Stimuli-responsive systems for controlled drug delivery

• US 20040202719A1
• Filed: 12/17/2003
• Published: 10/14/2004
• Est. Priority Date: 12/17/2002
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Ying, Jackie Y., Zion, Todd C., Zarur, Andrey
• Granted Patent: US 7,531,191 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/5161 Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A method of delivering a therapeutic agent by providing a cross-linked polymer encapsulating the therapeutic agent to a site in a patient. The degradation rate of the cross-linked polymer is correlated with a local concentration of an indicator, and the therapeutic agent is released as the cross-linked polymer degrades.

Claims

1. A material for delivery of a therapeutic agent, comprising:

a cross-linked polymer including a biodegradable polymer and a polyfunctional cross-linking agent;

an indicator analog incorporated into one of the biodegradable polymer and the cross-linking agent;

a cross-link receptor incorporated into the other of the biodegradable polymer and the cross-linking agent, wherein;

the biodegradable polymer is cross-linked by interactions between the indicator analog and the cross-link receptor;

the therapeutic agent is contained within the cross-linked polymer,

the degradation rate of the cross-linked polymer depends on the local concentration of the indicator whose analog one of the biodegradable polymer and the cross-linking agent is functionalized with, and

the interruption of the interaction between the indicator analog and the cross-link receptor causes the material to release the therapeutic agent.

2. The material of claim 1, wherein the indicator analog has essentially the same composition as the indicator.

3. The material of claim 1, wherein the polyfunctional cross-linking agent is covalently linked to the biodegradable polymer.

4. The material of claim 1, wherein the material is a plurality of particles.

5. The material of claim 4, wherein the particles have a size from about 100 nm to about 300 nm.

6. The material of claim 4, wherein the particles have a size from about 300 nm to about 500 nm.

7. The material of claim 4, wherein the particles have a size from about 500 nm to about 5 μ

m.

8. The material of claim 4 wherein the particles have a size from about 5 μ

m to about 50 μ

m.

9. The material of claim 4, wherein the particles have a size from about 50 μ

m to about 100 μ

m.

10. The material of claim 1, wherein the material is an insoluble hydrogel.

11. The material of claim 1, wherein the therapeutic agent is encapsulated within the material.

12. The material of claim 1, wherein the therapeutic agent is linked to the material by covalent interactions, non-covalent interactions, or both.

13. The material of claim 12, wherein the non-covalent interactions include ligand-receptor interactions, electrostatic interactions, chemical adsorption, ionic bonding, hydrophobic interactions, dipole-dipole interactions, hydrogen bonding, or van der Waals forces.

14. The material of claim 1, wherein the therapeutic agent is linked to the material by a bond that is susceptible to enzymatic cleavage.

15. The material of claim 1, wherein the cross-linking receptor and the indicator analog are linked to one another by covalent interactions, non-covalent interactions, or both.

16. The material of claim 14, wherein the non-covalent interactions include ligand-receptor interactions, electrostatic interactions, chemical adsorption, ionic bonding, hydrophobic interactions, dipole-dipole interactions, hydrogen bonding, or van der Waals forces.

17. The material of claim 14, wherein the cross-linking agent interacts with the polymer through at least one covalent interaction and at least one non-covalent interaction.

18. The material of claim 1, wherein the indicator analog is a portion of a side group of the biodegradable polymer.

19. The material of claim 1, wherein the biocompatible polymer is derivatized with the indicator or the indicator analog.

20. The material of claim 1, wherein the indicator analog is incorporated into the backbone of the polymer chain.

21. The material of claim 1, wherein the biodegradable polymer is selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), PLA-PGA co-polymers (PLGA), poly(anhydrides), poly(hydroxy acids), poly(ortho esters), poly(propylfumerates), poly(caprolactones), polyamides, polyamino acids, polyacetals, biodegradable polycyanoacrylates, biodegradable polyurethanes, polysaccharides, co-polymers of the above, adducts of the above, and mixtures of the above.

