Ligand-mediated controlled drug delivery

• US 20060153919A1
• Filed: 01/12/2005
• Published: 07/13/2006
• Est. Priority Date: 01/12/2005
• Status: Active Grant

• Current Assignee: Clemson University
• Original Assignee: Clemson University
• Inventors: Lin, Chien Chi, Chollangi, Srinivas, Metters, Andrew T.
• Granted Patent: US 8,128,952 B2
• Time in Patent Office: Days
• US Class Current: 424/486
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• 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

Abstract

Disclosed are systems and methods that can be utilized to define and control the delivery rate of a biological agent from a carrier matrix such as a biocompatible hydrogel. The carrier matrices of the present invention can include ligands incorporated within the matrix at a predetermined concentration level (C_LT). In addition, the ligands within the matrix can display a particular, predetermined affinity for the biologically active agents to be delivered by the system. In particular, the affinity between the ligand and the biologically active agent can have a known predetermined dissociation constant (K_D). When utilizing the system, the agent can be incorporated within the matrix due to association of the agent with the ligand. In addition, the agent can be protected from side reactions due to the association of the agent with the ligand. Through particular selection of the parameters C_LT and K_D, the rate of release of the biologically active agent from the matrix can be controlled. The disclosed methods and systems can be advantageously used in both in vivo clinical settings and ex vivo settings, such as tissue engineering applications.

Claims

1. A method for providing a predetermined rate of release of a biologically active agent from a carrier matrix comprising:

providing a biologically active agent;

selecting a ligand having an affinity for the biologically active agent, wherein the ligand is selected according to a predetermined dissociation constant describing the affinity of the biologically active agent for the ligand;

incorporating the ligand into a polymeric matrix at a predetermined concentration; and

incorporating the biologically active agent into the polymeric matrix, wherein the predetermined rate of release of the biologically active agent from the polymeric matrix is established upon incorporation of the biologically active agent into the polymeric matrix, the predetermined rate of release being dependent upon the values of the dissociation constant and the ligand concentration.

2. The method according to claim 1, wherein the dissociation constant is less than about 1.0E+1 mM.

3. The method according to claim 1, wherein the polymeric matrix is a hydrogel.

4. The method according to claim 3, wherein the hydrogel is a degradable hydrogel.

5. The method according to claim 4, wherein the rate of release is also dependent upon the degradation rate of the hydrogel.

6. The method according to claim 1, wherein the ligand is a naturally occurring ligand or a chimera of a naturally occurring ligand.

7. The method according to claim 1, wherein the ligand is a synthetic ligand, the method further comprising forming the synthetic ligand according to a combinatorial synthesis method.

8. The method according to claim 1, wherein the rate of release of the biologically active agent from the polymeric matrix describes a zero order release profile.

9. The method according to claim 1, wherein the rate of release of the biologically active agent from the polymeric matrix describes a biphasic release profile.

10. The method according to claim 1, further comprising:

providing a second biologically active agent;

incorporating the second biologically active agent into the polymeric matrix; and

wherein a predetermined rate of release of the second biologically active agent from the polymeric matrix is established upon incorporation of the second biologically active agent into the polymeric matrix, the rate of release of the second biologically active agent from the polymeric matrix being independent of the rate of release of the first biologically active agent from the polymeric matrix.

11. The method according to claim 10, wherein the second biologically active agent has an affinity for the first ligand described by a second predetermined dissociation constant, wherein the rate of release of the second biologically active agent from the polymeric matrix is dependent upon the values of the second dissociation constant and the ligand concentration.

12. The method according to claim 10, further comprising selecting a second ligand having an affinity for the second biologically active agent, wherein the second ligand is selected according to a predetermined dissociation constant describing the affinity of the second biologically active agent for the second ligand, wherein the rate of release of the second biologically active agent from the polymeric matrix is dependent upon the values of the dissociation constant describing the affinity of the second ligand for the second biologically active agent and the concentration of the second ligand.

13. The method according to claim 1, further comprising releasing the biologically active agent from the polymeric matrix when the polymeric matrix is adjacent a living cell.

14. The method according to claim 13, wherein the living cell is encapsulated by the polymeric matrix.

15. The method according to claim 1, further comprising binding the ligand to the polymeric matrix, wherein the affinity of the ligand for the polymeric matrix is greater than the affinity of the ligand for the biologically active agent.

16. The method according to claim 15, wherein the ligand is covalently bound to the polymeric matrix.

17. The method according to claim 1, further comprising forming a complex comprising the ligand and the biologically active agent, wherein the complex is formed prior to incorporation of the ligand and biologically active agent into the polymeric matrix such that the ligand and the biologically active agent are incorporated into the polymeric matrix together in the complex.

