Implantable and sealable system for unidirectional delivery of therapeutic agents to tissues

• US 7,195,774 B2
• Filed: 08/28/2002
• Issued: 03/27/2007
• Est. Priority Date: 08/29/2001
• Status: Active Grant

• Current Assignee: Alan Linn Murphree, Edward E. Schmitt, Ricardo Azevedo Pontes De Carvalho
• Original Assignee: Alan Linn Murphree, Edward E. Schmitt, Ricardo Azevedo Pontes De Carvalho
• Inventors: Schmitt, Edward E., Murphree, Alan Linn, Carvalho, Ricardo Azevedo Pontes de
• Primary Examiner(s): Kennedy; Sharon E.
• Application Number:
  US10/231,767
• Publication Number:
  US 20030064088A1
• Time in Patent Office: 1,672 Days
• Field of Search: 424/423, 424/130.1, 424427- 29, 623/4.1, 623/5.11, 623/5.13, 604/890.1
• US Class Current: 424/427
• CPC Class Codes: A61F 2/02 Prostheses implantable into the body closure means for urethra or rectum or for artificial body openings therefor A61F2/0004
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61F 2250/0068 the pharmaceutical product being in a reservoir
• CPC Class Codes: A61F 9/0017 implantable in, or in contact with, the eye, e.g. ocular inserts
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

A surgically implantable and sealable delivery device that upon contact of its contents via an interface window or port therein with an organ or tissue exposes a therapeutic agent to the organ or tissue surface, allowing a controlled, selective and unidirectional diffusion of the agent into the tissue or organ. The device protects adjacent organs or tissue structures from unnecessary high levels of the delivered agent. Novel methods to deliver chemotherapeutics or bioactive agents to mammalian organs or tissues through a surgically implanted device by the way of a selective and protected diffusion mechanism are disclosed as well as method to achieve the sealing properties of the device.

Claims

1. An implantable delivery device for delivery of at least a first therapeutic agent into a target tissue, comprising:

a housing, said housing comprising a reservoir with a release port for release of at least a first therapeutic agent into a target tissue, said reservoir having at least a first wall that is substantially impermeable to a first therapeutic agent to be placed therein,

a sealing base for sealing said release port to a target tissue, wherein when said release port is sealed to a target tissue a first therapeutic agent in said reservoir is substantially prohibited from release by said device other than through said release port into the target tissue, and

an attachment mechanism to facilitate sealing of said release port to a target tissue, said attachment mechanism comprising at least one member of the group consisting of a sufficient amount of an adhesive for adhering said sealing base to a target tissue wherein said adhesive is held within at least one cavity or channel within said sealing base, and at least one stabilizer on said first wall for engaging a buckling band or suture for sealably engaging said device with a target tissue.

2. The device of claim 1, wherein said target tissue is eye tissue.

3. The device of claim 1, wherein said release port has a perimeter, and said sealing base surrounds at least a portion of said perimeter, wherein said sealing base can be engaged by at least one suture to fix said device to a target tissue so that said release port is sealed to the tissue.

4. The device of claim 1, wherein said stabilizer comprises a suture holder, said release port has a perimeter, and said suture holder comprises at least one structure on said first wall, said structure selected from the group consisting of a bump on said first wall, and a depression in said first wall, wherein said at least one structure can be engaged by at least one suture to fix said device to a target tissue so that said release port is sealed to the tissue.

5. The device of claim 1, wherein said at least a first wall forming said reservoir comprises at least one material selected from the group consisting of an elastic material and a flexible material.

6. The device of claim 1, wherein said at least a first wall comprises at least one material selected from the group consisting of polyethylene, a silicone polymer, a hydrogel, a polyglycolic acid, a polylactic acid, a polycaprolactone, a polyvinyl alcohol, a polyorthoester, and a polyvinylpyrrolidone.

7. The device of claim 1, wherein said at least a first wall comprises at least one material selected from the group consisting of polyethylene, and a silicone polymer.

8. The device of claim 1, wherein said device further comprises a refill port.

9. The device of claim 8, wherein said refill port is visually distinguishable from said at least first wall.

10. The device of claim 8, wherein said refill port is formed of a self sealing polymer.

11. The device of claim 8, wherein said refill port projects outward from said device to facilitate access.

12. The device of claim 1, further comprising a first therapeutic or prophylactic agent.

13. The device of claim 12, wherein said first agent is selected from the group consisting of an antineoplastic agent, a peptide, an antibody, gene vector, hormone, protein, a radiosensitizer, a photosensitizer, a chemosensitizer, mammalian cells, a virus, a bacteria, and a nucleotide.

14. The device of claim 1, further comprising a cytotoxic agent.

15. The device of claim 12, further comprising a vehicle for said agent.

16. The device of claim 15, wherein said vehicle comprises at least one material selected from the group consisting of a poly-orthoester, a poly-glycolic acid, a poly-lactic acid, a poly-caprolactone, an acrylate, a cellulose, a polyvinyl-alcohol, polyvinylpyrrolidone, dextran, hyaluronic acid, fibrin, collagen, and gelatin.

