Compositions and methods for administration of pharmacologically active compounds

• US 6,537,579 B1
• Filed: 05/19/2000
• Issued: 03/25/2003
• Est. Priority Date: 02/22/1993
• Status: Expired due to Fees

• Current Assignee: Abraxis Bioscience LLC (Bristol-Myers Squibb Company)
• Original Assignee: American Bioscience, Inc. (Bristol-Myers Squibb Company)
• Inventors: Soon-Shiong, Patrick, Desai, Neil P.
• Primary Examiner(s): Pryor, Alton
• Application Number:
  US09/574,763
• Time in Patent Office: 1,040 Days
• Field of Search: 424/489
• US Class Current: 424/489
• CPC Class Codes: A23L 33/40 Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 9/0026 Blood substitute; Oxygen transporting formulations; Plasma extender
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/5052 Proteins, e.g. albumin
• CPC Class Codes: A61K 9/5169 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: Y10S 977/729 From protein or unit thereof, e.g. enzyme or carboxyl group
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/775 Nanosized powder or flake, e.g. nanosized catalyst
• CPC Class Codes: Y10S 977/896 Chemical synthesis, e.g. chemical bonding or breaking
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

In accordance with the present invention, there are provided compositions and methods useful for the in vivo delivery of substantially water insoluble pharmacologically active agents (such as the anticancer drug paclitaxel) in which the pharmacologically active agent is delivered in the form of suspended particles coated with protein (which acts as a stabilizing agent). In particular, protein and pharmacologically active agent in a biocompatible dispersing medium are subjected to high shear, in the absence of any conventional surfactants, and also in the absence of any polymeric core material for the particles. The procedure yields particles with a diameter of less than about 1 micron. The use of specific composition and preparation conditions (e.g., addition of a polar solvent to the organic phase), and careful election of the proper organic phase and phase fraction, enables the reproducible production of unusually small nanoparticles of less than 200 nm diameter, which can be sterile-filtered. The particulate system produced according to the invention can be converted into a redispersible dry powder comprising nanoparticles of water-insoluble drug coated with a protein, and free protein to which molecules of the pharmacological agent are bound. This results in a unique delivery system, in which part of the pharmacologically active agent is readily bioavailable (in the form of molecules bound to the protein), and part of the agent is present within.

Claims

1. A method for the delivery of substantially water insoluble pharmacologically active agents to a subject, said method comprising administering to said subject an effective amount of composition prepared by subjecting a mixture comprising:

an organic phase containing said pharmacologically active agents dispersed therein, and

aqueous medium containing biocompatible polymer,

wherein said mixture optionally contains substantially no surfactants, to high shear conditions in a high pressure homogenized at a pressure in the range of about 100 up to 100,000 psi.

2. A method according to claim 1 wherein said composition further comprises one or more of albumin, a polyalkylene glycol, or an oil.

3. A method according to claim 2 wherein said oil is an oil-soluble vitamin.

4. A method according to claim 3 wherein said vitamin is vitamin A, vitamin D, vitamin E or vitamin K.

5. A method according to claim 1 wherein said pharmacologically active agent is selected from the group of an anti-neoplastic, an anesthetic and a hormone.

6. A method according to claim 5 wherein said anti-neoplastic is a taxane.

7. A method according to claim 1 wherein said pharmacologically active agent is non-crystalline.

8. A method according to claim 5 wherein said anesthetic is propofol.

9. A method according to claim 5 wherein said hormone is a thyroid hormone.

10. A method for eliminating cancer cells with a cremophor free oncolytic comprising particles of an antineoplastic coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said antineoplastic is contained within said protein coating and a portion of said antineoplastic is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron.

11. A method according to claim 10 wherein the average diameter of said particles is less than 200 nm.

12. A method according to claim 11 wherein said cremophor free onolytic is sterile filtered.

13. A method according to claim 10 wherein said particles are amorphous, crystalline, or a mixture thereof.

14. A method according to claim 13 wherein said particles are substantially amorphous.

15. A method according to claim 10 wherein said antineoplastic is paclitaxel and said protein is albumin.

16. A method for reducing liver sequestration of pharmaceutical agents, said method comprising administering an effective amount of said pharmaceutical agent as part of a drug delivery system comprising particles of a solid or liquid, substantially water insoluble pharmacologically active agent, coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said pharmacologically active agent is contained within said protein coating and a portion of said pharmacologically active agent is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron.

17. A method according to claim 16 wherein said pharmacologically active agent is paclitaxel and said protein is albumin.

18. A method according to claim 16 wherein said pharmaceutical agent is selected from the group consisting of an anti-neoplastic, an anesthetic and a hormone.

19. A method according to claim 18 wherein said anti-neoplastic is a taxane.

20. A method according to claim 18 wherein said anesthetic is propofol.

21. A method according to claim 18 wherein said hormone is a thyroid hormone.

22. A method for the administration of paclitaxel to a patient in need thereof employing a dosing solution containing >

1 mg/ml of paclitaxel, said method comprising administering said paclitaxel as part of a drug delivery system comprising particles of a solid or liquid, substantially water insoluble pharmacologically active agent, coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said pharmacologically active agent is contained within said protein coating and a portion of said pharmacologically active agent is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron.

23. A method for the administration of paclitaxel to a patient in need thereof employing a total infusion volume for each effective dose of <

300 ml of paclitaxel-containing medium, said method comprising administering said paclitaxel as part of a drug delivery system comprising particles of a solid or liquid, substantially water insoluble pharmacologically active agent, coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said pharmacologically active agent is contained within said protein coating and a portion of said pharmacologically active agent is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron.

