Coated Controlled Release Polymer Particles as Efficient Oral Delivery Vehicles for Biopharmaceuticals

• US 20080268063A1
• Filed: 11/04/2005
• Published: 10/30/2008
• Est. Priority Date: 11/04/2004
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Langer, Robert S., Jon, Sangyong, Cheng, Jianjun, Farokhazd, Omid C.
• Granted Patent: US 9,492,400 B2
• Time in Patent Office: Days
• US Class Current: 424/491
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0065 Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
• CPC Class Codes: A61K 9/5036 Polysaccharides, e.g. gums, alginate; Cyclodextrin
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5192 Processes

Abstract

A composition for delivering an active agent to a patient. The composition includes a polymer core encapsulating the active agent and a mucoadhesive coating disposed about the core. The polymer may include covalently linked poly(ethylene glycol) chains, and the mucoadhesive coating may be selected to facilitate transfer of the particle through the intestinal mucosa. A molecular weight and cross-link density of the polymer may be selected such that the polymer core will decompose in a predetermined time interval. The fraction of the dose of the drug entering the system at circulation during the predetermined time interval may be between about 0.25% and about 25%. The composition may be formulated as a plurality of nanoparticles or microparticles that are combined with a pharmaceutically acceptable carrier to produce an edible or inhalable drug product.

Claims

1. A composition for delivering an active agent to a patient, comprising:

a polymer core encapsulating a predetermined amount of the active agent; and

a mucoadhesive coating disposed about the core to form a coated particle, wherein

the polymer is derivatized with a poly(alkylene glycol), the mucoadhesive coating is retained on the core through one or more of covalent interactions, electrostatic interactions, affinity interactions, metal coordination, physical adsorption, host-guest interactions, and hydrogen bonding interactions,

a molecular weight and cross-link density of the polymer is selected such that the polymer core will decompose in a predetermined time interval,

the mucoadhesive coating is selected to facilitate transfer of the particle through the intestinal mucosa, and

a fraction of the predetermined amount of the active agent entering the systemic circulation during the predetermined time interval is between about 0.25% and about 25%.

2. The composition of claim 1, further comprising a targeting agent disposed under the mucoadhesive coating.

3. The composition of claim 2, further comprising an intermediate layer disposed between the targeting agent and the mucoadhesive coating.

4. The composition of claim 3, wherein the intermediate layer comprises a first material and the mucoadhesive coating comprises a second material, wherein the first material and the second material have opposing electrostatic charges at pH 2.

5. The composition of claim 4, wherein the first material and the second material do not have opposing electrostatic charges at pH 7.4.

6. The composition of claim 3, wherein the intermediate layer comprises a biodegradable polymer.

7. The composition of claim 2, wherein the targeting agent is disposed at a surface portion of the polymer core.

8. The composition of claim 2, wherein the targeting agent is disposed at a surface portion of the polymer core and is also disposed at an interior portion of the polymer core.

9. The composition of claim 2, wherein the targeting agent is selected from nucleic acid aptamers, growth factors, hormones, cytokines, interleukins, antibodies, integrins, fibronectin receptors, p-glycoprotein receptors, and cell binding sequences.

10. The composition of claim 1, wherein the fraction of the dose of the drug entering the systemic circulation during the predetermined time interval is between about 5% and about 20%.

11. The composition of claim 1, wherein the fraction of the dose of the drug entering the systemic circulation during the predetermined time interval is between about 10% and about 15%.

12. The composition of claim 1, wherein the mucoadhesive coating is retained on the core though electrostatic interactions.

13. The composition of claim 1, wherein the core comprises PEGylated poly(lactic acid).

14. The composition of claim 1, wherein the poly(alkylene glycol) is carboxylated.

15. The composition of claim 1 wherein the poly(alkylene glycol) is selected from poly(ethylene glycol) and poly(propylene glycol).

16. The composition of claim 1, wherein the poly(alkylene glycol) has a molecular weight between about 100 and about 7000 Daltons.

17. The composition of claim 16, wherein the poly(alkylene glycol) has a molecular weight between about 100 and about 1000 Daltons.

18. The composition of claim 16, wherein the poly(alkylene glycol) has a molecular weight between about 1000 and about 3500 Daltons.

19. The composition of claim 16, wherein the poly(alkylene glycol) has a molecular weight between about 3500 and 7000 Daltons.

