pH-triggered microparticles

• US 20050123596A1
• Filed: 09/23/2004
• Published: 06/09/2005
• Est. Priority Date: 09/23/2003
• Status: Abandoned Application

• Current Assignee: Massachusetts Institute of Technology, The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Haining, William Nicholas, Anderson, Daniel G., Langer, Robert S., Kohane, Daniel S., Nadler, Lee M.
• Application Number:
  US10/948,981
• Publication Number:
  US 20050123596A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5192 Processes

Abstract

Microparticles that are designed to release their payload when exposed to acidic conditions are provided as a vehicle for drug delivery. Any therapeutic, diagnostic, or prophylatic agent may be encapsulated in a lipid-protein-sugar or polymeric matrix including a pH triggering agent to form pH triggerable microparticles. Preferably the diameter of the pH triggered microparticles ranges from 50 nm to 10 micrometers. The matrix of the particles may be prepared using any known lipid (e.g., DPPC), protein (e.g., albumin), or sugar (e.g., lactose). The matrix of the particles may also be prepared using any synthetic polymers such as polyesters. Methods of preparing and administering the particles are provided. Methods of immunization, transfection, and gene therapy are also provided by administering pH triggerable microparticles.

Claims

1. A microparticle comprising at least one agent to be delivered, a pH triggering agent, and a polymer, wherein the polymer is selected from the group of polymethacrylates and polyacrylates.

8. The microparticle of claim 1, wherein the pH triggering agent is an acid soluble polymer.

9. The microparticle of claim 1, wherein the pH triggering agent is selected from the group consisting of small molecules, ortho-esters, polymers, proteins, peptides, lipids, synthetic polymers, phospholipids, cationic proteins, polyacrylates, polymethacrylates, poly(beta-amino esters), and acid soluble polymers.

10. The microparticle of claim 1, wherein the pH triggering agent is a lipid or phospholipid.

11. The microparticle of claim 1, wherein the agent is selected from the group consisting of protein, peptide, polynucleotide, organic molecule, drug, and small molecule.

12. The microparticle of claim 1, wherein the agent is an antigen.

13. The microparticle of claim 1, wherein the agent is an antigenic protein.

14. The microparticle of claim 1, wherein the agent is a polynucleotide encoding an antigenic protein.

15. The microparticle of claim 1, wherein the pH triggering agent is a polymethacrylate.

16. The microparticle of claim 1, wherein the pH triggering agent is soluble in an aqueous solution of pH less than 7.

17. The microparticle of claim 1, wherein the pH triggering agent is soluble in an aqueous solution of pH less than 6.

18. The microparticle of claim 1, wherein the pH triggering agent is soluble in an aqueous solution of pH less than 5.

19. The microparticle of claim 1, wherein the pH triggering agent is a cationic protein at pH 7.4.

20. The microparticle of claim 1, wherein the pH triggering agent is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate (1:

2;

1) (Eudragit E100).

21. The microparticle of claim 1, wherein the percentage of pH triggering agent in the microparticle ranges from 1% to 80%.

22. The microparticle of claim 1, wherein the percentage of pH triggering agent in the microparticle ranges from 5% to 50%.

23. The microparticle of claim 1, wherein the percentage of pH triggering agent in the microparticle ranges from 10% to 40%.

24. The microparticle of claim 1, wherein the percentage of pH triggering agent in the microparticle is approximately 20%.

25. The microparticle of claim 1, wherein the percentage of pH triggering agent in the microparticle is at least 20%.

26. The microparticle of claim 1, wherein the density of the microparticle is between 0.3 g/ml and 0.1 g/ml.

27. The microparticle of claim 1, wherein the microparticle is approximately 1 to 10 microns in diameter.

28. The microparticle of claim 1, wherein the microparticle is approximately 2 to 4 microns in diameter.

30. The microparticle of claim 1, wherein the polymer is biocompatible and biodegradable.

2. A microparticle comprising at least one agent to be delivered, a pH triggering agent, and at least two components selected from the group consisting of lipids, proteins, sugars, and polymers.

3. The microparticle of claim 2 comprising at least one agent to be delivered, a pH triggering agent, and at least three components selected from the group consisting of lipids, proteins, sugars, and polymers.

4. The microparticle of claim 2 comprising at least one agent to be delivered, a pH triggering agent, a lipid, a protein, a sugar, and a polymer.

5. The microparticle of claim 2 comprising at least one agent to be delivered, a pH triggering agent, a polymer, and at least one component selected from the group consisting of lipids, proteins, and sugars.

6. The microparticle of claim 2 comprising at least one agent to be delivered and a pH triggering agent, wherein the agent is encapsulated in a lipid-protein-sugar matrix.

7. The microparticle of claim 2 comprising at least one agent to be delivered and a pH triggering agent, wherein the agent is encapsulated in a lipid-protein matrix.

29. The microparticle of claim 2, wherein the polymer is selected from the group consisting of polyesters, polyamides, polycarbonates, polycarbamates, polyacrylates, polymethacrylates, polystyrenes, polyureas, polyether, polythioethers, glycols, and polyamines.

31. A pharmaceutical composition comprising pH triggered microparticles, wherein the microparticles comprise at least one agent to be delivered, a polymer, and a pH triggering agent.

33. The pharmaceutical composition of claim 31, wherein the pH triggering agent is an acid soluble polymer.

35. The pharmaceutical composition of claim 31, wherein the agent is selected from the group consisting of protein, peptide, polynucleotide, organic molecule, drug, and small molecule.

