Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-09-17
2002-10-01
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S484000, C424S485000, C424S486000, C424S487000, C424S548000, C424S549000, C514S002600, C514S021800, C514S769000, C514S770000, C514S772300, C514S773000, C514S777000, C514S778000, C514S779000, C514S964000
Reexamination Certificate
active
06458763
ABSTRACT:
This invention relates to implantable biocompatible compositions that induce the repair of damaged or diseased bone, cartilage or other connective tissues upon contact of the damaged or diseased tissues with the composition in vivo. The invention also relates methods of inducing repair. More particularly the present invention is directed to the use of a composition comprising an effective amount of bone sialoprotein to induce repair of damaged or diseased connective tissues.
BACKGROUND OF THE INVENTION
Currently, bone defects are typically repaired by autografts or banked bone. Autografts have a good ability to unify the bone, and physicians often prefer to use bone from sources such as the iliac crest. However, procedures using autografts suffer from several drawbacks. First, autografts require a separate harvest operation, resulting in increased operative time and the use of blood transfusions. Secondly, patients often lack adequate amounts of material for harvesting and often experience donation site morbidity. Implantation of banked bone does not require the harvest operation, but its bone healing capability is not as high as that of autografts. Therefore, it is undesirable to use banked bone in severe conditions such as nonunion.
Because of these drawbacks, researchers have searched for compositions and methods for promoting bone growth without necessitating the use of autografts or banked bones. One potential source for bone growth promoting factors is the extracellular matrices of healthy bone and cartilage tissues. Extracellular bone matrix contains predominantly mineral (hydroxyapatite) and an organic matrix, where the major component of the organic matrix is collagen type I. The remaining components of bone matrices include a number of less abundant non-collagenous proteins and growth factors. For example, since the mid-1960's the osteoinductive activity of both demineralized bone matrix (DBM) and bone morphogenetic protein (BMP) have been studied (e.g., Ijiri, 1992). In addition to DBM and BMP, many of the bone matrix non-collagenous protein components possess biological cartilage development. However, in vitro results may vary due to a variety of factors, including cell type, cell density, cell isolation procedures, and type of growth medium. Therefore, while useful, in vitro studies are not always predictive of in vivo activity.
For example over the last two decades prostaglandins had been reported as both increasing bone resorption as well as increasing bone formation. Analysis of the literature references reporting the conflicting activities of prostaglandins reveals that almost all reports of bone resorption were performed in vitro, whereas almost all the studies reporting bone formation were done in vivo. The studies of bone growth in vitro were performed with tissue/organ cultures of bone or relatively pure isolated bone cell populations. The apparent conflicting reports of the predominant skeletal affects of the prostaglandins can be explained on the basis of the limitations of the cell culture systems used to study those effects. Similarly, initial reports of TGF- activity based on cell culture assays failed to correlate with observed in vivo activities. Therefore, skilled artisans appreciate that in vitro activity does not always predict in vivo results.
What is needed, are compositions shown to repair connective tissue in vivo.
SUMMARY OF THE INVENTION
In accordance with the present invention, compositions comprising bone sialoprotein are used to induce growth of bone or cartilage at an in vivo site in need of repair. The disclosed compositions are administered to a warm-blooded species, either by implanting or injecting the composition, for in vivo contact with the site in need of repair.
Another aspect of this invention is a method for inducing new bone or cartilage growth at a predetermined in vivo site of a vertebrate species comprising the steps of contacting the site with a composition comprising substantially purified bone sialoprotein, in an amount effective to induce endogenous tissue growth, and a pharmaceutically acceptable carrier. In a preferred embodiment, the composition is in liquid form and the site is contacted by injection of the composition. In another preferred embodiment, the carrier is a polymer matrix comprising a polymer selected from the group consisting of polyesters, ionomers, poly(amino acids), polyvinyl acetate, polyacrylates, polyorthoesters, polyanhydrides, collagens, fibrins, starches, alginate, and hyaluronic acid. Alternatively, the carrier may be a metal, glass, or mineral salt. Preferred mineral salts include tricalcium phosphate, hydroxyapatite, and gypsum.
Still another aspect of this invention is a method of treating a bone or cartilage pathogenic condition in a warm-blooded vertebrate by administering a composition systemically to the warm-blooded vertebrate, wherein the composition comprises substantially purified bone sialoprotein, in an amount effective to induce endogenous tissue growth, and a pharmaceutically acceptable carrier.
Additional features of the present invention will become apparent to those skilled in the art upon consideration of the following detailed description of embodiments including the best mode of carrying out the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed to compositions comprising bone sialoprotein in a substantially pure form, and the use of such compositions to enhance the repair of bone and cartilage defects in vivo. As used herein the term “bone sialoprotein” is intended to include native bone sialoprotein protein isolated from human or other warm-blooded vertebrates, naturally occurring isoforms of bone sialoprotein protein, recombinant protein produced from bone sialoprotein encoding nucleic acid sequences, and protein fragments/peptides of bone sialoprotein proteins. A bone sialoprotein gene is defined herein to include any nucleic acid sequence encoding for bone sialoprotein, including the native gene sequences isolated from human or other warm-blooded vertebrates, any nucleic acid sequences encoding active fragments of bone sialoprotein protein, or any recombinant derivative thereof. As used herein, the term “substantially pure” is intended to mean purified to at least 90% purity, and preferably to 95% purity, as determined by polyacrylamide gel electrophoresis or amino acid analysis. “Purity” and the like refers to degree of absence of contaminants.
The compositions of the present invention can be used in a method for inducing the repair of damaged or defective connective tissues of a warm-blooded vertebrate. More particularly, bone sialoprotein can be used to repair the tissues of orthopedic and non-orthopedic wound sites, including bone, cartilage, tendon, ligament, muscle, skin, and other soft tissues. In an embodiment the compositions of the present invention are used to repair fractures effectively and fill or bridge bone defects including for example, craniofacial defects or periodontal defects,joint fractures, chondral defects, superficial chondral defects, full thickness defects, osteochondritis dissecans, minuscule tears, ligament tears, tendon tears, muscle lesions, myotendinitis junction lesions, skeletal reconstruction following secondary bone loss to infection or neoplasm, and the treatment of various bone or cartilaginous diseases such as osteoporosis.
Many compounds isolated from connective tissues have been reported as having osteogenic properties based on the response of cells to those compounds in vitro. However, in vitro-established activities often fail to provide sufficient guidance for selecting compounds that will exhibit the desired in vivo bone and cartilage repair enhancing activity. Accordingly, the present invention uses an in vivo assay technique to identify bioactive agents that induce the repair of bone and cartilage tissues. Advantageously, the present in vivo assay avoids the use of delivery carriers, such as collagen, which are known to exhibit osteogenic properties themselves. This uniq
Glancy Todd P.
Nousek-Goebl Nancy
Peterson Dale R.
Barnes & Thornburg
Choi Frank
Dees Jose′ G.
DePuy Orthopeadics
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