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

• US 5,278,202 A
• Filed: 12/23/1991
• 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., English, James P., Vanderbilt, David D.
• Primary Examiner(s): Michl, Paul R.
• Assistant Examiner(s): MERRIAM, ANDREW EDWIN
• Application Number:
  US07/788,159
• Time in Patent Office: 750 Days
• Field of Search: 523/113, 424/426, 424/422, 424/78.26, 525/937, 525/411, 525/415, 526/320, 526/321, 604/187
• 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 biodegradable pharmaceutically acceptable implant in-situ within a living body, comprising an effective amount of a pharmaceutically acceptable liquid acrylic-ester terminated prepolymer of terminal acryloyl groups and a residue of an oligomer having terminal functional groups capable of reacting with acryloyl acylating groups wherein the prepolymer is capable of being cured into said implant in-situ within a living body and the cured form of the prepolymer is water insoluble and is biodegradable by simple or enzymatically antalyzed hydrolysis;

and an effective amount of a pharmaceutically acceptable curing agent.

2. The composition of claim 1, wherein said liquid acrylic ester terminated prepolymer is a product of a conversion of a polyol-terminated biodegradable prepolymer.

3. The composition of claim 2, wherein said polyol-terminated biodegradable prepolymer is a product of co-polymerization of DL-lactide and ε

-caprolactone with a polyol initiator.

4. The composition of claim 2, wherein said polyol-terminated biodegradable prepolymer is a product of co-polymerization of L-lactide and ε

-caprolactone with a polyol initiator.

5. The composition of claim 1, wherein said curing agent is azobisisbutyronitrile.

6. The composition of claim 1, wherein said curing agent is benzoyl peroxide.

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

8. The composition of claim 1, wherein said liquid acrylic-ester-terminated prepolymer is capable of being cured into said implant in-situ within a body.

9. The composition of claim 1, further comprising a filler.

10. The composition of claim 2, wherein said polyol-terminated prepolymer is selected from the group consisting essentially of polylactides, polyglycolides, polycaprolactones, polydioxanones, polycarbonates, polyhydroxybutyrates, polyalkylene oxalates, polyanhydrides, polyamides, polyesteramides, polyurethanes, polyacetals, polyketals, polyorthocarbonates, polyphosphazenes, polyhydroxyvalerates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyorthoesters, and copolymers, terpolymers and combinations and mixtures thereof.

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

an effective amount of a liquid acrylic-ester terminated prepolymer of terminal acryloyl groups and oligomer having terminal functional groups capable of reacting with an acryloyl compound wherein the prepolymer is capable of being cured into said implant in-situ in the living body and the cured form of the prepolymer is water insoluble and is biodegradable by simple or enzymatically catalyzed hydrolysis;

an effective amount of a curing agent in a suitable form for combination with the liquid prepolymer; and

,

a device for application of a liquid combination of the liquid prepolymer and curing agent, the device having a outlet for the liquid combination, an ejector for expelling the liquid combination through the outlet and a hollow tube fitted to the outlet for inserting the liquid combination into a site of the living body such that the liquid combination can form an implant in-situ at said site.