17. The device of claim 15, wherein the state of said vehicle is selected from the group consisting of solid, liquid, and gel, and the state of said agent is selected from the group consisting of solid, liquid and gel.

18. The device of claim 13, further comprising at least one therapeutic enhancer agent selected from the group consisting of an enzyme, a co-drug, and a substract of said therapeutic agent.

19. The device of claim 13, further comprising at least one therapeutic enhancer agent, said therapeutic enhancer agent comprising a protein.

20. The device of claim 19, wherein said protein comprises albumin.

21. The device of claim 13, further comprising a perfusion enhancer, said perfusion enhancer being capable of enhancing the penetration of said therapeutic or prophylactic agent into a target tissue.

22. The device of claim 21, wherein said perfusion enhancer comprises at least one compound selected from the group consisting of comprises an enzyme, a pro-enzyme, and a prostaglandin.

23. The device of claim 22, wherein said enzyme comprises at least one enzyme selected from the group consisting of collagenases, and a matrix metalloproteinase.

24. The device of claim 1, further comprising a barrier layer covering said release port.

25. The device of claim 24, wherein said barrier layer comprises a material selected from the group consisting of gelatin;

hyaluronic acid, methyl cellulose, polyglycolic acid, and polylactic acid.

26. The device of claim 5, wherein said device is sufficiently flexible to allow insertion through an incision smaller in dimensions than the largest dimension of said device and allows sealable attachment to an irregular organ surface.

27. The device of claim 1, wherein said attachment mechanism comprises at least one stabilizer on said first wall for engaging a buckling band or suture for sealably engaging said device with a target tissue.

28. The device of claim 1, further comprising a buckling band, wherein said buckling band can encircle said device and a portion of an organ to which said device is attachable.

29. The device of claim 28, wherein said buckling band can engage said device with the sclera of an eye.

30. The device of claim 1, wherein said stabilizer is shaped to engage a buckling band for secure attachment of said device to a surface, said surface being the sclera of an eye.

31. The device of claim 12, wherein said agent is in an encapsulated form.

32. The device of claim 12, wherein said agent is incorporated into liposomes or microspheres.

33. The device of claim 12, wherein said agent is in an inactive form.

34. The device of claim 15, wherein said vehicle comprises at least one of the group consisting of a polymer, a copolymer, and a tissue.

35. The device of claim 15, wherein said vehicle interacts with said agent to control release thereof.

36. The device of claim 12, further comprising a substance for controlling the release of said agent.

37. The device of claim 1, wherein said reservoir comprises at least two compartments.

38. The device of claim 37, wherein said at least two compartments are divided by a wall that also divides said release port into at least two outlets corresponding to each of said at least two compartments, at least a portion of said wall is capable of sealable attachment to a tissue when said sealing base is attached thereto, wherein agents contained in separate compartments of said at least two compartments are substantially isolated from each other.

39. The device of claim 12, further comprising a second therapeutic or prophylactic agent, wherein said second therapeutic agent can be delivered to a target tissue after a portion of said first therapeutic or prophylactic agent is delivered to a target tissue.

40. The device of claim 12, further comprising an osmotic agent.

41. The device of claim 24, wherein said barrier layer is biodegradable.

42. A method of targeted delivery of a therapeutic or prophylactic substance to a tissue, comprising delivering a therapeutic or prophylactic substance to a target area of a tissue using the device of claim 1.

43. The method of claim 42, wherein said target area comprises myocardial tissue.

44. The method of claim 42, wherein said target area comprises scleral tissue.

45. The method of claim 42, wherein said target area comprises pericardial tissue.

46. The method of claim 42, wherein said target area comprises hepatic tissue.

47. The method of claim 42, wherein said target area comprises renal tissue.

48. The method of claim 42, wherein said target area comprises uterine tissue.

49. The method of claim 42, wherein said substance is delivered to treat cancer.

50. The method of claim 42, wherein said substance is delivered to treat retinoblastoma.

51. The method of claim 42, wherein said substance is delivered to cause an effect selected from the group consisting of treatment of an ocular disorder, treatment of a renal disorder, treatment of a hepatic disorder, treatment of a cardiac disorder, treatment of a gastrointestinal disorder, treatment of a genital-urinary disorder, treatment of an endocrine disorder, treatment of a neurological disorder, and treatment of an immunological disorder.

52. The method of claim 51, wherein said treatment is prophylactic.

53. The method of claim 51, wherein said ocular disorder is selected from the group consisting of an ocular tumor, glaucoma, a macular degenerative condition, and an immune response to an ocular surgery.

54. The method of claim 42, wherein the substance is delivered to a target tissue to cause an effect other than or in addition to an effect caused in said target tissue.

