Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-06-18
2001-09-11
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S056000, C514S059000, C514S062000, C536S053000, C536S122000, C536S123000, C536S123100, C536S124000, C424S423000, C424S426000, C424S488000
Reexamination Certificate
active
06288043
ABSTRACT:
The present invention is directed to an injectable composition for the therapeutic repair of bone cartilage tissue, methods of producing such compositions and methods of using it to promote tissue growth.
In particular, the invention is directed to an injectable gel which binds growth, differentiation and other factors to induce cell proliferation and differentiation in vitro or in vivo at a desired site of bone or cartilage growth.
BACKGROUND OF THE INVENTION
The development of therapeutic products to restore or replace the function of impaired connective tissues has been stimulated by an aging population, bone donor scarcity and the potential of transmission of infectious diseases. Due to the self-regenerative capacity of bone and cartilage, there has been extensive research into the development of biomaterials which support tissue induction from of repairative tissue surrounding tissue.
One approach to tissue repair involves the administration of growth factors in solution with an appropriate delivery system at the desired tissue site. See Kenley et al., Pharm. Res. 10:1393 (1993); Anderson et al., Curr. Opin. Ther. Patents, 4:17 (1994). A primary inducer of mesoderm formation in embryogenesis, bFGF, apparently plays a role in osteogenesis. Bone morphogenic proteins (BMPs), members of the transforming growth factor superfamily of proteins, are bone inducers. Sampath et al., J. Biol. Chem., 267:20352 (1992); Wozney et al., Science, 242:1528 (1988). These molecules are involved in cell proliferation and differentiation both in vitro and in vivo. The biological functions of these growth factors are mediated by the interaction of the growth factors with high-affinity cell-surface receptors and subsequent alterations in gene expression within the stimulated cells.
However, development of effective delivery systems for these growth factors has been a major obstacle. The development of an effective and reliable delivery system is crucial to the viable use of growth factors in bone or cartilage repair. Synthetic polymeric prostheses, inorganic ceramics, hydrogels, and injectable vehicles from natural or synthetic polymers have been investigated with the intention of localizing and sustaining active agents at the administered site, but it has been difficult to create a delivery system that incorporates growth factor stability and optimal release profiles. See Hollinger et al., J. Craniofac. Surg. 4:115 (1993); J. Control. Red. 39:287 (1996); Miyamoto et al., Clin. Orthop. Red. Res., 274:266 (1992).
Hyaluronic acid is a natural component of the extracellular matrix of most tissues and is readily sterilized, is biodegradable and can be produced in a wide range of consistencies and formats. It is generally water-soluble, biocompatible and its resorption characteristics can be controlled by the manipulation of monomers. It is a linear polymer made up of repeating glycosaminoglycan (GAG) disaccharide units of D-glucuronic acid and N-acetylglycosamine in &bgr;(1-3)and &bgr;(1-4) linkages.
Sulfated GAGs, such as dermatan sulfate, heparan sulfate, chondroitin sulfate and keratan sulfate are found mostly in the extracellular matrix and on the cell surface as proteoglycans. These macromolecules are secreted by cells and play a role in both signal transduction and storage of some growth factors such as FGFs, TGF-&bgr;s and BMPs. See Viodavsky et al., PNAS, 84:2292 (1987); Nakagawa et al., Exp. Cell Res. 182:572 (1989). Hyaluronic acid and sulfated GAGs are easily sterilized, biodegradable, and can be produced in a wide range of consistencies and formats. See Robinson et al., Calcif. Tissue Int., 46:246 (1990).
SUMMARY OF THE INVENTION
The present invention is directed to an injectable composition for inducing tissue growth at a target bone or cartilage site comprising hyaluronic acid (HA) cross-linked to a sulfated polysaccharide (SP) through linkage groups. The linkage group is a preferrably diamine or amino-terminated polyalkylene glycol. The sulfated polysaccharides are organic sulfates such as heparin, dermatan sulfate, chondroitin sulfate, heparan sulfate, dextran sulfate, keratan sulfate, and similar sulfated polysaccharides such as hexuronyl hexosaminoglycan sulfate, inositol hexasulfate and sucrose octasulfate which have a binding affinity for growth factors.
