Materials and methods for drug delivery and uptake

• US 20040052865A1
• Filed: 09/13/2002
• Published: 03/18/2004
• Est. Priority Date: 09/13/2002
• Status: Active Grant

• Current Assignee: University of Florida (State University System of Florida)
• Original Assignee: University of Florida (State University System of Florida)
• Inventors: Kurz, Allison, Sheth, Piyush, Gower, Laurie B., Ossenbeck, Michael, Patel, Vishal M.
• Granted Patent: US 7,090,868 B2
• Time in Patent Office: Days
• US Class Current: 424/687
• CPC Class Codes: A61K 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: A61K 9/501 Inorganic compounds

Abstract

The subject invention pertains to novel materials and methods for use in delivering and sequestering substances, such as pharmacological agents, within a patient. One aspect of the invention is directed towards core-shell particles having a core encapsulated within a calcium carbonate shell, with an intermediate layer composed of an amphiphilic compound surrounding the core. When the particles of the subject invention are administered to a patient, they are capable of removing lipophilic drugs by absorption of the drug through their mineral shell and into their core. The particles of the subject invention can also be administered to a patient as controlled release, drug delivery vehicles. Thus, in another aspect, the subject invention concerns a method of delivering pharmacological agents by administering the core-shell particles of the subject invention to a patient in need of such administration.

Claims

1. A core-shell particle comprising:

(a) a shell, wherein said shell comprises calcium carbonate;

(b) a core; and

(c) an intermediate layer between said shell and said core, wherein said intermediate layer comprises an amphiphilic compound, and wherein said core and said intermediate layer are surrounded by said shell.

2. The core-shell particle of claim 1, wherein said core is hollow.

3. The core-shell particle of claim 1, wherein said core comprises a lipophilic liquid.

4. The core-shell particle of claim 3, wherein said lipophilic liquid is an oil.

5. The core-shell particle of claim 4, wherein said oil comprises dodecane.

6. The core-shell particle of claim 3, wherein said lipophilic liquid is selected from the group consisting of cyclohexane, n-hexane, benzene, cottonseed oil, rapeseed oil, squalane, squalene, waxes, styrene, divinylbenzene, butyl acrylate, 2-ethylhexyl acrylate, cyclohexyl acryalate, decyl acrylate, lauryl acrylate, dodecenyl acrylate, myristyl acrylate, palmityl acrylate, hexadecenyl acrylate, stearyl acrylate, octadecenyl acrylate, behenyl acrylate, butyl methacrylate, 2-ethylhexyl methacrylate, cyclohexyl methacrylate, decyl methacrylate, lauryl methacrylate, dodecenyl methacrylate, myristyl methacrylate, palmityl methacrylate, hexadecenyl methacrylate, stearyl methacrylate, octadecenyl methacrylate, behenyl methacrylate, and silicone macromonomers.

7. The core-shell particle of claim 1, wherein said amphiphilic compound has a partially deprotonated carboxylic acid headgroup functionality.

8. The core-shell particle of claim 1, wherein said amphiphilic compound is selected from the group consisting of stearic acid and arachidic acid.

9. The core-shell particle of claim 1, wherein said intermediate layer comprises a film of said amphiphilic compound

10. The core-shell particle of claim 1, wherein said intermediate layer comprises a monolayer of said amphiphilic compound.

11. The core-shell particle of claim 1, wherein said shell is porous.

12. The core-shell particle of claim 1, wherein said shell has a diameter within the range of about 1 μ

m to about 100 μ

m in diameter.

13. The core-shell particle of claim 1, wherein said shell has a diameter within the range of about 1 μ

m to about 50 μ

m in diameter.

14. The core-shell particle of claim 1, wherein said shell has a diameter within the range of about 1 μ

m to about 5 μ

m in diameter.

15. The core-shell particle of claim 1, wherein said shell has a thickness within the range of about 200 nm to about 500 nm in thickness.