18. A drug delivery method comprising:

providing a biologically active agent;

selecting a ligand having an affinity for the biologically active agent, wherein the ligand is selected according to a predetermined dissociation constant describing the affinity of the biologically active agent for the ligand;

providing the ligand at a predetermined ligand concentration;

forming a complex comprising the ligand non-covalently and reversibly bound to the biologically active agent; and

incorporating the complex into a polymeric matrix, wherein a predetermined rate of release of the biologically active agent from the ligand is established upon incorporation of the complex into the polymeric matrix, the rate of release being dependent upon the predetermined dissociation constant and the ligand concentration, wherein the biologically active agent is nonreactive to the matrix and to the matrix components while held in the complex.

19. The method according to claim 18, wherein the efficiency of the release of the biologically active agent from the matrix is increased upon formation of the complex.

20. The method according to claim 18, wherein the dissociation constant is less than about 1.0E+1 mM.

21. The method according to claim 18, wherein the ligand is a naturally occurring ligand or a chimera of a naturally occurring ligand.

22. The method according to claim 18, wherein the ligand is a synthetic ligand, the method further comprising forming the synthetic ligand according to a combinatorial synthesis method.

23. The method according to claim 18, wherein the polymeric matrix is a hydrogel.

24. The method according to claim 18, wherein the complex can freely diffuse through the polymeric matrix.

25. The method according to claim 18, further comprising releasing the biologically active agent from the ligand when the polymeric matrix is adjacent a living cell.

26. The method according to claim 23, wherein the living cell is encapsulated by the polymeric matrix.

27. A drug delivery system configured to provide a predetermined rate of release of a biologically active agent comprising:

a polymeric matrix;

a ligand incorporated into the polymeric matrix at a predetermined concentration, the ligand having an affinity for a biologically active agent, the affinity being described by a predetermined dissociation constant; and

the biologically active agent incorporated into the polymeric matrix by association with the ligand according to the affinity between the biologically active agent and the ligand; and

wherein the predetermined rate of release of the biologically active agent from the polymeric matrix is dependent upon the values of the dissociation constant and the ligand concentration.

28. The system of claim 27, wherein the dissociation constant is less than about 1.0E+1 mM.

29. The system of claim 27, wherein the dissociation constant is less than about 1.0E−

5 mM.

30. The system of claim 27, wherein the dissociation constant is between about 1.0E−

9 mM and about 1.0E−

5 mM.

31. The system of claim 27, wherein the polymeric matrix is a hydrogel.

32. The system of claim 31, wherein the hydrogel is a poly(ethylene glycol) based hydrogel.

33. The system of claim 27, wherein the polymeric matrix has a mesh size greater than the average size of the biologically active agent.

34. The system of claim 27, wherein the polymeric matrix has a mesh size smaller than the average size of a complex comprising the ligand in association with the biologically active agent.

35. The system of claim 27, wherein the ligand is a naturally occurring ligand or a chimera of a naturally occurring ligand.

36. The system of claim 27, wherein the ligand is a synthetic ligand.

37. The system of claim 27, wherein the rate of release of the biologically active agent from the polymeric matrix describes a zero order release profile.

38. The system of claim 27, wherein the rate of release of the biologically active agent from the polymeric matrix describes a biphasic release profile.

39. The system of claim 27, wherein the biologically active agent is selected from the group consisting of a protein, a polypeptide, an oligonucleotide, and a small molecule.

40. The system of claim 27, further comprising a second biologically active agent incorporated into the polymeric matrix, wherein the rate of release of the second biologically active agent from the polymeric matrix that is independent of the rate of release of the first biologically active agent from the polymeric matrix.

41. The system of claim 27, wherein the polymeric matrix is a tissue-engineering scaffold.

42. The system of claim 41, wherein the polymeric matrix further comprises living cells encapsulated by the matrix.

43. The system of claim 42, wherein the polymeric matrix further comprises cell membrane receptor ligands with affinity for the living cells encapsulated by the matrix.

44. The system of claim 27, wherein the ligand is bound to the polymeric matrix, wherein the affinity of the ligand for the polymeric matrix is greater than the affinity of the ligand for the biologically active agent.

45. The system of claim 44, wherein the ligand is covalently bound to the polymeric matrix.

46. The system of claim 27, wherein the biologically active agent is nonreactive to the matrix and to the matrix components when the biologically active agent is associated the ligand.

47. The system of claim 27, wherein the biologically active agent is a macromolecular biologically active agent having a molecular weight between about 1 kDa and about 200 kDa.