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

• US 5,739,176 A
• Filed: 03/18/1994
• Issued: 04/14/1998
• 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: Vanderbilt, David D., Dunn, Richard L., Cowsar, Donald R., English, James P.
• Primary Examiner(s): MERRIAM, ANDREW EDWIN
• Application Number:
  US08/210,891
• Time in Patent Office: 1,488 Days
• Field of Search: 523/113, 523/115, 524/96, 524/601, 525/937, 525/408, 525/412, 525/413, 424/422, 424/78.38, 604/51, 604/54, 604/26, 604/290
• 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 method of forming a solid, biodegradable implant in-situ, in a body, comprising:

(a) dissolving a biocompatible, water-insoluble, biodegradable thermoplastic polymer in a biocompatible, water-soluble organic solvent to form a composition;

the organic solvent being capable of dissipating or diffusing into a body fluid upon placement within a body tissue;

and the thermoplastic polymer being selected from the group consisting of;

(i) a copolymer of a biodegradable, water-insoluble monomer or polymer and a biodegradable, water-soluble monomer or polymer, wherein the amount of water-insoluble monomer or polymer is sufficient to render the copolymer water-insoluble;

(ii) a copolymer of polyethylene glycol with polylactide, polyglycolide or polycaprolactone, or a terpolymer thereof;

(iii) a copolymer of lactide with glycolide or caprolactone, or a terpolymer thereof;

(iv) a copolymer of lactide with a carbonate; and

(v) a polyanhydride; and

(b) placing the composition into an implant site within the body; and

(c) allowing the organic solvent to dissipate or diffuse into body fluid, and the thermoplastic polymer to coagulate or solidify to produce the biodegradable solid implant;

wherein the proportion of polymer in solvent and the molecular weight of the polymer are effective to provide said dissipation or diffusion and said coagulation.

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

3. The method 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.

4. The method of claim 1, further comprising combining an effective amount of a biologically active agent with the thermoplastic polymer and water-soluble, organic solvent, the implant releasing said agent by diffusion, erosion or a combination thereof as the implant biodegrades.

5. The method of claim 1, and further comprising delivering the composition in-situ through a needle.

6. The method of claim 1, wherein the organic solvent is a mixture of a first organic solvent capable of dissolving the thermoplastic polymer and a second organic solvent incapable or less capable than the first solvent of dissolving the thermoplastic polymer, said first and second solvents included in said mixture at a ratio such that the thermoplastic polymer is soluble therein, and coagulates to form a solid matrix upon placing the composition within the body and the dissipation or diffusion of the solvent into body fluid.

7. The method of claim 6, wherein said second solvent is selected from the group consisting of water, ethanol and propylene glycol.

8. The method of claim 6, wherein the first solvent is selected from the group consisting of:

N-methyl-2-pyrrolidone, 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.

9. The method of claim 1, wherein step (b) comprises applying the composition to a tissue, such that the implant functions to adhere a first tissue to a second tissue, to adhere a second implant to a tissue, or a combination thereof.

10. The method of claim 1, wherein step (b) comprises injecting the composition subdermally such that the implant functions to build up a tissue.

11. The method of claim 1, wherein step (b) comprises placing the composition into a wound such that the implant functions to inhibit scar formation.

12. The method of claim 1, wherein step (b) comprises placing the composition into a bone defect or a gap in a bone such that the implant functions as a filler material.

13. The method of claim 1, wherein step (b) comprises placing the composition into a soft tissue defect such that the implant provides a scaffold for growth of tissue thereon.

14. The method of claim 1, wherein step (b) comprising placing the composition into a cavity selected from the group consisting of periodontal, oral, vaginal, rectal, and nasal, and the implant is formed therein.

15. The method of claim 1, wherein step (b) comprises placing the composition into a periodontal pocket for treatment of periodontal disease.

16. The method of claim 1, further comprising combining a biologically active agent with the thermoplastic polymer and water-soluble organic solvent;

the biologically active agent selected from the group consisting of anti-inflammatory agent, antimicrobial agent, antibiotic, and mixtures thereof.

