Biodegradable in-situ forming implants and methods of producing the same

• US 5,278,201 A
• Filed: 04/24/1990
• Issued: 01/11/1994
• Est. Priority Date: 10/03/1988
• Status: Expired due to Term

• Current Assignee: Atrix Laboratories, Inc. (TOLMAR Holding, Inc.)
• Original Assignee: Atrix Laboratories, Inc. (TOLMAR Holding, Inc.)
• Inventors: Dunn, Richard L., Cowsar, Donald R., Vanderbilt, David P., English, James P.
• Primary Examiner(s): Michl, Paul R.
• Assistant Examiner(s): MERRIAM, ANDREW EDWIN
• Application Number:
  US07/513,782
• Time in Patent Office: 1,358 Days
• Field of Search: 523/105, 523/113, 524/173, 524/113, 524/233, 524/361, 524/386, 524/391, 424/422, 424/426, 525/937
• US Class Current: 523/113
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2002/30583 filled with hardenable fluid, e.g. curable in-situ
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2210/0085 hardenable in situ, e.g. epoxy resins
• 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: A61L 15/44 Medicaments
• CPC Class Codes: A61L 15/62 Compostable, hydrosoluble or hydrodegradable materials
• CPC Class Codes: A61L 2300/25 Peptides having up to 20 amino acids in a defined sequence
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• 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 2300/604 Biodegradation
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 24/0026 Sprayable compositions
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: A61L 24/06 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043, A61L24/046 take precedence
• CPC Class Codes: A61L 26/0019 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 26/0066 : Medicaments; Biocides
• CPC Class Codes: A61L 26/0076 : Sprayable compositions
• CPC Class Codes: A61L 26/009 : Materials resorbable by the body
• 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 27/26 : Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/34 : Macromolecular materials
• 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 27/58 : Materials at least partially resorbable by the body
• CPC Class Codes: C08L 67/04 : Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: C08L 75/04 : Polyurethanes
• CPC Class Codes: Y10S 525/937 : Utility as body contact e.g. implant, contact lens or I.U.D.

Abstract

A biodegradable polymer is provided for use in providing syringeable, in-situ forming, solid biodegradable implants for animals. The polymer is placed into the animal in liquid form and cures to form the implant in-situ. A thermoplastic system to form said implant comprises the steps of dissolving a non-reactive polymer in biocompatible solvent to form a liquid, placing the liquid within the animal, and allowing the solvent to dissipate to produce the implant. An alternative, thermosetting system comprises mixing together effective amounts of a liquid acrylic ester terminated, biodegradable prepolymer and a curing agent, placing the liquid mixture within an animal and allowing the prepolymer to cure to form the implant. Both systems provide a syringeable, solid biodegradable delivery system by the addition of an effective level of biologically active agent to the liquid before injection into the body.

Claims

1. A pharmaceutical composition for forming a solid or coagulated biodegradable implant in-situ within a body, comprising a liquid solution of a non-reactive, biocompatible, pharmaceutically acceptable thermoplastic linear polymer that is water-insoluble and is biodegradable by simple or enzymatically catalyzed hydrolysis, and a pharmaceutically acceptable biocompatible solvent that is water-soluble, wherein the concentrations and formulas of said polymer and said solvent in said solution are effective to form said implant in-situ when said solution contacts body fluid.

14. The composition of claim 1, wherein said solvent is selected from the group consisting essentially of N-methyl-2-pyrrolidone, ethanol, propylene glycol, 2-pyrrolidone, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid and 1-dodecylazacycloheptan-2-one and combinations and mixtures thereof.

15. The composition of claim 1, wherein said solvent is selected from the group consisting essentially of N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide and acetone, and a combination or mixture thereof.

16. The composition of claim 1, further comprising an effective amount of a biologically active agent.

17. The pharmaceutical composition according to claim 1, wherein the concentrations and formulas of said polymer and said solvent are effective to form a space filling implant when said composition is inserted into a site within the body.

