Polymer-based, sustained release drug delivery system

• US 20040022853A1
• Filed: 05/30/2003
• Published: 02/05/2004
• Est. Priority Date: 04/26/2001
• Status: Abandoned Application

• Current Assignee: Control Delivery Systems Inc. (EyePoint Pharmaceuticals, Inc.)
• Original Assignee: Control Delivery Systems Inc. (EyePoint Pharmaceuticals, Inc.)
• Inventors: Guo, Hong, Ashton, Paul, Chen, Jianbing
• Application Number:
  US10/449,855
• Publication Number:
  US 20040022853A1
• Time in Patent Office: Days
• US Class Current: 424/468
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• 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 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61L 17/005 containing a biologically active substance, e.g. a medicament or a biocide
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence

Abstract

Disclosed is a sustained release system that includes a polymer and a pharmaceutically active agent dispersed in the polymer. The agent is in granular or particulate form, and has a rate of release from the system that is limited primarily by the rate at which the agent dissolves from the granules into the polymer matrix. Advantageously, the polymer is permeable to the agent and is non-release-rate-with limiting with respect to the rate of release of the agent from the polymer.

Claims

1. A sustained-release formulation comprising:

at least one granule comprising a therapeutically effective amount of at least one agent, and

a polymer matrix coating the at least one agent, wherein the at least one agent has a rate of release from the formulation that is limited primarily by the rate at which the at least one agent dissolves into the matrix.

2. The sustained-release formulation of claim 1, wherein the at least one agent has a solubility in the polymer matrix of about 10 mg/ml or less.

3. The sustained-release formulation of claim 1, wherein the at least one agent has a solubility in the polymer matrix of about 1 mg/ml or less.

4. The sustained-release formulation of claim 1, wherein the at least one agent has a solubility in the polymer matrix of about 0.1 mg/ml or less.

5. The sustained-release formulation of claim 1, wherein the at least one agent has a solubility in the polymer matrix of about 0.01 mg/ml or less.

6. The sustained-release formulation of claim 1, wherein sustained release of the at least one agent occurs for a period of at least 3 hours.

7. The sustained-release formulation of claim 1, wherein diffusion of the at least one agent through the polymer matrix is primarily non-release-rate-limiting with respect to the rate of release of the at least one agent from the matrix.

8. The sustained-release formulation of claim 1, wherein the polymer matrix is a hydrogel.

9. The sustained-release formulation of claim 1, wherein the at least one agent is a codrug.

10. The sustained-release formulation of claim 1, wherein the polymer matrix is a biocompatible fluid or semisolid, in either case selected so that the at least one agent has low solubility therein.

11. The sustained-release formulation of claim 10, wherein the semisolid contains long chain polyethylene glycol (PEG).

12. The sustained release formulation of claim 1, wherein the microenvironment of the polymer matrix has a non-physiological pH.

13. The sustained-release formulation of claim 12, wherein the microenvironment of the polymer matrix has a neutral pH.

14. The sustained-release formulation of claim 1, wherein the at least one agent has low solubility in water.

15. The sustained-release formulation of claim 1, wherein the at least one agent has moderate solubility in water.

16. The sustained-release formulation of claim 1, wherein the at least one agent is not ionized within the polymer matrix.

17. The sustained-release formulation of claim 1, wherein the polymer matrix is non-bioerodible.

18. The sustained-release formulation of claim 1, wherein the polymer matrix is bioerodible.

19. The sustained-release formulation of claim 1, wherein the polymer matrix is impermeable to peptides or proteins of about 10 kD or greater.

20. The sustained-release formulation of claim 1, further comprising a bio-adhesive or muco-adhesive coating covering at least a portion of said formulation.

21. The sustained-release formulation of claim 1, wherein the formulation is affixed to a physiological system.

22. A drug delivery device comprising:

a substrate having a surface, and

a sustained-release formulation adhered to the surface, the sustained-release formulation comprising a therapeutically effective amount of at least one agent, wherein the at least one agent is dispersed in granular form within a polymer matrix and has a solubility in the polymer matrix of about 0.01 mg/ml or less.

23. The device of claim 22, wherein the release rate of the at least one agent is limited primarily by the rate at which the at least one agent dissolves within the matrix.

24. The device of claim 22, wherein the polymer matrix is a hydrogel.

25. The device of claim 22, wherein the at least one agent is a codrug.

26. The device of claim 22, wherein the polymer matrix is a biocompatible fluid or semisolid, in either case selected so that the at least one agent has low solubility therein.