17. The method of claim 1, wherein step (b) comprises placing the composition into the cul-de-sac of an eye.

18. A pharmaceutical composition for forming a biodegradable implant in-situ within a body, comprising:

an effective amount of a biocompatible, water-insoluble, biodegradable thermoplastic polymer dissolved in an effective amount of a biocompatible, water-soluble organic solvent;

wherein,

the solvent is capable of dissipating or diffusing into a body fluid and the polymer is capable of coagulating or solidifying upon contact with body fluid;

the thermoplastic polymer is selected from the group consisting of;

(i) a copolymer of a biodegradable, water-insoluble monomer or polymer and a biodegradable, water-soluble monomer or polymer, wherein the amount of water-insoluble monomer or polymer is sufficient to render the copolymer water-insoluble;

(ii) a copolymer of polyethylene glycol with polylactide, polyglycolide or polycaprolactone, or a terpolymer thereof;

(iii) a copolymer of lactide with glycolide or caprolactone, or a terpolymer thereof;

(iv) a copolymer of lactide with a carbonate; and

(v) a polyanhydride; and

the amounts of the polymer and the solvent and the polymer molecular weight in the pharmaceutical composition are effective to form a coherent, solid implant in situ when the pharmaceutical composition contacts body fluid.

22. The composition of claim 18, wherein said polymer is the copolymer or terpolymer of a water-insoluble polymer and a water-soluble polymer;

wherein the water-insoluble polymer is polylactide, polyglycolide or polycaprolactone; and

the water-soluble polymer is polyethylene glycol or polyvinylpyrrolidone.

23. The composition of claim 18, wherein the solvent is selected from the group consisting of:

N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol, 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.

24. The composition of claim 18, wherein the solvent is a mixture of water, ethanol or propylene glycol with a solvent selected from the group consisting of:

N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, acetone, ethyl acetate, methyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid and 1-dodecylazacycloheptan-2-one, and combinations and mixtures thereof.

25. The composition of claim 18, wherein the organic solvent is a mixture of a first organic solvent capable of dissolving the thermoplastic polymer, and a second organic solvent incapable or less capable than the first solvent of dissolving the thermoplastic polymer;

said first and second solvents included in said mixture at a ratio such that the thermoplastic polymer is soluble therein, and coagulates to form a solid matrix upon placing the composition within the body and the dissipation or diffusion of the solvent into body fluid.

26. The composition of claim 25, wherein the second solvent is selected from the group consisting of water, ethanol and propylene glycol.

27. The composition of claim 25, wherein the first solvent is selected from the group consisting of:

N-methyl-2-pyrrolidone, 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.

28. The composition of claim 18, further comprising a biologically active agent.

29. The composition of claim 28, wherein the biologically active agent is selected from the group consisting of:

a peptide drug, protein drug, desensitizing agent, antigen, vaccine, anti-infective, antibiotic, antimicrobial, antiallergenic, anti-inflammatory agent, decongestant, miotic, anticholinergic, sympathomimetic, sedative, hypnotic, psychic energizer, tranquilizer, steroid, estrogen, progestational agent, humoral agent, prostaglandin, analgesic, antispasmodic, antimalarial, antihistamine, cardioactive agent, antiparkinsonian agent, antihypertensive agent, β

-adrenergic blocking agent, nutritional agent, benzophenanthridine alkaloid, and mixtures thereof.

30. The composition of claim 29, wherein the biologically active agent comprises a protein or peptide drug.

31. The composition of claim 29, wherein the biologically active agent comprises an antigen or vaccine.

32. The composition of claim 28, wherein the biologically active agent is in the form of an uncharged molecule, molecular complex, salt, ether, ester, or amide;

said form becoming biologically activated upon placement within a body.