36. The pharmaceutical composition of claim 31, wherein the agent is an antigen.

38. The pharmaceutical composition of claim 31, wherein the pH triggering agent is a polymethacrylate.

39. The pharmaceutical composition of claim 31, wherein the pH triggering agent is soluble in an aqueous solution of pH less than 7.

40. The pharmaceutical composition of claim 31, wherein the pH triggering agent is soluble in an aqueous solution of pH less than 6.

41. The pharmaceutical composition of claim 31, wherein the pH triggering agent is soluble in an aqueous solution of pH less than 5.

42. The pharmaceutical composition of claim 31, wherein the pH triggering agent is a cationic protein at pH 7.4.

43. The pharmaceutical composition of claim 31, wherein the pH triggering agent is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate (1:

2;

1) (Eudragit E110).

46. The pharmaceutical composition of claim 31, wherein the percentage of pH triggering agent in the microparticles ranges from 1% to 80%.

47. The pharmaceutical composition of claim 31, wherein the percentage of pH triggering agent in the microparticles ranges from 5% to 50%.

48. The pharmaceutical composition of claim 31, wherein the percentage of pH triggering agent in the microparticles ranges from 10% to 40%.

49. The pharmaceutical composition of claim 31, wherein the percentage of pH triggering agent in the microparticles is approximately 20%.

50. The pharmaceutical composition of claim 31, wherein the percentage of pH triggering agent in the microparticles is at least 20%.

51. The pharmaceutical composition of claim 31, wherein the density of the microparticles ranges from 0.3 g/ml to 0.1 g/ml.

52. The pharmaceutical composition of claim 31, wherein the microparticles are approximately 1 to 10 microns in diameter.

53. The pharmaceutical composition of claim 31, wherein the microparticles are approximately 2 to 4 microns in diameter.

54. The pharmaceutical composition of claim 31 further comprising an adjuvant.

55. The pharmaceutical composition of claim 54, wherein the adjuvant is selected from the group consisting of lipids, proteins, DNA, DNA-protein, DNA-RNA hybrids, lipoproteins, aptamers, and antibodies.

32. A pharmaceutical composition comprising pH-triggered microparticles of at least one agent encapsulated in a matrix comprising a lipid, a protein, and a pH triggering agent.

34. The pharmaceutical composition of claim 32, wherein the pH-triggered microparticles further comprise a sugar.

37. The pharmaceutical composition of claim 32, wherein the lipid is dipalmitoylphosphatidylcholine (DPPC).

44. The pharmaceutical composition of claim 32, wherein the protein is albumin.

45. The pharmaceutical composition of claim 34, wherein the sugar is lactose.

56. A method of administering a pH-triggered microparticles, the method comprising steps of:

providing a patient;

providing a pharmaceutical composition comprising pH-triggered microparticles comprising at least one agent, a protein, a lipid, and a pH triggering agent;

administering the pharmaceutical composition to the patient.

57. The method of claim 56, wherein the step of administering comprises administering the composition parenterally.

58. The method of claim 56, wherein the step of administering comprises administering the composition inhalationally.

59. The method of claim 56, wherein the step of administering comprises administering the composition orally.

60. The method of claim 56, wherein the step of administering comprises administering the composition to a mucosal surface of the patient.

61. The method of claim 56, wherein the step of administering comprises administering the composition to the skin of the patient.

62. The method of claim 56, wherein the step of administering results in intracellular delivery of the agent to be delivered.

63. The method of claim 56, wherein the agent is an antigen.

64. A method of transfection, the method comprising steps of:

providing at least one cell;

providing a composition comprising pH-triggered microparticles comprising a polynucleotide, a protein, a lipid, and a pH triggering agent;

contacting the cell with the composition to achieve transfection of the polynucleotide into the cell.

65. A method of immunizing a patient, the method comprising steps of:

providing a patient to be immunized;

providing a pharmaceutical composition comprising an antigen encapsulated in a matrix of lipid, protein, and pH triggering agent;

administering an effective amount of the pharmaceutical composition to the patient to stimulate an immune response.

66. The method of claim 65, wherein the antigen is a protein.

67. The method of claim 65, wherein the step of administering comprises administering the composition to a mucosal surface of the patient.

68. A method of treating a patient in need of gene therapy, the method comprising steps of:

providing a patient to be treated;

providing a pharmaceutical composition comprising a polynucleotide encapsulated in a matrix of lipid, protein, and pH triggering agent;

administering an effective amount of the pharmaceutical composition to the patient to result in transfection of at least one cell of the patient.

69. A method of preparing pH-triggered microparticles, the method comprising steps of:

providing an agent;

contacting the agent with a pH triggering agent and at least one component selected from the group consisting of lipids, proteins, sugars, and polymers; and

spray-drying resulting mixture to create microparticles.

70. The method of claim 69, wherein the step of contacting comprises contacting the agent with a pH triggering agent and at least two components selected from the group consisting of lipids, proteins, sugars, and polymers.

71. The method of claim 69, wherein the step of contacting comprises contacting the agent with a pH triggering agent and at least three components selected from the group consisting of lipids, proteins, sugars, and polymers.

72. The method of claim 69, the method comprising steps of:

providing an agent;

contacting the agent with a mixture of a lipid, a protein, and pH triggering agent; and

spray drying resulting mixture to create microparticles.