20. The composition of claim 1, wherein the polymer is a biodegradable polymer or a non-biodegradable polymer.

21. The composition of claim 20, wherein the biodegradable polymer is selected from poly(arylates), poly(anhydrides), poly(hydroxy acids), polyesters, poly(lactic acid), poly(glycolic acid), poly(ortho esters), polycarbonates, poly(propylene fumerates), poly(caprolactones), polyamides, polyphosphazenes, polyamino acids, polyethers, polyacetals, polylactides, polyhydroxyalkanoates, polyglycolides, polyketals, polyesteramides, poly(dioxanones), polyhydroxybutyrates, polyhydroxyvalyrates, polycarbonates, polyorthocarbonates, poly(vinyl pyrrolidone), biodegradable polycyanoacrylates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(methyl vinyl ether), poly(ethylene imine), poly(acrylic acid), poly(maleic anhydride), biodegradable polyurethanes, polysaccharides, PEG-functionalized derivatives of the above, co-polymers of the above, adducts of the above, and mixtures of the above.

22. The composition of claim 20, wherein the non-biodegradable polymer is selected from polystyrene, polyesters, non-biodegradable polyurethanes, polyureas, poly(vinyl alcohol), polyamides, poly(tetrafluoroethylene), poly(ethylene vinyl acetate), polypropylene, polyacrylate, non-biodegradable polycyanoacrylates, non-biodegradable polyurethanes, polymethacrylate, poly(methyl methacrylate), polyethylene, polypyrrole, polyanilines, polythiophene, poly(ethylene oxide), PEG-functionalized derivatives of the above, co-polymers of the above, adducts of the above, and mixtures of the above.

23. The composition of claim 1, wherein the coating comprises chitosan, poly(lysine), poly(ethylene imine), lecithin, lectin, polycarboxylic acids, poly(acrylic acids), polysaccharides, hydrogels, monosaccharides, oligosaccharides, oligopeptides, polypeptides, co-polymers of the above, or any combination of the above.

24. The composition of claim 1, wherein the coating comprises chitosan, lectin, or both.

25. The composition of claim 1, wherein the coating is a block co-polymer having a mucoadhesive block and a block that is adapted to participate in an interaction selected from electrostatic interactions, affinity interactions, metal coordination, physical adsorption, host-guest interactions, and hydrogen bonding interactions.

26. The composition of claim 1, wherein the active agent is a biomolecule, bioactive agent, small molecule, drug, protein, vaccine, or polynucleotide.

27. The composition of claim 26, wherein the active agent is a vaccine.

28. The composition of claim 26, wherein the active agent is a protein.

29. The composition of claim 28, wherein the active agent is insulin.

30. A composition for administering an active agent to a patient, comprising:

a plurality of particles, each particle comprising a polymer core encapsulating a predetermined amount of the active agent and a mucoadhesive coating disposed about the core to form a coated particle; and

a pharmaceutically acceptable carrier combined with the plurality of particles, wherein the pharmaceutically acceptable carrier is edible or inhalable, wherein;

the mucoadhesive coating is retained on the core through one or more of covalent interactions, electrostatic interactions, affinity interactions, metal coordination, physical adsorption, host-guest interactions, and hydrogen bonding interactions,

a molecular weight and cross-link density of the biodegradable polymer is selected such that the polymer core will decompose in vivo in a predetermined time interval, and

a fraction of the predetermined amount of the bioactive agent entering the systemic circulation during the predetermined time interval is between about 0.25% and about 25%.

31. The composition of claim 30, wherein each particle further comprises a targeting agent disposed under the mucoadhesive coating.

32. The composition of claim 31, wherein each particle further comprises an intermediate layer disposed between the targeting agent and the mucoadhesive coating.

33. The composition of claim 32, wherein the intermediate layer comprises a first material and the mucoadhesive coating comprises a second material, wherein the first material and the second material have opposing electrostatic charges at pH 2.

34. The composition of claim 33, wherein the first material and the second material do not have opposing electrostatic charges at pH 7.4.

35. The composition of claim 32, wherein the intermediate layer comprises a biodegradable polymer.

36. The composition of claim 31, wherein the targeting agent is disposed at a surface portion of the polymer core.

37. The composition of claim 31, wherein the targeting agent is disposed at a surface portion of the polymer core and is also disposed at an interior portion of the polymer core.

38. The composition of claim 31, wherein the targeting agent is selected from nucleic acid aptamers, growth factors, hormones, cytokines, interleukins, antibodies, integrins, fibronectin receptors, p-glycoprotein receptors, and cell binding sequences.

39. The composition of claim 30, wherein the fraction of the dose of the drug entering the systemic circulation during the predetermined time interval is between about 5% and about 20%.

40. The composition of claim 30, wherein the fraction of the dose of the drug entering the systemic circulation during the predetermined time interval is between about 10% and about 15%.

41. The composition of claim 30, wherein the mucoadhesive coating is retained on the core though electrostatic interactions.