24. A method for the rapid administration of paclitaxel to a patient in need thereof, said method comprising administering said paclitaxel as part of a drug delivery system comprising particles of a solid or liquid, substantially water insoluble pharmacologically active agent, coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said pharmacologically active agent is contained within said protein coating and a portion of said pharmacologically active agent is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron.

25. A method of administering a pharmacologically active agent which must be administered in multiple doses, said method comprising administering the pharmacologically active agent, as part of a drug delivery system comprising particles of a solid or liquid, substantially water insoluble pharmacologically active agent, coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said pharmacologically active agent is contained within said protein coating and a portion of said pharmacologically active agent is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron, over a reduced cycle time.

26. A method according to claim 25 wherein said pharmacologically active agent is selected from the group consisting of an anti-neoplastic, an anesthetic and a hormone.

27. A method according to claim 26 wherein said anti-neoplastic is a taxane.

28. A method according to claim 26 wherein said anesthetic is propofol.

29. A method according to claim 26 wherein said hormone is a thyroid hormone.

30. A method of reducing the myelosuppressive effects of a pharmacologically active agent administered to a patient in need thereof, said method comprising administering the pharmacologically active agent, as part of a drug delivery system comprising particles of a solid or liquid, substantially water insoluble pharmacologically active agent, coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said pharmacologically active agent is contained within said protein coating and a portion of said pharmacologically active agent is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron, over a reduced cycle time.

31. A method of reducing the neurotoxic effects of a pharmacologically active agent administered to a patient in need thereof, said method comprising administering the pharmacologically active agent, as part of a drug delivery system comprising particles of a solid or liquid, substantially water insoluble pharmacologically active agent, coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said pharmacologically active agent is contained within said protein coating and a portion of said pharmacologically active agent is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron, over a reduced cycle time.

32. A method of administering pharmacologically active agent(s) to a patient having a disease capable of treatment by the pharmacologically active agent(s), said method comprising administering to the patient the pharmacologically active agent(s), as part of a drug delivery system comprising particles of a solid or liquid, substantially water insoluble pharmacologically active agent, coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said pharmacologically active agent is contained within said protein coating and a portion of said pharmacologically active agent is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron.

33. The method of claim 32, wherein the disease is a proliferative disease and the pharmacologically active agent(s) comprises an anti-neoplastic agent.

34. The method of claim 32, wherein the disease is a cancer treatable by systemic administration of pharmacologically active agent(s), the administration is intravenous, and the pharmacologically active agent(s) comprises an anti-neoplastic agent.

35. The method of claim 32, wherein the disease is a cancer treatable by systemic administration of pharmacologically active agent(s), the administration is intraarterial, and the pharmacologically active agent(s) comprises an anti-neoplastic agent.

36. The method of claim 32, wherein the administration of the composition is done without administration corticosteroid premedication.

37. The method of claim 36, wherein the administration of the composition is done in combination with administration of biochemotherapy agent(s).

38. The method of claim 32, wherein the administration of the composition is done without administration of cytokines.

39. A method according to claim 32 wherein said pharmacologically active agent is non-crystalline.

40. A method of delivering pharmacologically active agent(s) to a localized area of a patient for sustained release of the pharmacologically active agent over an extended period of time, said method comprising administering to the patient the pharmacologically active agent(s), as part of a drug delivery system comprising particles of a solid or liquid, substantially water insoluble pharmacologically active agent, coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said pharmacologically active agent is contained within said protein coating and a portion of said pharmacologically active agent is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron, wherein the composition has been dispersed within a matrix of suitable biocompatible material prior to administration to the patient.

41. A method according to claim 40 wherein said pharmacologically active agent is selected from the group consisting of an anti-neoplastic, an anesthetic and a hormone.

42. A method according to claim 41 wherein said anti-neoplastic is a taxane.

43. A method according to claim 41 wherein said anti-neoplastic is propofol.

44. A method according to claim 41 wherein said hormone is a thyroid hormone.

45. A method of orally administering pharmacologically active agent(s) to a patient in need thereof, said method comprising orally administering the pharmacologically active agent(s), as part of a drug delivery system comprising particles of a solid or liquid, substantially water insoluble pharmacologically active agent, coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said pharmacologically active agent is contained within said protein coating and a portion of said pharmacologically active agent is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron, in combination with intestinal cell efflux inhibitor(s).

46. A method according to claim 45 wherein said pharmacologically active agent is selected from the group consisting of an anti-neoplastic and a hormone.

47. A method according to claim 45 wherein said anti-neoplastic is a taxane.

48. A method according to claim 45 wherein said hormone is a thyroid hormone.

49. A method of administering a combination of pharmacologically active agent(s) to a patient in need thereof, said method comprising administering to the patient 25-75% of the generally accepted effective dosage level of each of the pharmacologically active agent(s), as part of a drug delivery system comprising particles of a solid, or liquid, substantially water insoluble pharmacologically active agent, coated with protein,

wherein said protein coating has free protein associated therewith,

wherein a portion of said pharmacologically active agent is contained within said protein coating and a portion of said pharmacologically active agent is associated with said free protein, and

wherein the average diameter of said particles is no greater than about 1 micron.

50. A method according to claim 49 wherein said pharmacologically active agent is selected from the group consisting of an anti-neoplastic, an anesthetic and a hormone.

51. A method according to claim 50 wherein said anti-neoplastic is a taxane.

52. A method according to claim 50 wherein said anesthetic is propofol.

53. A method according to claim 50 wherein said hormone is a thyroid hormone.