Drug releasing biodegradable fiber implant

• US 6,596,296 B1
• Filed: 08/04/2000
• Issued: 07/22/2003
• Est. Priority Date: 08/06/1999
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Romero-Sanchez, Andres A., Smith, George M., Alikacem, Nadir, Radulescu, Delia, Waggoner, Paula, Hu, Zhibing, Nelson, Kevin D.
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US09/632,457
• Time in Patent Office: 1,082 Days
• Field of Search: 424/426, 514/772.3
• US Class Current: 424/426
• CPC Class Codes: A61B 17/1128 of nerves
• 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 9/70 Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug hollow drug-filled fibres A61K9/0092
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/258 Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: D01F 1/10 Other agents for modifying properties
• CPC Class Codes: D01F 6/625 derived from hydroxy-carboxylic acids, e.g. lactones
• CPC Class Codes: D01F 8/14 with at least one polyester as constituent
• CPC Class Codes: D06M 15/03 Polysaccharides or derivatives thereof
• CPC Class Codes: D06M 16/00 Biochemical treatment of fibres, threads, yarns, fabrics, or fibrous goods made from such materials, e.g. enzymatic
• CPC Class Codes: Y10T 428/30 : Self-sustaining carbon mass or layer with impregnant or other layer
• CPC Class Codes: Y10T 442/2525 : Coating or impregnation functions biologically [e.g., insect repellent, antiseptic, insecticide, bactericide, etc.]

Abstract

The invention provides tissue engineering compositions and methods wherein three-dimensional matrices for growing cells are prepared for in vitro and in vivo use. The matrices comprise biodegradable polymer fibers capable of the controlled delivery of therapeutic agents. The spatial and temporal distribution of released therapeutic agents is controlled by use of defined nonhomogeneous patterns of therapeutic agents in the matrices.

Claims

1. A composition comprising at least one biodegradable polymer fiber wherein said fiber is composed of a first phase and a second phase, the first and second phases being immiscible, and wherein the second phase comprises one or more therapeutic agents.

2. The composition of claim 1, wherein said second phase is derived from an aqueous solution, a hydrogel or polymer.

3. The composition of claim 1, wherein said fiber forms a scaffold and further wherein, said second phase is manipulated to form an internal porous structure within the fiber.

4. The composition of claim 1, wherein said fiber is woven, braided or knitted in an assembly with other fibers, and at least one fiber in the assembly comprises one or more therapeutic agents.

5. The composition of claim 1, wherein the one or more therapeutic agents are distributed within the second phase in a nonhomogenous pattern.

6. The composition of claim 1, wherein the concentration of said one or more therapeutic agents varies along the longitudinal axis of the fiber.

7. The composition of claim 6, wherein the concentration of said one or more therapeutic agents varies linearly, exponentially or in any desired fashion, as a function of distance along the longitudinal axis of the fiber.

8. The composition of claim 1, wherein the concentration of said one or more therapeutic agents decreases from a first end of the fiber to a second end of the fiber.

9. The composition of claim 1, wherein said one or more therapeutic agents vary in a bidirectional manner, and the content of said one or more therapeutic agents increases from the first end of said fiber to a maximum and then decreases towards the second end of said fiber.

10. The composition of claim 1, further comprising at least one biodegradable polymer fiber containing no therapeutic agent.

11. The composition of claim 1, wherein said one or more therapeutic agents are selected from the group consisting of drugs, proteins, enzymes, growth factors, immunomodulators, compounds promoting angiogenesis, compounds inhibiting angiogenesis, anti-inflammatory compounds, antibiotics, cytokines, anti-coagulation agents, procoagulation agents, chemotactic agents, agents to promote apoptosis, agents to inhibit apoptosis, and mitogenic agents.

12. The composition of claim 1, wherein said one or more therapeutic agents include a radioactive agent or a contrast agent for imaging studies.

13. The composition of claim 1, wherein said one or more therapeutic agents is selected from the group consisting of viral vector, polynucleotide and polypeptide.

14. The composition of claim 1, wherein said one or more therapeutic agents comprise an angiogenesis-promoting agent.

15. The composition of claim 14, wherein said angiogenesis-promoting agent is vascular endothelial growth factor.

16. The composition of claim 1, wherein said biodegradable polymer is a single polymer, a co-polymer, or a mixture of polymers selected from the group consisting of polypeptides, polydepsipeptides, nylon copolyamides, aliphatic polyesters, polydihydropyrans, polyphosphazenes, poly(ortho ester), poly(cyano acrylates), polyanhydride, modified polysaccharides and modified proteins.

17. The composition of claim 16, wherein said aliphatic polyesters are selected from the group consisting of poly(glycolic acid), poly(lactic acid), poly(alkylene succinates) poly(hydroxybutyrate), poly(butylene diglycolate), poly(epsilon-caprolactone) and copolymers, blends and mixtures thereof.

18. The composition of claim 16, wherein said modified polysaccharides are selected from the group consisting of cellulose, starch-alginate and the glycosaminoglycans, chondroitin sulfate, heparin, heparin sulfate, dextran, dextran sulfate, chitin, chitosan and chitosan sulfate.

19. The composition of claim 16, wherein said modified proteins are selected from the group consisting of collagen and fibrin.

20. The composition of claim 1, wherein said fiber comprises a plurality of polymer layers, wherein an outer layer circumscribes an adjacent inner layer.

21. The composition of claim 20, wherein said plurality of layers optionally contain one or more therapeutic agents.

22. The composition of claim 21, wherein said one or more therapeutic agents are released over time from said plurality of layers.

23. The composition of claim 1, wherein the fiber contains more than one therapeutic agent along its length.

24. The composition of claim 23, wherein the concentration of said more than one therapeutic agent varies along the length of said subset of fibers.

25. The composition of claim 23, wherein said more than one therapeutic agents are released at varying rates over time from said fiber.

26. The composition of claim 1, wherein said one or more therapeutic agents are released at varying rates over time from said fiber.

31. The composition of claim 21, wherein said one or more therapeutic agents are distributed within the plurality of layers in a nonhomogenous pattern.

32. The composition of claim 31, wherein the concentration of said one or more therapeutic agents varies linearly, exponentially or in any desired fashion, as a function of distance within the plurality of layers.

27. A composition comprising a three-dimensional scaffold, said scaffold comprising fibers that are woven, non-woven, or knitted, or braided, wherein said fibers comprise fibers containing chitosan or a reconstituted extracellular matrix composition.

28. The composition of claim 27, wherein said chitosan is sulfated chitosan.

29. A composition comprising fibers containing chitosan, reconstituted extracellular matrix composition and a therapeutic agent.

30. The composition of claim 29, wherein said chitosan is sulfated chitosan.