27. The device claim 26, wherein the semisolid is contains long chain polyethylene glycol (PEG).

28. The device of claim 22, wherein the microenvironment of the polymer matrix has a non-physiological pH.

29. The sustained-release formulation of claim 28, wherein the microenvironment of the polymer matrix has a neutral pH.

30. The device of claim 22, wherein the at least one agent is of low solubility in water.

31. The device of claim 22, wherein the at least one agent is of moderate solubility in water.

32. The device of claim 22, wherein the at least one agent is not ionized within the polymer matrix.

33. The device of claim 22, wherein the polymer matrix is non-bioerodible.

34. The device of claim 22, wherein the polymer matrix is bioerodible.

35. The device of claim 22, wherein the polymer matrix is impermeable to proteins or peptides of about 10 kD or greater.

36. The device of claim 22, further comprising a bio-adhesive or muco-adhesive coating covering at least a portion of said formulation.

37. The device of claim 22, wherein the formulation is affixed to a physiological system.

38. A method of providing sustained-release administration of granular drugs comprising:

providing a therapeutically effective amount of at least one agent in granular form;

forming a sustained-release formulation by combining the at least one agent with a polymer matrix such that the at least one agent remains substantially in granular form, wherein the at least one agent has a solubility in the polymer matrix of about 0.01 mg/ml or less; and

administering the sustained-release formulation to a patient.

39. The method of claim 38, wherein the release rate of the at least one agent is limited primarily by the rate at which the at least one agent dissolves within the matrix.

40. The method of claim 38, wherein the polymer matrix is a hydrogel.

42. The method of claim 38, wherein the at least one agent is a codrug.

43. The method of claim 38, wherein the polymer matrix is a biocompatible fluid or semisolid, in either case selected so that the at least one agent has low solubility therein.

44. The method of claim 43 wherein the semisolid comprises long chain polyethylene glycol (PEG).

45. The method of claim 38 wherein the microenvironment of the polymer matrix has a non-physiological pH.

46. The method of claim 45, wherein the microenvironment of the polymer matrix has a neutral pH.

47. The method of claim 38, wherein the at least one agent has low solubility in water.

48. The method of claim 38, wherein the at least one agent has moderate solubility in water.

49. The method of claim 38, wherein the at least one agent is not ionized within the polymer matrix.

50. The method of claim 38, wherein the polymer matrix is non-bioerodible.

51. The method of claim 38, wherein the polymer matrix is bioerodible.

52. The method of claim 38, wherein the polymer matrix is impermeable to peptides or proteins of about 10 kD or greater.

53. The method of claim 38, further comprising a bio-adhesive or muco-adhesive coating covering at least a portion of said formulation.

54. The method of claim 38, wherein the formulation is affixed to a physiological system.

55. The method of claim 38 further comprising providing the sustained-release formulation in a pharmaceutically acceptable carrier.

56. A sustained-release formulation comprising:

a plurality of granules comprising a therapeutically effective amount of a codrug, and

a polymer matrix, wherein the polymer matrix is essentially non-release rate limiting with respect to the rate of release of the agent from the matrix.

59. The sustained-release formulation of any of claims 56, 57, or 58 wherein the codrug is in prodrug form.

57. A sustained-release formulation comprising:

a polymer matrix surrounded by physiological tissue, and

a plurality of granules comprising a therapeutically effective amount of a codrug dispersed in said matrix, wherein the granules have a surface area that is at least partially exposed to the surrounding tissue, and wherein the release rate of the codrug from the formulation is proportional to the exposed surface area of the granules.

58. A sustained-release formulation comprising:

a plurality of granules comprising a therapeutically effective amount of a codrug having a form selected from I, Ia, II, IIa, III, IIIa, and IV below,

A₁*(—

L—

A₂*)_n 

 

(I)A₁*(—

A₂*)_n 

 

(Ia)A₁*—

L—

A₂* 

 

(II)A₁*—

A₂* 

 

(IIa)A₂*—

L—

A₁*—

L—

A₂* 

 

(III)A₂*—

A₁*—

A₂* 

 

(IIIa),

 

Wherein A₁*is a residue of a first biologically active compound A_1,

A₂*is a residue of a second biologically active compound A_2,

L is a linking group selected from a direct bond and a divalent organic linking group, and

n is an integer having a value of from 1 to 4; and

a polymer matrix, coating the at least one agent, wherein the at least one

agent has a rate of release from the formulation that is limited primarily by the rate at which the at least one agent dissolves into the matrix.