Fabrication of drug loaded biodegradable polymer fibers

• US 20050106211A1
• Filed: 12/21/2004
• Published: 05/19/2005
• Est. Priority Date: 08/06/1999
• Status: Active Grant

• 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: Nelson, Kevin, Hu, Zhibing, Waggoner, Paula, Smith, George M., Alikacem, Nadir, Radulescu, Delia, Romero-Sanchez, Andres A.
• Granted Patent: US 7,514,095 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• 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

1-198. -198. (canceled)

199. A method of fabricating fibers, comprising:

a) obtaining a water-in-oil type emulsion comprising an aqueous phase containing an active biomolecule in a biodegradable polymer solution, wherein said emulsion is stabilized by a surfactant; and

b) extruding said emulsion into a coagulating bath.

200. The method of claim 199, wherein the biodegradable polymer may be any synthetic biodegradable polymer.

201. The method of claim 199, wherein the polymer is solublilized in solvent that is a good solvent for the polymer, is substantially immiscible with water and is highly miscible with the coagulating bath solvent, and said coagulating bath solvent is a poor solvent for the polymer.

202. The method of claim 199, wherein the surfactant may be selected from the group consisting of bovine serum albumin (BSA), poly(vinyl alcohol), pluronics, or a naturally occurring surfactant.

203. The method of claim 202, wherein the naturally occurring surfactant is a phospholipid.

204. The method of claim 199, wherein the coagulating bath solvent is a non-solvent for the polymer and highly miscible with the polymer solvent.

205. The method of claim 200, wherein the polymer is selected from the group consisting of poly(L-lactic acid), poly(DL-lactic acid), poly(glycolic acid), polycaprolactone, and polyanhydride.

206. The method of claim 205, wherein the polymer may be a copolymer or blend of any polymer selected from the group consisting of poly(L-lactic acid), poly(DL-lactic acid), poly(glycolic acid), polycaprolactone and polyanhydride.

207. The method of claim 201, wherein the polymer solvent comprises at least one solvent that is a good solvent for the polymer and at least one solvent that is a poor solvent for the polymer.

208. The method of claim 199, wherein the coagulation bath further comprises a polymer solvent.

209. The method of claim 199, wherein the coagulation bath further comprises a viscous solvent or viscous additive.

210. The method of claim 209, wherein the viscous solvent is glycerol.

211. The method of claim 210, wherein the glycerol concentration is between about 8% and about 20% v/v.

212. A method of fabricating fibers with a linear gradient of bioactive molecules, said method comprising:

a) obtaining a first polymer solution and a second polymer solution; and

b) mixing said first polymer solution and said second polymer solution in a continuously changing ratio to obtain a mixture of said first and second polymer solutions, while extruding said mixture into a coagulating bath.

213. The method of claim 212, wherein at least one of said first polymer solution and said second polymer solution is a surfactant stabilized water-in-oil type emulsion of an aqueous phase comprising an active biomolecule of interest in a biodegradable polymer solution.

214. The method of claim 212, wherein the second polymer comprises a surfactant and lacks an active biomolecule, or contains a different active biomolecule.

215. The method of claim 213, wherein the ratio of said first polymer solution and said second polymer solution is controlled using a butterfly valve.

216. The method of claim 213, wherein said first polymer solution and said second polymer solution are contained in separate pumps and are mixed in a mixing chamber.

217. The method of claim 212, wherein the polymer solution comprises a good solvent for the polymer, said solvent being substantially immiscible with water and highly miscible with the coagulating bath.

218. The method of claim 212, wherein the surfactant may be selected from the group consisting of bovine serum albumin (BSA), poly(vinyl alcohol), pluronics, or a naturally occurring surfactant.

219. The method of claim 218, wherein the coagulating bath solvent is a non-solvent for the polymer.

220. The method of claim 218, wherein the polymer is at least one polymer selected from the group consisting of poly(L-lactic acid), poly(DL-lactic acid), poly(glycolic acid), polycaprolactone, and polyanhydride.

221. The method of claim 218, wherein the polymer 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 polyanhydride.

222. The method of claim 212, wherein the polymer solvent comprises a mixture of at least one good solvent for the polymer and at least one poor solvent for the polymer.

224. The method of claim 217, wherein the coagulating bath solvent comprises a viscous solvent or viscous additive.

223. The method of claim 253, wherein the coagulating bath solvent further comprises a polymer solvent.