42. The composition of claim 30, wherein the polymer is derivatized with a poly(alkylene glycol).

43. The composition of claim 42 wherein the poly(alkylene glycol) is selected from poly(ethylene glycol) and poly(propylene glycol).

44. The composition of claim 30, wherein the core comprises PEGylated poly(lactic acid).

45. The composition of claim 42, wherein the poly(alkylene glycol) is carboxylated.

46. The composition of claim 42, wherein the poly(alkylene glycol) has a molecular weight between about 100 and about 7000 Daltons.

47. The composition of claim 46, wherein the poly(alkylene glycol) has a molecular weight between about 100 and about 1000 Daltons.

48. The composition of claim 46, wherein the poly(alkylene glycol) has a molecular weight between about 1000 and about 3500 Daltons.

49. The composition of claim 46, wherein the poly(alkylene glycol) has a molecular weight between about 3500 and 7000 Daltons.

50. The composition of claim 30, wherein the polymer is a biodegradable polymer or a non-biodegradable polymer.

51. The composition of claim 50, wherein the biodegradable polymer is selected from poly(arylates), poly(anhydrides), poly(hydroxy acids), polyesters, poly(ortho esters), polycarbonates, poly(propylene fumerates), poly(caprolactones), polyamides, polyphosphazenes, polyamino acids, polyethers, polyacetals, polylactides, polyhydroxyalkanoates, polyglycolides, polyketals, polyesteramides, poly(dioxanones), polyhydroxybutyrates, polyhydroxyvalyrates, polycarbonates, polyorthocarbonates, poly(vinyl pyrrolidone), biodegradable polycyanoacrylates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(methyl vinyl ether), poly(ethylene imine), poly(acrylic acid), poly(maleic anhydride), biodegradable polyurethanes, polysaccharides, PEG-functionalized derivatives of the above, co-polymers of the above, adducts of the above, and mixtures of the above.

52. The composition of claim 50, wherein the non-biodegradable polymer is selected from polystyrene, polyesters, non-biodegradable polyurethanes, polyureas, poly(vinyl alcohol), polyamides, poly(tetrafluoroethylene), poly(ethylene vinyl acetate), polypropylene, polyacrylate, non-biodegradable polycyanoacrylates, non-biodegradable polyurethanes, polymethacrylate, poly(methyl methacrylate), polyethylene, polypyrrole, polyanilines, polythiophene, poly(ethylene oxide), PEG-functionalized derivatives of the above, co-polymers of the above, adducts of the above, and mixtures of the above.

53. The composition of claim 30, wherein the coating comprises chitosan, poly(lysine), poly(ethylene imine), lecithin, lectin, polycarboxylic acids, poly(acrylic acids), polysaccharides, hydrogels, monosaccharides, oligosaccharides, oligopeptides, polypeptides, co-polymers of the above, or any combination of the above.

54. The composition of claim 30, wherein the coating comprises chitosan, lectin, or both.

55. The composition of claim 30, wherein the coating is a block co-polymer having a mucoadhesive block and a block that is adapted to participate in an interaction selected from electrostatic interactions, affinity interactions, metal coordination, physical adsorption, host-guest interactions, and hydrogen bonding interactions.

56. The composition of claim 30, wherein the active agent is a biomolecule, bioactive agent, small molecule, drug, protein, vaccine, or polynucleotide.

57. The composition of claim 56, wherein the active agent is a vaccine.

58. The composition of claim 56, wherein the active agent is a protein.

59. The composition of claim 58, wherein the active agent is insulin.

60. A method for administering an active agent to a patient, comprising:

orally or nasally administering to the patient a composition comprising;

A) a plurality of particles, each particle comprising;

a polymer core encapsulating a predetermined amount of the active agent; and

a mucoadhesive coating disposed about the core to form a coated particle; and

B) a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is edible or inhalable, wherein

the mucoadhesive coating is retained on the core through one or more of covalent interactions, electrostatic interactions, affinity interactions, metal coordination, physical adsorption, host-guest interactions, and hydrogen bonding interactions,

a molecular weight and cross-link density of the polymer is selected such that the polymer core will decompose in vivo in a predetermined time interval, and

a fraction of the predetermined amount of the bioactive agent entering the systemic circulation during the predetermined time interval is between about 0.25% and about 25%.

61. The method of claim 60, wherein each particle further comprises a targeting agent disposed under the mucoadhesive coating.

62. The method of claim 61, wherein each particle further comprises an intermediate layer disposed between the targeting agent and the mucoadhesive coating.

63. The method of claim 62, wherein the intermediate layer comprises a first material and the mucoadhesive coating comprises a second material, wherein the first material and the second material have opposing electrostatic charges at pH2.