16. The core-shell particle of claim 1, wherein said shell has a thickness within the range of about 100 nm to about 1000 nm in thickness.

17. The core-shell particle of claim 1, wherein said intermediate layer comprises stearic acid.

18. The core-shell particle of claim 1, wherein said shell is a sphere.

19. The core-shell particle of claim 1, wherein said core and said intermediate layer are together an emulsion.

20. The core-shell particle of claim 1, wherein said core comprises a biologically active agent.

21. The core-shell particle of claim 3, wherein said core further comprises a biologically active agent.

22. The core-shell particle of claim 20, wherein said biologically active agent is selected from the group consisting of medicaments, vitamins, and mineral supplements.

23. The core-shell particle of claim 20, wherein said biologically active agent is selected from the group consisting of antifungal agents, antibacterial agents, anti-viral agents, anti-parasitic agents, growth factors, angiogenic factors, anaesthetics, mucopolysaccharides, metals, antibodies, antibody fragments, and cells.

24. The core-shell particle of claim 20, wherein said biologically active agent is a lipophilic drug.

25. The core-shell particle of claim 24, wherein said lipophilic drug comprises a tricyclic anti-depressant selected from the group consisting of amitriptyline, clomipramine, desipramine, imipramine, norclomipramine, nortriptyline, and trimipramine.

26. The core-shell particle of claim 1, wherein said core comprises a catabolic enzyme.

27. The core-shell particle of claim 3, wherein said core further comprises a catabolic enzyme.

28. The core-shell particle of claim 27, wherein said catabolic enzyme is a cytochrome P450 enzyme.

29. The core-shell particle of claim 28, wherein said cytochrome P450 enzyme is selected from the group consisting of CYP1A2, CYP2A6, CYP286, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.

30. A method for making a core-shell particle, wherein the method comprises the steps of:

(a) preparing a core; and

(b) encapsulating the core with a calcium carbonate shell.

31. The method according to claim 30, wherein said step (a) comprises forming an emulsion droplet, and wherein said step (b) comprises contacting the emulsion droplet with a calcium-containing solution.

32. The method according to claim 31, wherein the emulsion droplet comprises an oil phase and an amphiphilic compound.

33. The method according to claim 32, wherein the amphiphilic compound has a partially deprotonated carboxylic acid headgroup functionality.

34. The method according to claim 32, wherein the amphiphilic compound is selected from the group consisting of stearic acid and arachidic acid.

35. The method according to claim 31, wherein said method further comprises adding a source of Mg ion to the calcium-containing solution.

36. The method according to claim 31, wherein said method further comprises adding a short-chained acidic polymer to the calcium-containing solution.

37. The method according to claim 36, wherein the short-chained acidic polymer is selected from the group consisting of polyacrylic acid, polymethacrylate, sulfonated polymer, phosphorylated peptide, phosphorylated polymer, sulfated glycoprotein, polyaspartic acid, polyglutamic acid, and copolymers thereof.

38. The method according to claim 37, wherein the short-chained acid polymer comprises poly-(α

,β

)-D,L-aspartic acid.

39. The method according to claim 36, wherein the short-chained acid polymer is added at a concentration within the range of about 1 μ

g/ml and about 100 μ

g/ml.

40. The method according to claim 36, wherein the short-chained acid polymer is added at a concentration of about 10 μ

g/ml.

41. The method according to claim 31, wherein pH of the calcium carbonate solution is within the range of about 7 to about 11.

42. The method according to claim 31, wherein said forming an emulsion droplet comprises contacting a hydrophobic compound with an aqueous solution.

43. The method according to claim 42, wherein said forming an emulsion droplet further comprises adding an amphiphilic compound to the aqueous solution.

44. The method according to claim 43, wherein the amphiphilic compound is selected from the group consisting of stearic acid and arachidic acid.