2. A pharmaceutical composition for forming a solid or coagulated biodegradable implant in-situ within a body, comprising a liquid solution of a non-reactive, biocompatible, pharmaceutically acceptable, thermoplastic linear polymer that is water-insoluble and a pharmaceutically acceptable biocompatible solvent that is water-soluble, wherein the concentrations and formulas of said polymer and said solvent in said solution are effective to form said implant in situ when said solution contacts body fluid;

and wherein said polymer is selected from the group consisting essentially of polylactides, polyglycolides, polycaprolactones, polydioxannones, polycarbonates, polyhydroxybutyrates, polyalkyene oxalates, polyanhydrides, polyamides, polyesteramides, polyurethanes, polyacetals, polyketals, polyorthocarbonates, polyphosphazenes, polyhydroxyvalerates, polyalkylene succinates, poly(malic acid), poly(amino acids), chitin, chitosan, polyorthoesters, and copolymers, terpolymers and combinations and mixtures thereof.

3. The composition of claim 2, wherein said polymer is selected from the group consisting essentially of polylactides, polycaprolactones and copolymers thereof with glycolide.

4. The composition of claim 2, wherein said solvent is selected from the group consisting essentially of N-methyl-2-pyrrolidone, ethanol, propylene glycol, 2-pyrrolidone, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid and 1-dodecylazacycloheptan-2-one and combinations and mixtures thereof.

5. The composition of claim 2, wherein said solvent is selected from the group consisting essentially of N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide and acetone, and a combination or mixture thereof.

6. The composition of claim 2, and further comprising an effective amount of a biologically active agent.

7. The pharmaceutical composition according to claim 2, wherein the concentrations and formulas of said polymer and said solvent are effective to form a space filling implant when said composition is inserted into a site within the body.

8. The pharmaceutical composition according to claim 3, wherein the weight % of said polymer in said solution is between about 20% and 75%.

9. A pharmaceutical kit suitable for in situ formation of a biodegradable implant in a body, which comprises:

A) a solution of a biodegradable, biocompatible, pharmaceutically acceptable thermoplastic polymer that is water-insoluble and a pharmaceutically acceptable solvent that is water-soluble, wherein the concentrations and formulas of the polymer and the solvent in the solution are effective to form an implant in situ when said solution contacts body fluid and wherein said polymer is selected from the group consisting essentially of polylactides, polyglycolides, polycaprolactones, polydioxannones, polycarbonates, polyhydroxybutyrates, polyalkyene oxalates, polyanhydrides, polyamides, polyesteramides, polyurethanes, polyacetals, polyketals, polyorthocarbonates, polyphosphazenes, polyhydroxyvalerates, polyalkylene succinates, poly(malic acid), poly(amino acids), chitin, chitosan, polyorthoesters, and copolymers, terpolymers and combinations and mixtures thereof; and

,

B) a device containing said solution, said device having an outlet for the solution, an ejector for expelling the solution through the outlet and a hollow tube fitted to the outlet for inserting the solution into a site of the body such that the solution can form an implant in situ at said site.

10. The pharmaceutical kit according to claim 9, further comprising a biologically active agent dissolved or dispersed within said solution.

11. The pharmaceutical kit according to claim 9, wherein said concentrations and formulas of said polymer and said solvent in said solution contained within said device are effective to form an implant in situ when the solution contacts body fluid.

12. The pharmaceutical kit according to claim 9, wherein said concentrations and formulas of the polymer and the organic solvent are effective to form a space filling implant when the solution is inserted into said site.

13. The pharmaceutical kit according to claim 9, wherein said polymer is selected from the group consisting of polylactides, polycaprolactones and copolymers thereof with glycolide.

18. A pharmaceutical kit suitable for in-situ formation of a biodegradable implant in a body, which comprises:

A) a solution of a biocompatible, pharmaceutically acceptable thermoplastic polymer that is water-insoluble and is biodegradable by a simple or enzymatically catalyzed hydrolysis, and a pharmaceutically acceptable solvent that is water-soluble, wherein the concentrations and formulas of the polymer and the solvent in the solution are effective to form an implant in-situ when said solution contacts body fluid; and

,

B) a device containing said solution, said device having an outlet for the solution, an ejector for expelling the solution through the outlet and a hollow tube fitted to the outlet for inserting the solution into a site of the body such that the solution can form an implant in-situ at said site.

19. The pharmaceutical kit according to claim 18, further comprising a biologically active agent dissolved or dispersed within said solution.

20. The pharmaceutical kit according to claim 18, wherein said concentrations and formulas of said polymer and said solvent in said solution contained within said device are effective to form an implant in situ when the solution contacts body fluid.

21. The pharmaceutical kit according to claim 18, wherein said concentrations and formulas of the polymer and the organic solvent are effective to form a space filling implant when the solution is inserted into said site.