Delivery system for controlled release of bioactive factors

• US 5,545,409 A
• Filed: 04/05/1994
• Issued: 08/13/1996
• Est. Priority Date: 02/22/1989
• Status: Expired due to Fees

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Glowacki, Julianne, Langer, Robert S., Lucas, Paul A., Laurencin, Cato T., Domb, Abraham, Syftestad, Glenn T.
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US08/222,880
• Time in Patent Office: 861 Days
• Field of Search: 424/423, 424/426, 514/2, 514/21, 530/300, 530/353, 530/840, 623/14
• 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 composition for the controlled release of a bioactive substance for inducing formation of cartilage or bone in an animal or wound healing comprising:

a. a shaped matrix sized and adapted for administration of the bioactive substance to an animal and formed of a polymer selected from the group consisting of polyanhydride and polyorthoester; and

b. a therapeutically effective amount of a bioactive substance selected from the group consisting of water soluble chondrogenic or osteogenic proteins derived from demineralized bone matrix, TGF-beta, EGF, FGF and PDGF, wherein the bioactive substance is present in an amount of between about 10 and 90 percent by weight of matrix;

wherein the composition erodes at a controlled rate over a period of time, thereby administering the bioactive substance to the animal in an amount effective to induce formation of cartilage and bone or wound healing.

2. The composition of claim 1 wherein the polyanhydride is 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]--sebacid acid copolymer.

3. The composition of claim 1 wherein the water soluble chondrogenic or osteogenic proteins derived from demineralized bone matrix is a mixture of cold water-soluble proteins.

4. The composition of claim 3 wherein the cold water-soluble proteins are proteins derived from demineralized bone matrix.

5. The composition of claim 1 wherein the chondrogenic or osteogenic proteins is derived from demineralized bovine femur bone matrix.

6. The composition of claim 1 where in the bioactive substance is selected from the group consisting of TGF-beta, EGF, FGF and PDGF.

7. The composition of claim 1 wherein the composition comprises a continuous matrix having a bioactive substance interspersed therethrough.

8. The composition of claim 1 wherein the matrix is sized, shaped and adapted for use as an implant.

9. The composition of claim 1 which is adapted for releasing bioactive substance intramuscularly.

10. The composition of claim 1

wherein the shaped matrix sized and adapted for administration of the cartilage and bone inducing substance is formed from a polyanhydride polymer selected from the group consisting of poly(bis(p-carboxyphenoxy)propane anhydride), poly(bis(p-carboxyphenoxy)methane anhydride) and

poly(bis(p-carboxyphenoxy)propane anhydride-sebacic acid);

and

the cartilage and bone inducing amount of a protein preparation derived from demineralized bone matrix consists of a mixture of cold water-soluble proteins capable of inducing chondrogenesis and osteogenesis having a range of molecular weight of from about 10 to about 100 Kd.