Fabrication of drug loaded biodegradable polymer fibers

• US 6,858,222 B2
• Filed: 05/02/2003
• Issued: 02/22/2005
• 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: Hu, Zhibing, Nelson, Kevin D, Waggoner, Paula, Smith, George M., Alikacem, Nadir, Radulescu, Delia, Romero-Sanchez, Andres A.
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US10/428,354
• Publication Number:
  US 20030203003A1
• Time in Patent Office: 662 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 method of extruding a drug releasing fiber from chitosan comprising use of hydrochloric acid as a solvent and Tris base as coagulating bath.

2. The method of claim 1, wherein the hydrochloric acid concentration is from about 0.25% to about 5%.

3. The method of claim 1, wherein the tris base concentration is from about 2% to about 25%.

4. The method of claim 1, comprising using a heterogeneous mixture comprising chitosans with different degrees of deacetylation.

5. The method of claim 1, comprising creating a drug releasing fiber comprising segments of chitosan with different degrees of deacetylation.

6. The method of claim 1, comprising creating a drug releasing fiber from chitosan and an extracellular matrix.

7. The method of claim 6, wherein the chitosan concentration is from about 0.5 wt. % to about 10 wt. %.

8. The method of claim 6, wherein said extracellular matrix comprises Matrigel.

9. The method of claim 6, wherein the extracellular matrix concentration is from about 1 vol. % to about 20 vol. %.

10. The method of claim 1, comprising coating said fiber with said extracellular matrix.

11. The method of claim 1, wherein a portion of said chitosan is sulfated chitosan.

12. The method of claim 1, wherein the sulfated chitosan concentration is from about 0.025 wt % to about 2 wt %.

13. A method of creating a drug releasing fiber from chitosan, said method comprising:

a) obtaining a polymer solution comprising chitosan and a hydrochloric acid; and

b) extruding the polymer solution into a coagulating bath comprising tris base.

14. The method of claim 13, wherein the concentration of the hydrochloric acid is about 1%.

15. The method of claim 13, wherein the concentration of tris base is between about 5% and about 15%.

16. The method of claim 13, is further comprising adding microspheres comprising at least one biomolecule to the chitosan solution prior to extruding.

17. The method of claim 16, wherein the biomolecule microsphere is made from a either a pure polymer, or is a copolymer or blend of the polymers selected from the group consisting of poly(L-lactic acid), poly(DL-lactic acid), poly(glycolic acid), polycaprolactone, and polyanhydridepoly(L-lactic acid).

18. The method of claim 13, further comprising applying at least one polymer coating comprising containing a biomolecule emulsion to said fibers thereby rendering said fibers capable of temporally controlling release of said multiple biomolecules, wherein said applying step is prior to the extruding step.

19. The method of claim 18, wherein said applying comprises passing said fiber through a spinneret comprising the emulsion.

20. The method of claim 13, further comprising assembling multiple fibers into a fabric, each wherein one or more fibers of said fabric comprising at least one biomolecule having a specific activity for a certain cell type, wherein said biomolecule may differ from the biomolecule in other fibers in said fabric.

21. The method of claim 20, wherein the fibers release the biomolecules over a period of time.

22. The method of claim 20, wherein at least a portion of the fibers may be coated to release various factors and chemicals over a period of time.

23. The method of claim 22, wherein a first portion of the coated fibers correspond to a first phase of dermal wound healing, a second portion of the coated fibers correspond to a second phase of dermal wound healing and a third portion of the coated fibers correspond to a third phase of dermal wound healing.