Multi-layer structure having a predetermined layer pattern including an agent

• US 20060269475A1
• Filed: 04/11/2006
• Published: 11/30/2006
• Est. Priority Date: 04/11/2005
• Status: Abandoned Application

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Inventors: Ryu, WonHyoung, Prinz, Friedrich B., Fasching, Rainer J., Greco, Ralph S.
• Application Number:
  US11/402,651
• Publication Number:
  US 20060269475A1
• Time in Patent Office: Days
• US Class Current: 424/1.110
• CPC Class Codes: A61K 51/1282 Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• 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 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/0097 Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips intradermal microneedle arrays A61K9/0021; MEMS in general B81B7/02
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence

Abstract

Improved controlled therapy is provided with a polymer multi-layer structure having a predetermined micro-fabricated spatial pattern (e.g., reservoirs and channels). More specifically, all geometrical details of the spatial pattern are substantially predetermined. The increased control of pattern geometry provided by the invention allows for improved control of therapy. In preferred embodiments, the polymer multi-layer structure of the invention is biodegradable, but has an in vivo lifetime that is greater than the duration of the therapy being provided. Thus, the geometrical pattern of the polymer structure that controls delivery of the therapy persists without significant change during therapy, and the structure degrades after completion of therapy. In this manner, possible interference of degradation by-products with therapy is minimized, and delivery of therapy does not depend on details of how degradation proceeds.

Claims

1. Apparatus comprising:

a matrix layer comprising a matrix polymer having a microstructured matrix layer spatial pattern having voids, wherein all geometrical details of the matrix layer spatial pattern are substantially predetermined;

one or more agents disposed in the voids; and

an encapsulation layer comprising an encapsulation polymer and disposed to cover the matrix layer spatial pattern.

2. The apparatus of claim 1, wherein said matrix polymer comprises a polymer selected from the group consisting of:

aliphatic polyesters, copoly(ether-esters), polyalkylene oxalates, polyamides, polyorthoesters, polyoxaesters, poly(anhydrides), poly(dimethylsiloxane), silicone elastomers, polyurethane, poly(tetrafluoroethylene), polyethylene, polysulfone, poly(methyl methacrylate), poly(2-hydroxyethyl methacrylate), polyacrylonitrile, polyamides, polypropylene, poly(vinyl chloride), poly(ethylene-co-(vinyl acetate)), polystyrene, poly(vinyl pyrrolidine), saccharides, cellulose, chitin, dextran, proteins, collagen, albumin, acrylates, acrylamides, poly(acryl acid), polyacrylamide, poly(1-hydroxyethyl methacrylate), poly(ethylene glycol), yellow wax, petrolatum cholesterol, stearyl alcohol, white wax, white petrolatum, methylparaben, propylparaben, sodium lauryl sulfate, and mixtures, dispersions or co-polymers thereof.

3. The apparatus of claim 1, wherein said encapsulation polymer comprises a polymer selected from the group consisting of:

aliphatic polyesters, copoly(ether-esters), polyalkylene oxalates, polyamides, polyorthoesters, polyoxaesters, poly(anhydrides), poly(dimethylsiloxane), silicone elastomers, polyurethane, poly(tetrafluoroethylene), polyethylene, polysulfone, poly(methyl methacrylate), poly(2-hydroxyethyl methacrylate), polyacrylonitrile, polyamides, polypropylene, poly(vinyl chloride), poly(ethylene-co-(vinyl acetate)), polystyrene, poly(vinyl pyrrolidine), and mixtures or co-polymers thereof.

4. The apparatus of claim 1, wherein said matrix layer and said encapsulation layer are both biodegradable, whereby said apparatus has an in vivo lifetime.

5. The apparatus of claim 4, wherein said in vivo lifetime is greater than a duration of said therapy, whereby delivery of said therapy is substantially independent of degradation of said matrix layer and said encapsulation layer.

6. The apparatus of claim 1, further comprising one or more additional matrix layers, each additional matrix layer having a predetermined spatial pattern including voids, wherein voids in each matrix layer include different therapeutic agents, whereby controlled delivery of multiple therapies is provided.

7. The apparatus of claim 1, wherein said one or more therapeutic agents comprises one or more chemical agents.

8. The apparatus of claim 7, wherein said matrix layer and said encapsulation layer have thicknesses between about 50 μ

m and about 150 μ

m.

9. The apparatus of claim 7, further comprising a barrier layer disposed between and in contact with said encapsulation layer and said matrix layer.

10. The apparatus of claim 7, wherein said barrier layer is biodegradable or solvable in tissue fluid and has a barrier layer lifetime less than a duration of said therapy.