43. The composition of claim 28, wherein the biologically active agent is a tetracycline.

19. A method of forming a solid, biodegradable implant in-situ, in a body, comprising:

(a) dissolving a water-insoluble, biodegradable thermoplastic polymer a biocompatible, water-soluble organic solvent to form a composition;

the organic solvent being capable of dissipating or diffusing into a body fluid upon placement within a body tissue;

wherein the organic solvent is comprised of a mixture of a first organic solvent capable of dissolving the polymer, and a second organic solvent incapable or less capable than the first organic solvent of dissolving the thermoplastic polymer;

said first and second solvents included in said mixture at a ratio such that the thermoplastic polymer is soluble therein and coagulates to form a solid implant upon placing the composition within the body and the dissipation or diffusion of the solvent into body fluid; and

(b) placing the composition into an implant site within the body; and

(c) allowing the organic solvent to dissipate or diffuse into the body fluid, and the thermoplastic polymer to coagulate or solidify to produce the biodegradable, solid implant;

wherein the proportion of polymer in solvent and the molecular weight of the polymer are effective to provide said dissipation or diffusion and said coagulation.

20. The method of claim 19, wherein said second solvent is selected from the group consisting of water, ethanol and propylene glycol.

21. The method of claim 19, wherein the first solvent is selected from the group consisting of:

N-methyl-2-pyrrolidone, 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.

33. A pharmaceutical composition for forming a solid biodegradable implant in situ within a body, comprising:

an effective amount of a biocompatible, water-insoluble, biodegradable thermoplastic polymer dissolved in an effective amount of a biocompatible, water-soluble organic solvent;

wherein the solvent is capable of dissipating or diffusing into a body fluid and the thermoplastic polymer is capable of coagulating or solidifying upon contact with body fluid; and

the organic solvent is a mixture of a first organic solvent capable of dissolving the thermoplastic polymer, and a second organic solvent incapable or less capable than the first solvent of dissolving the thermoplastic polymer;

said first and second solvents included in said mixture at a ratio such that the thermoplastic polymer is soluble therein, and coagulates to form a coherent solid implant upon placement of the composition within the body;

and the amounts of the polymer and the solvent and the polymer molecular weight in the composition are effective to form the coherent, solid implant in situ when the composition contacts body fluid.

34. The composition of claim 33, wherein the first solvent is selected from the group consisting of:

N-methyl-2-pyrrolidone, 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.

35. The composition of claim 33, wherein the second solvent is selected from the group consisting of water, ethanol and propylene glycol.

36. The composition of claim 33, wherein said polymer is selected from the group consisting of:

polylactides, polyglycolides, polycaprolactones, polydioxanones, polycarbonates, polyhydroxybutyrates, polyalkylene oxalates, polyanhydrides, polyamides, polyesteramides, polyurethanes, polyacetates, polyketals, polyorthocarbonates, polyphosphazenes, polyhydroxyvalerates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyorthoesters, and copolymers, terpolymers, or combinations and mixtures thereof.

37. The composition of claim 36, wherein the polymer is selected from the group consisting of:

polylactides, polyglycolides, polycaprolactones, and copolymers thereof.

38. The composition of claim 33, further comprising a biologically active agent.

39. The composition of claim 38, wherein the biologically active agent is selected from the group consisting of:

a peptide drug, protein drug, desensitizing agent, antigen, vaccine, anti-infective, antibiotic, antimicrobial, antiallergenic, anti-inflammatory agent, decongestant, miotic, anticholinergic, sympathomimetic, sedative, ⃡

hypnotic, psychic energizer, tranquilizer, steroid, estrogen, progestational agent, humoral agent, prostaglandin, analgesic, antispasmodic, antimalarial, antihistamine, cardioactive agent, antiparkinsonian agent, antihypertensive agent, β

-adrenergic blocking agent, nutritional agent, benzophenanthridine alkaloid, and mixtures thereof.

40. The composition of claim 39, wherein the biologically active agent comprises a protein or peptide drug.

41. The composition of claim 39, wherein the biologically active agent comprises an antigen or vaccine.

42. The composition of claim 38, wherein the biologically active agent is in the form of an uncharged molecule, molecular complex, salt, ether, ester, or amide;

said form becoming biologically activated upon placement within a body.