45. The method according to claim 31, wherein the calcium-containing solution comprises CaCl₂.

46. The method according to claim 31, wherein the calcium-containing solution comprises about 20 mM CaCl₂.

47. The method according to claim 31, wherein the calcium-containing solution further comprises Mg.

48. The method according to claim 47, wherein the calcium-containing solution comprises about a 1:

1 ratio of Ca/Mg.

49. The method according to claim 31, wherein the calcium-containing solution further comprises MgCl₂.

50. The method according to claim 31, wherein the calcium-containing solution further comprises MgCl₂ at a concentration within the range of about 20 mM and about 100 mM.

51. The method according to claim 31, wherein the calcium-containing solution further comprises about 20 mM MgCl₂.

52. The method according to claim 49, wherein the calcium-containing solution further comprises CO₃²⁻

counterion.

53. The method according to claim 52, wherein the calcium-containing solution further comprises about 150 mM CO₃²⁻

counterion.

54. The method according to claim 49, wherein said method further comprises adding CO₃²⁻

counterion to the calcium-containing solution.

55. The method according to claim 54, wherein the CO₃²⁻

counterion is added to the calcium-containing solution by peristaltic pumping.

56. A core-shell particle produced by a method comprising forming an emulsion droplet, contacting the emulsion droplet with a calcium-solution, adding Mg to the solution, and adding a short-chained acid polymer to the solution, wherein said core-shell particle comprises:

(a) a shell, wherein said shell comprises calcium carbonate;

(b) a core; and

(c) an intermediate layer between said shell and said core, wherein said intermediate layer comprises an amphiphilic compound, and wherein said core and said intermediate layer are surrounded by said shell.

57. The core-shell particle of claim 56, wherein said core is hollow.

58. The core-shell particle of claim 56, wherein said core comprises a lipophilic liquid.

59. A method for sequestering a lipophilic agent within a patient comprising administering an effective amount of core-shell particles to the patient, wherein the core-shell particles comprise:

(a) a shell, wherein the shell comprises calcium carbonate;

(b) a core; and

(c) an intermediate layer between the shell and the core, wherein the intermediate layer comprises an amphiphilic compound, and wherein the core and the intermediate layer are surrounded by the shell.

60. The method according to claim 59, wherein the core is hollow.

61. The method according to claim 59, wherein the core comprises an oil.

62. The method according to claim 61, wherein the core further comprises an enzyme that degrades the lipophilic agent.

63. The method according to claim 59, wherein the enzyme comprises a cytochrome P450 enzyme.

64. The method according to claim 62, wherein the lipophilic agent is absorbed into the core-shell particles, and wherein the enzyme subsequently degrades the lipophilic agent.

65. The method according to claim 59, wherein the core-shell particles are administered to the patient intravenously.

66. The method according to claim 59, wherein a toxic amount of the lipophilic agent is present within the patient prior to said administration of the core-shell particles.

67. The method according to claim 62, wherein the enzyme is adsorbed onto the shell of the particles.

68. A method for sequestering a lipophilic agent from the surrounding environment comprising contacting an effective amount of core-shell particles with the lipophilic agent, wherein the core-shell particles comprise:

(a) a shell, wherein the shell comprises calcium carbonate;

(b) a core; and

(c) an intermediate layer between the shell and the core, wherein the intermediate layer comprises an amphiphilic compound, and wherein the core and the intermediate layer are surrounded by the shell.

69. The method according to claim 68, wherein said contacting is carried out in vivo.

70. The method according to claim 68, wherein the surrounding environment is a patient'"'"'s bloodstream.

71. A method for delivering a biologically active agent to a patient comprising administering an effective amount of core-shell particles to the patient, wherein said core-shell particles comprise:

(a) a shell, wherein said shell comprises calcium carbonate;

(b) a core, wherein said core comprises a biologically active agent; and

(c) an intermediate layer between said shell and said core, wherein said intermediate layer comprises an amphiphilic compound, and wherein said core and said intermediate layer are surrounded by said shell.