22. The material of claim 1, wherein the biodegradable polymer is selected from carboxylated polysaccharides, —

NH₂ pendant polysaccharides, hydroxylated polysaccharides, alginate, collagen-glycosaminoglycan, collagen, dextran, pullulan, mannan, amylose, amylopectin, glycogen, cellulose, hyaluronate, chondroitin, dextrin, chitosan, co-polymers of aminated and non-aminated amino acids, co-polymers of hydroxylated and non-hydroxylated amino acids, co-polymers of carboxylated and non-carboxylated amino acids, co-polymers of the above, adducts of the above, and mixtures of the above.

23. The material of claim 1, wherein the cross-linking agent is selected from phytohemoagglutinins, human mannan binding protein (MBP), human pulmonary surfactant protein A (SP-A), human pulmonary surfactant protein D, CL-43, and conglutinin.

24. The material of claim 23, wherein the phytohemoagglutinin is selected from concanavalin A (Con A) and phytohemoagglutinins derived from pisum sativum (pea), lathyrus odoratus (sweet pea), lens culinaris (lentil), narcissus pseudonarcissus (daffodil), vicia faba (fava bean), and vicia sativa (garden vetch).

25. The material of claim 1, wherein the cross-linking agent is a polyfunctional binding protein.

28. The material of claim 1, wherein the therapeutic agent is selected from a biomolecule, a small molecule, and a bioactive agent.

29. The material of claim 1, further comprising a fluorophore.

30. The material of claim 29, wherein the fluorophore is covalently or non-covalently linked to the biocompatible polymer, the therapeutic agent, or the cross-linking agent.

31. The material of claim 1, wherein the biodegradable polymer is a polysaccharide and the cross-linking agent is a plant lectin or a mammalian analog to a plant lectin.

32. The material of claim 31, wherein the therapeutic agent is selected from insulin, an antibiotic, a lipid-reducing agent, a triglyceride reducing agent, an insulin secretogue, and an anti-cancer agent.

33. The material of claim 1, wherein the biodegradable polymer is dextran or mannose-derivatized dextran, the cross-linking agent is concanavalin A, and the therapeutic agent is insulin.

34. The material of claim 1, wherein the biodegradable polymer is iron-derivatized dextran, the cross-linking agent is a polyfunctional lactoferrin, and the therapeutic agent is deferoxamine.

35. The material of claim 1, wherein the biodegradable polymer is a thyroxine-derivatized —

NH₂ bearing polymer, the cross-linking agent is a polyfunctional thyroxine-binding globulin, and the therapeutic agent is selected from methimazole, propylthiouracil, and a mixture of both.

36. The material of claim 1, wherein the biodegradable polymer is a folate-derivatized carboxyl bearing polymer and the cross-linking agent is a polyfunctional folate-binding protein.

37. The material of claim 1, wherein the biodegradable polymer is lactate-derivatized dextran and the cross-linking agent is a polyfunctional lactate binding protein.

38. The material of claim 1, wherein the indicator is glucose and the therapeutic agent is insulin or an insulin secretogue.

39. The material of claim 1, wherein the indicator is glucose and the therapeutic agent is a biomolecule, a bioactive agent, or a small molecule.

40. The material of claim 1, wherein the indicator is iron and the therapeutic agent is deferoxamine.

41. The material of claim 1, wherein the indicator is thyroxine and the therapeutic agent is selected from methimazole, propylthiouracil, and a mixture of both.

26. The material of claim !, wherein the cross-linking agent is a plurality of monofunctional binding proteins or binding fragments of proteins linked to one another.

27. The material of claim 26, wherein the cross-linking agent is a plurality of monofunctional binding proteins or binding fragments of proteins covalently attached to a polymer.

42. A method of producing a delivery vehicle for a therapeutic agent, comprising:

forming a reverse microemulsion by adding an aqueous solution to a mixture of a hydrophobic liquid and at least one surfactant and agitating the mixture, wherein the aqueous solution comprises a biodegradable polymer functionalized with an indicator analog, a cross-linking agent that cross-links the biodegradable polymer by interacting with two or more indicator analogs, and the therapeutic agent; and

causing the cross-linking agent to interact with the polymer to form a plurality of cross-linked hydrogel particles retaining the therapeutic agent therein.