11. The apparatus of claim 7, wherein said barrier layer comprises a material selected from the group consisting of:

aliphatic polyesters, copoly(ether-esters), polyalkylene oxalates, polyamides, polyorthoesters, polyoxaesters, poly(anhydrides), saccharides, cellulose, chitin, dextran, proteins, collagen, albumin, acrylates, acrylamides, poly(acryl acid), polyacrylamide, poly(1-hydroxyethyl methacrylate), and poly(ethylene glycol), and mixtures, dispersions or co-polymers thereof.

12. The apparatus of claim 7, wherein said encapsulation layer has an encapsulation layer spatial pattern comprising through holes and wherein all geometrical details of the encapsulation layer spatial pattern are substantially predetermined.

13. The apparatus of claim 12, wherein a delivery rate of said one or more chemical agents as a function of time is predetermined, in part, by said encapsulation layer spatial pattern.

14. The apparatus of claim 13, wherein said delivery rate is primarily diffusion-limited.

15. The apparatus of claim 13, wherein said delivery rate is primarily osmosis-driven.

16. The apparatus of claim 12, wherein said matrix layer spatial pattern and said encapsulation layer spatial pattern combine to form reservoirs containing said therapeutic agent and channels for regulating delivery of said therapy, wherein the channels extend from the reservoirs to said through holes.

17. The apparatus of claim 16, wherein said channels include a biodegradable or solvable material having a lifetime less than a duration of said therapy.

18. The apparatus of claim 16, wherein at least one of said reservoirs includes two or more compartments.

19. The apparatus of claim 16, wherein said reservoirs have a diameter of about 1 mm and a height of about 100 μ

m.

20. The apparatus of claim 16, wherein said channels have a length less than about 3 cm and have a diameter between about 25 μ

m and about 50 μ

m.

21. The apparatus of claim 16, wherein said through holes have a diameter from about 200 μ

m to about 1 mm.

22. The apparatus of claim 1, wherein said encapsulation layer includes no through holes, and wherein said one or more therapeutic agents comprises one or more radioactive agents, each having a half life, whereby said therapy comprises radiotherapy.

23. The apparatus of claim 22, wherein said matrix layer and said encapsulation layer are both biodegradable, and wherein said matrix layer and said encapsulation layer each have an in vivo lifetime greater than about 10 times the longest of said half lives.

24. The apparatus of claim 22, wherein said voids are generally channel-shaped and have a length between about 10 mm and about 60 mm, a width between about 20 μ

m and about 300 μ

m, and a height between about 25 μ

m and about 100 μ

m.

25. The apparatus of claim 22, wherein said one or more therapeutic agents comprise a beta emitter having a half life of less than about 400 hours.

26. The apparatus of claim 1, wherein said one or more agents are selected from the group consisting of therapeutic agents, cell culture agents, tissue engineering agents or combinations thereof.

27. A method for providing therapy, the method comprising:

providing a polymer structure including;

a matrix layer comprising a matrix polymer having a microstructured matrix layer spatial pattern having voids; and

an encapsulation layer comprising an encapsulation polymer and disposed to cover the matrix layer spatial pattern;

wherein all geometrical details of the matrix layer spatial pattern are substantially predetermined;

providing one or more therapeutic agents disposed in the voids; and

delivering the polymer structure to an organism being treated.

28. The method of claim 27, wherein said delivering the polymer structure comprises applying the polymer structure to a surface of said organism.

29. The method of claim 27, wherein said delivering the polymer structure comprises implanting the polymer structure in said organism.

30. The method of claim 29, wherein said polymer structure is disposed on an outer surface of an implant.

31. The method of claim 30, wherein said implant is selected from the group consisting of stents, catheters, and joint replacements.

32. The method of claim 27, wherein said providing one or more therapeutic agents disposed in the voids is performed shortly prior to said delivering the polymer structure.

33. The method of claim 27, wherein said one or more therapeutic agents are provided in liquid form, and wherein said providing one or more therapeutic agents disposed in the voids comprises loading said voids via capillary action.

34. The method of claim 27, wherein said therapy is selected from the group consisting of:

delivery of antibiotics for periodontitis;

delivery of medication for glaucoma treatment;

delivery of agents for skin treatment;

transdermal delivery of drugs or medications;

delivery of growth factors, peptides, or DNA for wound healing, skin tissue repair, peripheral or central nervous system repair, skeletal or muscle tissue repair, vascular tissue regeneration, and/or controlled differentiation of stem cells;

delivery of pain relief agents and/or antibiotics for post-operative treatment;

temporary or permanent implantation; and

local delivery of anti-cancer medication, radio-sensitizer and/or radiation for cancer treatment.

35. A method for providing controlled release of an agent, the method comprising:

providing a polymer structure including;

a matrix layer comprising a matrix polymer having a microstructured matrix layer spatial pattern having voids; and

an encapsulation layer comprising an encapsulation polymer and disposed to cover the matrix layer spatial pattern;

wherein all geometrical details of the matrix layer spatial pattern are substantially predetermined; and

providing one or more agents disposed in the voids.