Methods are provided for producing such compositions by oxidizing hyaluronic acid under conditions such that aldehyde groups are formed on the hyaluronic acid, then reacting the oxidized hyaluronic acid with the amino-terminated linking group. The oxidized sulfated polysaccharide also contains aldehyde groups and is reacted with the other amino end of the linking group to form the cross-linked composition.
Methods of using the injectable composition are also provided by mixing the cross-linked composition with one or more growth factors and injecting the mixture at a site of desired bone growth in a subject.
As used in the present application, repair is defined as growth of new tissue. The basic cellular properties involved in repair include adhesion, proliferation, migration and differentiation. By conduction, it is meant that the tissue grows by extension on existing cells of the same type.
REFERENCES:
patent: 3706633 (1972-12-01), Katchalski et al.
patent: 4582865 (1996-04-01), Balazs et al.
patent: 5011918 (1991-04-01), Billmers et al.
patent: 5128326 (1992-07-01), Balazs et al.
patent: 5942499 (1999-08-01), Radomsky
patent: 2752843 (1998-03-01), None
patent: 98/08897 (1998-03-01), None
patent: WO 99/01143 (1999-01-01), None
patent: PCT/US00/16793 (2000-06-01), None
Miyamoto et al., Clin. Orthop. Red. Res., 274:266, May 1992.
Bitter et al., “A Modified Uronic Acid Carbazole Reaction”, Anal. Biochem., 4:330-334, 1962.
Bubnis et al., “The Determination of Amino Groups in Soluble and Poorly Soluble Proteinaceous Materials”, Anal. Biochem., 207:129-133, 1992.
Lin-Shu Liu et al., “An osteoconductive collagen/hyaluronate matrix for bone regeneration”, Biomaterials, 20:1097-1108, 1999.
Cory et al., “Use of an Aqueous Soluble Tetrazolium/Formazan Assay for Cell Growth Assays in Culture”, Cancer Commun., 3:207, 1991.
“Poly -hydroxy acid carrier for delivering recombinant human bone morphogenic protein-2 for bone regeneration”, J. Control.Release., 39:287, 1996.
Lin-Shu Liu et al., “Controlled release of interleukin-2 for tumour immunotherapy using alginate/chitosan porous micropheres”, J. Control. Release., 43:65-74, 1997.
Holinger et al., “Factors for Osseous Repair and Delivery:Part 1”, J. Craniofac. Surg. 4:115, 1993.
Kenley et al., “Biotechnology and Bone Graft Substitutes”, Pharm. Res. 10:1393, Oct. 1993.
Nakagawa et al., “Extracellurar Matrix Organization Modulates Gibroblast Growth and Growth Factor Responsiveness”, Exp. Cell Res. 182:572, Jun. 1989.
Robinson et al., “Regenerating Hyaline Cartilage in Articular Defects of Old chickens Using Implants of Embryonal Chick Chondrocytes Embedded in a New Natural Delivery Substance”, Calcif. Tissue Int., 46:246, Apr. 1990.
Sampath et al., “Recombinant Human Osteogenic Protein-1 Induces New Bone Formation in Vivo with a Specific Activity Comparable with Natural Bovine Osteogenic Protein and Stimulates Osteoblast”, J.Biol. Chem., 267:20352, Oct. 1992.
Vlodavsky et al., “Endothelial cell-derived basic fibroblast growth factor: Synthesis and deposition into subendothelial extracellular matrix”, PNAS, 84:2292, Apr. 1987.
Wozney et al., “Novel Regulators of Bone Formation: Molecular Clones and Activities”, Science, 242:1528, Dec. 1988.
Anderson et al., “Recent advances in methods for inducing bone formation” Curr. Opin. Ther. Patents, 4:17 1994.
Liu, Lin-Shu (1/1999) “An osteoconductive collagen/hyaluronate matrix for bone regeneration” Biomaterials, Elsevier Science publishers, Barking, GB, vol. 20, pp. 1097-1108.
Liu Lin-Shu
Spiro Robert C.
Fish & Richardson PC
Fonda Kathleen K.
Orquest, Inc.
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