43. The method of claim 42, further comprising separating the hydrogel particles from the remaining components of the reverse microemulsion.

44. The method of claim 42, wherein the hydrophobic liquid is selected from soybean oil, Arlacel 186, Captex 355, Capmul MCM, Myvacet, and Myverol 18-92, or a combination of two or more of these.

45. The method of claim 42, wherein the surfactant is selected from Tween 80, Span 80, Cremophor EL, and combinations of two or more of these.

46. The method of claim 42, wherein the pH of the aqueous solution is about 7.

47. The method of claim 42, wherein the therapeutic agent is linked to the material by covalent interactions, non-covalent interactions, or both.

48. The method of claim 47, wherein the non-covalent interactions include ligand-receptor interactions, electrostatic interactions, chemical adsorption, ionic bonding, hydrophobic interactions, dipole-dipole interactions, hydrogen bonding, or van der Waals forces.

49. The method of claim 42, wherein the therapeutic agent is linked to the material by a bond that is susceptible to enzymatic cleavage.

50. The method of claim 42, wherein the cross-linking receptor and the indicator analog are linked to one another by covalent interactions, non-covalent interactions, or both.

51. The method of claim 49, wherein the non-covalent interactions include ligand-receptor interactions, electrostatic interactions, chemical adsorption, ionic bonding, hydrophobic interactions, dipole-dipole interactions, hydrogen bonding, or van der Waals forces.

52. The method of claim 49, wherein the cross-linking agent interacts with the polymer through at least one covalent interaction and at least one non-covalent interaction.

53. The method of claim 42, wherein the indicator analog is a portion of a side group of the biodegradable polymer.

54. The method of claim 42, wherein the polymer chain is derivatized with the indicator analog.

55. The method of claim 42, wherein the indicator analog is incorporated into the backbone of the polymer chain.

56. The method of claim 42, wherein the biodegradable polymer is selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), PLA-PGA co-polymers (PLGA), poly(anhydrides), poly(hydroxy acids), poly(ortho esters), poly(propylfumerates), poly(caprolactones), polyamides, polyamino acids, polyacetals, biodegradable polycyanoacrylates, biodegradable polyurethanes, polysaccharides, co-polymers of the above, adducts of the above, and mixtures of the above.

57. The method of claim 42, wherein the biodegradable polymer is selected from carboxylated polysaccharides, —

NH₂ pendant polysaccharides, hydroxylated polysaccharides, alginate, collagen-glycosaminoglycan, collagen, dextran, pullulan, mannan, amylose, amylopectin, glycogen, cellulose, hyaluronate, chondroitin, dextrin, chitosan, co-polymers of aminated and non-aminated amino acids, co-polymers of hydroxylated and non-hydroxylated amino acids, co-polymers of carboxylated and non-carboxylated amino acids, co-polymers of the above, adducts of the above, and mixtures of the above.

58. The method of claim 42, wherein the cross-linking agent is selected from phytohemoagglutinins, human mannan binding protein (MBP), human pulmonary surfactant protein A (SP-A), human pulmonary surfactant protein D, CL-43, and conglutinin.

59. The method of claim 58, wherein the phytohemoagglutinin is selected from concanavalin A (Con A) and phytohemoagglutinins derived from pisum sativum (pea), lathyrus odoratus (sweet pea), lens culinaris (lentil), narcissus pseudonarcissus (daffodil), vicia faba (fava bean), and vicia sativa (garden vetch).

60. The method of claim 42, wherein the cross-linking agent is a polyfunctional binding protein.

61. The method of claim 42, wherein the cross-linking agent is a plurality of monofunctional binding proteins or binding fragments of proteins linked to one another.

62. The method of claim 61, wherein the cross-linking agent is a plurality of monofunctional binding proteins or binding fragments of proteins attached to a polymer.

63. The method of claim 42, wherein the aqueous solution further comprises a fluorophore.

64. The method of claim 63, wherein the fluorophore is covalently or non-covalently linked to the biocompatible polymer, the therapeutic agent, or the cross-linking agent.

65. The method of claim 42, wherein the biodegradable polymer is dextran or mannose-derivatized dextran, the cross-linking agent is concanavalin A, and the therapeutic agent is insulin.

