pharmaceutical agent as fine particle colloidal dispersions of said pharmaceutical agent, followed by a salt removal step by diafiltration or dialysis and then a step of concentrating the dispersion.

14. The process of claim 13 wherein the pharmaceutical agent is selected from:

therapeutic agent and diagnostic agent.

15. The process of claim 13 wherein the nanoparticulate dispersion is characterized by a Z-average particle diameter less than 400 nm as measured by photon correlation spectroscopy.

16. The process of claim 13 wherein the base is selected from any one or a combination of the following:

NaOH

KOH

CsOH

trialkyl amines and

pyridine.

17. The process of claim 13 wherein the neutralizing acid is selected from:

a weak acid and

a strong acid.

18. The process of claim 13 wherein the neutralizing acid is selected from one of the following:

HCl

HNO₃

HClO₄

H₂ SO₄

formic acid

propionic acid

acetic acid and

butyric acid.

19. The process of claim 13 wherein the surface modifier is a mixture selected from the following:

an anionic surfactant

a nonionic surfactant

a polymeric molecule and

an oligomeric molecule.

20. The process of claim 13 wherein the clean up and concentration of the dispersion is achieved by one of the methods selected from the following:

diafiltration

dialysis and

evaporation.

21. The process of claim 13 wherein the nanoparticulate dispersion is characterized by a Z-average particle diameter less than 300 nm a measured by photon correlation spectroscopy.

22. The process of claim 13 wherein the pharmaceutical agent is a X-ray contrast agent.

23. The process of claim 13 wherein the nanoparticulate pharmaceutical agent is concentrated to contain anywhere between 2 to 20% of the agent.

24. The method of claim 13 practiced in any mode selected from the following:

a batch process,

a semicontinuous batch process and

a continuous process.

25. The process of claim 13 wherein the salt removal step is diafiltration.

26. The process of claim 13 wherein the salt removal step is dialysis.

28. A process of preparing an aqueous dispersions of a pharmaceutical agent comprising:

continuously providing a first flow of a solution comprising water and surface modifier or a mixture thereof,

continuously providing a second flow of a second solution comprising a pharmaceutical agent in aqueous base, and

continuously providing third flow of a neutralizing acid solution, and

mixing the three flows continuously to precipitate a nanoparticulate dispersion of said pharmaceutical agent to form a fine particle dispersion of the said pharmaceutical agent, followed by a salt removal step by diafiltration or dialysis and then a step of concentrating the said dispersion.

29. The process of claim 28 wherein the nanoparticulate dispersion is characterized by a Z-average particle diameter less than 400 nm as measured by photon correlation spectroscopy.

30. The process of claim 28 wherein the base is selected from any one or a combination of the following:

NaOH

KOH

CsOH

trialkyl amines and

pyridine.

31. The process of claim 28 wherein the neutralizing acid is selected from:

a weak acid and

a strong acid.

32. The process of claim 28 wherein the neutralizing acid is selected from one of the following:

HCl

HNO₃

HClO₄

H₂ SO₄

formic acid

propionic acid

acetic acid and

butyric acid.

33. The process of claim 28 wherein the surface modifier is a mixture selected from the following:

an anionic surfactant

a nonionic surfactant

a polymeric molecule and

an oligomeric molecule.

34. The process of claim 28 wherein the clean up and concentration of the dispersion is achieved by one of the methods selected from the following:

diafiltration

dialysis and

evaporation.

35. The process of claim 28 wherein the nanoparticulate dispersion is characterized by a Z-average particle diameter less than 300 nm a measured by photon correlation spectroscopy.

36. The process of claim 28 wherein the pharmaceutical agent is a X-ray contrast agent.

37. The process of claim 28 wherein the nanoparticulate pharmaceutical agent is concentrated to contain anywhere between 2 to 20% of the agent.

38. The method of claim 28 practiced in any mode selected from the following:

a batch process,

a semicontinuous batch process and

a continuous process.

39. The method of claim 28 wherein the surface modifier is base degradable.

40. The process of claim 28 wherein the continuous mixing is carried out in:

a static mixer or

a tubular reactor.

42. The process of claim 40 wherein the nanoparticulate dispersion is characterized by a Z-average particle diameter less than 400 nm as measured by photon correlation spectroscopy.

43. The process of claim 40 wherein the base is selected from any one or a combination of the following:

NaOH

KOH

CsOH

trialkyl amines and

pyridine.

44. The process of claim 40 wherein the neutralizing acid is selected from:

a weak acid and

a strong acid.

45. The process of claim 40 wherein the neutralizing acid is selected from one of the following:

HCl

HNO₃

HClO₄

H₂ SO₄

formic acid

propionic acid

acetic acid and

butyric acid.

46. The process of claim 40 wherein the surface modifier is a mixture selected from the following:

an anionic surfactant

a nonionic surfactant

a polymeric molecule and

an oligomeric molecule.

47. The process of claim 40 wherein the clean up and concentration of the dispersion is achieved by one of the methods selected from the following:

diafiltration

dialysis and

evaporation.

48. The process of claim 40 wherein the nanoparticulate dispersion is characterized by a Z-average particle diameter less than 300 nm a measured by photon correlation spectroscopy.

49. The process of claim 40 wherein the pharmaceutical agent is a X-ray contrast agent.

50. The process of claim 40 wherein the nanoparticulate pharmaceutical agent is concentrated to contain anywhere between 2 to 20% of the agent.

51. The method of claim 40 practiced in any mode selected from the following:

a batch process,

a semicontinuous batch process and

a continuous process.

52. The surface modifier of the process of claim 40 is base degradable.

54. The process of claim 52 wherein the neutralization pH is at any pH value between 3.0 and 7.0.

55. The process of claim 52 wherein the surface modifier is base degradable.

41. A process of preparing an aqueous dispersions of a pharmaceutical agent comprising:

continuously providing a first solution comprising water and surface modifier or a mixture thereof into a solution comprising a pharmaceutical agent in aqueous base to form a first flow, and then neutralizing the first flow with a second flow of an acid solution at a desired pH to form a fine particle dispersion of a pharmaceutical agent,

followed by a step of salt removal by diafiltration or dialysis and then a step of concentrating the said dispersion.

53. A process of preparing aqueous dispersions of a pharmaceutical agent comprising:

continuously providing a first solution comprising water and surface modifier or a mixture thereof into a solution comprising a pharmaceutical agent in aqueous base to form a first flow, and then neutralizing the first flow with a second flow of an acid solution at a desired pH to form a fine particle dispersion of a pharmaceutical agent,

followed by a step of salt removal by diafiltration or dialysis and then a step of concentrating the said dispersion.