Method and composition for treating a bone tissue defect

• US 6,071,530 A
• Filed: 06/26/1997
• Issued: 06/06/2000
• Est. Priority Date: 07/24/1989
• Status: Expired due to Term

• Current Assignee: Atrix Laboratories, Inc. (TOLMAR Holding, Inc.)
• Original Assignee: Atrix Laboratories, Inc. (TOLMAR Holding, Inc.)
• Inventors: Peterson, Kenneth S., Lowe, Bryan K., Cox, Charles P., Polson, Alan M., Dunn, Richard L., Norton, Richard L., Swanbom, Deryl D.
• Primary Examiner(s): Spear, James M.
• Application Number:
  US08/883,260
• Time in Patent Office: 1,076 Days
• Field of Search: 424/422, 424/423, 424/426, 424/424, 424/428, 424/427
• US Class Current: 424/426
• CPC Class Codes: A61K 31/74 Synthetic polymeric materials
• CPC Class Codes: A61K 33/42 Phosphorus; Compounds thereof
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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 9/0063 Periodont
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/43 Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 27/16 obtained by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/14 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 31/148 : Materials at least partially resorbable by the body
• CPC Class Codes: B29C 41/08 : Coating a former, core or other substrate by spraying or fluidisation, e.g. spraying powder spray-up of reinforcing fibres B29C70/305
• CPC Class Codes: B29C 41/12 : Spreading-out the material on a substrate , e.g. on the surface of a liquid
• CPC Class Codes: B29C 67/06 : Coagulating
• CPC Class Codes: B29K 2995/0056 : Biocompatible, e.g. biopolymers or bioelastomers
• CPC Class Codes: B29K 2995/006 : Bio-degradable, e.g. bioabsorbable, bioresorbable or bioerodible
• CPC Class Codes: C08L 67/04 : Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

The invention is directed to a biodegradable implant precursor having a two-part structure made of an outer sac and a liquid content. The implant precursor is composed of a biodegradable, water-coagulable thermoplastic polymer and a water-miscible organic solvent. When administered to an implant site in an animal, the implant precursor will solidify in situ to a solid, microporous matrix by dissipation of the organic solvent to surrounding tissue fluids and coagulation of the polymer. The invention also includes methods of making the implant precursor, an apparatus for forming the precursor, and a kit containing the apparatus. Also provided are methods of using the implant precursor for treating a tissue defect in an animal, for example, for enhancing cell growth and tissue regeneration, wound and organ repair, nerve regeneration, soft and hard tissue regeneration, and the like, for delivery of biologically-active substances to tissue or organs, and other like therapies.

Claims

1. A method of treating a bone tissue defect in an animal, the method comprising:

dispensing a polymer solution onto a support substrate surrounded by an aqueous medium or body fluid;

wherein the polymer solution comprises a pharmaceutically acceptable biodegradable, thermoplastic polymer that is insoluble in the aqueous medium or body fluid;

in combination with a biocompatible organic solvent that solubilizes the polymer and is miscible to dispersible in the aqueous medium or body fluid; and

a bone growth promoting substance, wherein the polymer solution is in a liquid form, wherein the support substrate is a tissue in the animal and the organic solvent diffuses into the aqueous medium or body fluid and the thermoplastic polymer coagulates to form a solid microporous implant in which the bone growth promoting substance is incorporated when the polymer solution is dispensed on the support substrate.

2. The method of claim 1 wherein the bone growth promoting substance is hydroxyapatite.

3. The method of claim 1 wherein the bone growth promoting substance is bone morphogenic protein.

4. The method of claim 1, wherein the thermoplastic polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, polymalic acid, polyamino acids, polymethyl vinyl ether, chitin, and chitosan.

5. The method of claim 1, wherein the thermoplastic polymer is selected from the group consisting of polylactide, polycaprolactone, and polyglycolide.

6. The method of claim 1, wherein the organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol, propylene carbonate, acetone, acetic acid, ethyl acetate, ethyl lactate, methyl acetate, methyl ethyl ketone, dimethylforamide, dimethyl sulfoxide, dimethyl sulfone, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, N,N-diethyl-m-toluamide, and 1-dodecylazacycloheptan-2-one, and combinations thereof.

7. A pharmaceutical composition suitable for treating a bone tissue defect in an animal, the composition comprising:

a pharmaceutically acceptable, biodegradable, thermoplastic polymer that is insoluble in an aqueous medium or body fluid;

a biocompatible organic solvent that solubilizes the polymer and is miscible to dispersible in the aqueous medium or body fluid; and

an effective amount of bone growth promoting substance, wherein the bone growth promoting substance is hydroxyapatite;

wherein, the composition is flowable when the composition is placed in contact with the aqueous medium or body fluid, and upon contacting the body fluid or aqueous medium the organic solvent diffuses into the aqueous medium or body fluid and the thermoplastic polymer coagulates to form a solid microporous implant in situ in which the bone growth promoting substance is incorporated.

8. A pharmaceutical composition suitable for treating a bone tissue defect in an animal, the composition comprising:

a pharmaceutically acceptable, biodegradable, thermoplastic polymer that is insoluble in an aqueous medium or body fluid;

a biocompatible organic solvent that solubilizes the polymer and is miscible to dispersible in the aqueous medium or body fluid, wherein the solvent is selected from the group consisting of N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, ethyl lactate and propylene carbonate; and

an effective amount of bone growth promoting substance;

wherein, the composition is flowable when the composition is placed in contact with the aqueous medium or body fluid, and upon contacting the body fluid or aqueous medium the organic solvent diffuses into the aqueous medium or body fluid and the thermoplastic polymer coagulates to form a solid microporous implant in situ in which the bone growth promoting substance is incorporated.

9. The composition of claim 8, wherein the bone growth promoting substance is hydroxyapatite.

10. The composition of claim 8, wherein the bone growth promoting substance is bone morphogenic protein.

11. The composition of claim 8, wherein the thermoplastic polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, polymalic acid, polyamino acids, polymethyl vinyl ether, chitin, and chitosan.

12. The composition of claim 8, wherein the thermoplastic polymer is selected from the group consisting of polylactide, polycaprolactone, and polyglycolide.