55. The method of claim 42, wherein the target tissue is transplanted tissue.

56. The method of claim 42, wherein said tissue comprises a material selected from the group consisting of mammalian tissue, an artificial organ, and a synthetic or biological scaffold for cells or biological agents.

57. The method of claim 42, wherein said tissue is transplant tissue.

58. The device of claim 1, wherein said device further comprises at least one first therapeutic agent, wherein the effect or diffusion of said at least one first therapeutic agent may be started or enhanced by the use of at least one second agent selected from the group consisting of a biological agent, a physical agent, and a chemical agent.

59. The device of claim 1, wherein said sealing base has a similar curvature as the targeted tissue surface.

60. The device of claim 1, wherein said sealing base comprises at least one cavity to hold an adhesive in place.

61. The device of claim 1, wherein said sealing base comprises at least one channel to hold an adhesive in place.

62. The device of claim 1, wherein said sealing base is composed of a different material from said first wall.

63. The device of claim 62, wherein said sealing base is composed of a material selected from the group consisting of a poly-ethylene, silicone, a hydrogel, a poly-orthoester, poly-glycolic acid, poly-lactic acid, poly-caprolactone, polyvinyl-alcohol, polyvinyl-pylirridone, hyaluronic acid, fibrin, methyl-cellulose, collagen, and gelatin.

64. The device of claim 37, further comprising at least one refill port connected to said reservoir.

65. The device of claim 1, wherein said release port has a perimeter, and said sealing base surrounds said release port perimeter.

66. An implantable delivery device for delivery of at least a first therapeutic agent into a target tissue, comprising:

a housing, said housing comprising a reservoir with a release part for release of at least a first therapeutic agent into a target tissue, said reservoir having at least a first wall that is substantially impermeable to a first therapeutic agent to be placed therein, a sealing base for sealing said release port to a target tissue, wherein when said release port is sealed to a target tissue a first therapeutic agent in said reservoir is substantially prohibited from release by said device other than through said release port into the target tissue, and

an attachment mechanism to facilitate sealing of said release port to a target tissue,

wherein said attachment mechanism comprises a sufficient amount of an adhesive for adhering said sealing base to a target tissue, wherein said adhesive is held within at least one cavity or channel within said sealing base.

67. The device of claim 66, wherein said adhesive comprises at least one of the group consisting of fibrin, hydrogel, and hyaluronate.

68. The device of claim 66, wherein said adhesive comprises an acrylate.

69. The device of claim 66, further comprising a peelable layer apposed to said adhesive.

70. An implantable delivery device for delivery of at least a first therapeutic agent into a target tissue, comprising:

a housing, said housing comprising a reservoir with a release port for release of at least a first therapeutic agent into a target tissue, said reservoir having at least a first wall, a sealing base for sealing said release port to a target tissue, wherein when said release port is sealed to a target tissue a first therapeutic agent in said reservoir can be released through said release port into the target tissue, and

an attachment mechanism to facilitate sealing of said release port to a target tissue, wherein said attachment mechanism comprises a suture holder for engaging at least one suture operatively attached to tissue surrounding a target tissue, and wherein said first wall is impermeable to a first therapeutic agent placed in said reservoir, wherein said release port has a perimeter, and said suture holder comprises at least one groove in said first wall, wherein said at least one groove can be engaged by at least one suture or buckling band to fix said device to a target tissue so that said release port is sealed to the tissue.

71. An implantable delivery device for delivery of at least a first therapeutic agent into a target tissue, comprising:

a housing, said housing comprising a reservoir with a release port for release of at least a first therapeutic agent into a target tissue, said reservoir having at least a first wall, a sealing base for sealing said release port to a target tissue, wherein when said release port is sealed to a target tissue a first therapeutic agent in said reservoir can be released through said release port into the target tissue, and

an attachment mechanism to facilitate sealing of said release port to a target tissue,

wherein said device further comprises a refill port, wherein said refill port comprises a material selected from the group consisting of a dye, a radiosensitive marker, and an echogenic marker so that said refill port is indicated by said material.

72. An implantable delivery device for delivery of at least a first therapeutic agent into a target tissue, comprising:

a housing, said housing comprising a reservoir with a release port for release of at least a first therapeutic agent into a target tissue, said reservoir having at least a first wall that is substantially impermeable to a first therapeutic agent to be placed therein,

a sealing base for sealing said release port to a target tissue, wherein when said release port is sealed to a target tissue a first therapeutic agent in said reservoir is substantially prohibited from release by said device other than through said release port into the target tissue, and

an attachment mechanism to facilitate sealing of said release port to a target tissue, said attachment mechanism comprising at least one member of the group consisting of a sufficient amount of an adhesive for adhering said sealing base to a target tissue wherein said adhesive is held within at least one cavity or channel within said sealing base, and at least one stabilizer on said first wall for engaging a buckling band or suture for sealably engaging said device with a target tissue, wherein said sealing base has a greater curvature than the targeted tissue surface.