64. The method of claim 63, wherein the first material and the second material do not have opposing electrostatic charges at pH 7.4.

65. The method of claim 62, wherein the intermediate layer comprises a biodegradable polymer.

66. The method of claim 61, wherein the targeting agent is disposed at a surface portion of the polymer core.

67. The method of claim 61, wherein the targeting agent is disposed at a surface portion of the polymer core and is also disposed at an interior portion of the polymer core.

68. The method of claim 61, wherein the targeting agent is selected from nucleic acid aptamers, growth factors, hormones, cytokines, interleukins, antibodies, integrins, fibronectin receptors, p-glycoprotein receptors, and cell binding sequences.

69. The method of claim 60, wherein the fraction of the dose of the drug entering the systemic circulation during the predetermined time interval is between about 5% and about 20%.

70. The method of claim 60, wherein the fraction of the dose of the drug entering the systemic circulation during the predetermined time interval is between about 10% and about 15%.

71. The method of claim 60, wherein the polymer is derivatized with a poly(alkylene glycol).

72. The method of claim 71, wherein the poly(alkylene glycol) is selected from poly(ethylene glycol) and poly(propylene glycol).

73. The method of claim 71, wherein the core comprises PEGylated poly(lactic acid).

74. The method of claim 71, wherein the poly(alkylene glycol) is carboxylated.

75. The method of claim 71, wherein the poly(alkylene glycol) has a molecular weight between about 100 and about 7000 Daltons.

76. The method of claim 71, wherein the poly(alkylene glycol) has a molecular weight between about 100 and about 1000 Daltons.

77. The method of claim 71, wherein the poly(alkylene glycol) has a molecular weight between about 1000 and about 3500 Daltons.

78. The method of claim 71, wherein the poly(alkylene glycol) has a molecular weight between about 3500 and 7000 Daltons.

79. The method of claim 60, wherein the mucoadhesive coating is retained on the core though electrostatic interactions.

80. The method of claim 60, wherein the core comprises PEGylated poly(lactic acid).

81. The method of claim 60, wherein the polymer is a biodegradable polymer or a non-biodegradable polymer.

82. The method of claim 81, wherein the biodegradable polymer is selected from poly(arylates), poly(anhydrides), poly(hydroxy acids), polyesters, poly(ortho esters), polycarbonates, poly(propylene fumerates), poly(caprolactones), polyamides, polyphosphazenes, polyamino acids, polyethers, polyacetals, polylactides, polyhydroxyalkanoates, polyglycolides, polyketals, polyesteramides, poly(dioxanones), polyhydroxybutyrates, polyhydroxyvalyrates, polycarbonates, polyorthocarbonates, poly(vinyl pyrrolidone), biodegradable polycyanoacrylates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(methyl vinyl ether), poly(ethylene imine), poly(acrylic acid), poly(maleic anhydride), biodegradable polyurethanes, polysaccharides, PEG-functionalized derivatives of the above, co-polymers of the above, adducts of the above, and mixtures of the above.

83. The method of claim 81, wherein the non-biodegradable polymer is selected from polystyrene, polyesters, non-biodegradable polyurethanes, polyureas, poly(vinyl alcohol), polyamides, poly(tetrafluoroethylene), poly(ethylene vinyl acetate), polypropylene, polyacrylate, non-biodegradable polycyanoacrylates, non-biodegradable polyurethanes, polymethacrylate, poly(methyl methacrylate), polyethylene, polypyrrole, polyanilines, polythiophene, poly(ethylene oxide), PEG-functionalized derivatives of the above, co-polymers of the above, adducts of the above, and mixtures of the above.

84. The method of claim 60, wherein the coating comprises chitosan, poly(lysine), poly(ethylene imine), lecithin, lectin, polycarboxylic acids, poly(acrylic acids), polysaccharides, hydrogels, monosaccharides, oligosaccharides, oligopeptides, polypeptides, co-polymers of the above, or any combination of the above.

85. The method of claim 60, wherein the coating comprises lectin, chitosan, or both.

86. The method of claim 60, wherein the coating is a block co-polymer having a mucoadhesive block and a block that is adapted to participate in an interaction selected from electrostatic interactions, affinity interactions, metal coordination, physical adsorption, host-guest interactions, and hydrogen bonding interactions.

87. The method of claim 60, wherein the active agent is a biomolecule, bioactive agent, small molecule, drug, protein, vaccine, or polynucleotide.

88. The method of claim 87, wherein the active agent is a vaccine.

89. The method of claim 87, wherein the active agent is a protein.

90. The method of claim 87, wherein the active agent is insulin.