66. The method of claim 42, wherein the biodegradable polymer is a polysaccharide and the cross-linking agent is a plant lectin or a mammalian analog to a plant lectin.

67. The method of claim 42, wherein the indicator is glucose and the therapeutic agent is insulin.

68. A method of producing a delivery vehicle for a therapeutic agent, comprising:

providing a biocompatible polymer derivatized with a therapeutic agent;

providing a polyfunctional cross-linking agent adapted and constructed to cross-link the polymer by interacting with the biocompatible polymer; and

combining the biocompatible polymer and the polyfunctional cross-linking agent under conditions in which the polyfunctional cross-linking agent cross-links the polymer to form an insoluble hydrogel.

69. The method of claim 68, wherein providing a biocompatible polymer comprises providing a first solution containing the polymer and providing a polyfunctional cross-linking agent comprises providing a second solution containing the cross-linking agent, and wherein combining comprises combining the first and second solutions.

70. The method of claim 68, wherein one of the biocompatible polymer and the cross-linking agent includes an indicator analog and the other includes a cross-link receptor, wherein the cross-linking agent cross-links the polymer through an interaction between the indicator analog and the cross-link receptor.

71. The method of claim 68, wherein the bond between the therapeutic agent and the biocompatible polymer is susceptible to enzymatic cleavage.

72. The method of claim 68, wherein the cross-linking agent is a plurality of monofunctional binding proteins or binding fragments of proteins linked to one another.

73. The method of claim 72, wherein the cross-linking agent is a plurality of monofunctional binding proteins or binding fragments of proteins attached to a polymer.

74. A method of delivering a therapeutic agent, comprising:

providing a cross-linked polymer entrapping the therapeutic agent to a site in a patient, wherein;

the degradation rate of the cross-linked polymer is correlated with a local concentration of an indicator, and

the therapeutic agent is released as the cross-linked polymer degrades.

75. The method of claim 74, wherein the cross-linked polymer is provided as a plurality of particles.

76. The method of claim 74, wherein the step of providing comprises:

forming a reverse microemulsion by adding an aqueous solution to a mixture of a hydrophobic liquid and at least one surfactant and agitating the mixture, wherein the aqueous solution comprises a biodegradable polymer functionalized with an indicator analog, a cross-linking agent that cross-links the biodegradable polymer by interacting with two or more indicator analogs, and the therapeutic agent; and

causing the cross-linking agent to interact with the polymer to form a plurality of cross-linked hydrogel particles retaining the therapeutic agent therein.

77. The method of claim 76, wherein the step of providing further comprises separating the hydrogel particles from the remaining components of the reverse microemulsion.

78. The method of claim 74, wherein the step of providing comprises combining a biodegradable polymer and a polyfunctional cross-linking agent under conditions where the cross-linking agent will cross-link the biodegradable polymer, wherein one of the biodegradable polymer and the polyfunctional cross-linking agent includes an indicator analog and the other includes a cross-link receptor that forms a non-covalent bond with the indicator analog

79. The method of claim 74, wherein the cross-linked polymer is provided through inhalation, injection, or ingestion.

80. The method of claim 74, wherein the cross-linked polymer is cross-linked through the interaction of an indicator analog and a cross-link receptor, and wherein the cross-linked polymer degrades because the indicator competes with the indicator analog to interact with the cross-link receptor.

81. The method of claim 74, wherein the therapeutic agent is attached to the cross-linked polymer by a covalent or a non-covalent interaction.

82. The method of claim 74, wherein the therapeutic agent is attached to the cross-linked polymer by a covalent bond that is susceptible to enzymatic cleavage.

83. A method for controlling a concentration of a substance in a patient, comprising:

placing a reservoir of a therapeutic agent in the patient; and

causing release of the therapeutic agent in response to the concentration of the substance.

84. The method of claim 83, wherein the reservoir is a cross-linked biodegradable polymer encapsulating the therapeutic agent.

85. The method of claim 83, wherein the reservoir is a cross-linked biodegradable polymer to which the therapeutic agent is attached through covalent or non-covalent interactions.