Delivery system for controlled release of bioactive factors

• US 5,356,630 A
• Filed: 05/07/1993
• Issued: 10/18/1994
• Est. Priority Date: 02/22/1989
• Status: Expired due to Fees

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Langer, Robert S., Lucas, Paul A., Laurencin, Cato T., Domb, Abraham, Syftestad, Glenn T., Glowacki, Julianne
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): AZPURU, CARLOS A
• Application Number:
  US08/059,516
• Time in Patent Office: 529 Days
• Field of Search: 424/422, 424/423, 424/426, 424/484, 424/489, 424/486, 524/499, 514/21, 514/772.3, 530/350, 530/356
• US Class Current: 424/426
• 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 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/204 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• 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: C08G 67/04 Polyanhydrides
• CPC Class Codes: C08L 67/00 Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain of polyester-amides C08L77/12; of polyester-imides C08L79/08; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 73/02 Polyanhydrides
• CPC Class Codes: Y10S 530/84 Bones; tendons; teeth; cartilage

Abstract

A composition and method for controlled release of water-soluble proteins comprising a surface-eroding polymer matrix and water-soluble bioactive factors is described. The composition bioerodes in the biological environment of the subject at a controlled rate, thereby releasing the water soluble proteins at a rate which allows them to interact with local cell populations.

Claims

1. A method of selectively delivering a bioactive substance for inducing formation of cartilage and bone in an animal or wound healing to a specific physical site in an animal comprising implanting in the animal at the selected site a delivery composition comprising a shaped matrix sized and adapted for administration of the bioactive substance to an animal, wherein

a. the matrix is formed of from about 10 percent to about 90 percent by weight of a surface eroding polyanhydride or polyorthoester polymer;

and

b. the matrix contains from about 90 percent to about 10 percent by weight of a bioactive substance selected from the group consisting of a mixture of water soluble chondrogenic or osteogenic proteins derived from demineralized bone matrix, TGF-beta, EGF, FGF and PDGF;

wherein the composition erodes at a controlled rate over a period of time as a result of hydrolysis of the polymer, thereby administering the bioactive substance to the animal in an amount effective to induce formation of cartilage and bone or wound healing, wherein the same amount administered to the animal in the absence of the matrix is not effective to induce formation of cartilage and bone or wound healing.

3. The method of claim 1 wherein the polyanhydride is selected from the group consisting of poly(bis(p-carboxyphenoxy)propane anhydride), poly(bis(p-carboxy)methan anhydride), and poly(bis(p-carboxyphenoxy)propane anhydride)sebacic acid copolymer.

4. The method of claim 1 wherein the composition is implanted intramuscularly.

5. The method of claim 1, wherein the bioactive substance is a protein preparation derived from demineralized bone matrix comprising a mixture of water-soluble proteins derived from demineralized bone matrix capable of inducing chondrogenesis and osteogenesis having a range of molecular weight of from about 10 to about 100 kd.

2. A method of inducing chondrogenesis and osteogenesis in an animal comprising implanting intramuscularly in the animal a delivery composition comprising

a. a shaped matrix sized and adapted for administration of the chondrogenic and osteogenic substance, said matrix being formed from a polyanhydride polymer selected from the group consisting of poly(bis(p-carboxyphenoxy)propane anhydride), poly(bis(p-carboxy)methane anhydride), and poly(bis(p-carboxyphenoxy)propane anhydride)sebacic acid copolymer;

and

b. a protein preparation derived from demineralized bone matrix comprising a mixture of water-soluble proteins derived from demineralized bone matrix capable of inducing chondrogenesis and osteogenesis having a range of molecular weight of from about 10 to about 100 kd;

wherein the composition contains from about 10 to about 90 percent by weight of the polyanhydride polymer and from about 90 to about 10 percent by weight of the water-soluble proteins in an amount effective to induce bone and cartilage formation when implanted intramuscularly, the polymer eroding by hydrolysis at a controlled rate over a period of time, thereby administering said protein preparation over a period of time.