Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-09-17
2001-10-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S400000, C424S422000, C424S423000, C424S424000
Reexamination Certificate
active
06303138
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 endothelin to induce repair of damaged or diseased bone and cartilage 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) has been studied, e.g., Ijiri (1992). In addition to DBM and BMP, many compounds possess biological activity and find wide use in medical applications such as prosthetic devices, drugs, blood components, and the like.
Endothelins, are a class of 21-amino acid vasoactive peptides with intra chain disulfide bonds. The proteins were initially isolated and purified from conditioned medium of cultures of porcine aortic endothelial cells. Endothelins have subsequently been found to be produced by many cells, and their production modulated by systemic hormones and local factors (Rubanyi and Polokoff, 1994). Endothelin can be isolated from a wide variety of warm-blooded vertebrate tissue sources using standard extraction techniques known to those skilled in the art.
It has been reported that incubation of cell populations with the endothelial cell polypeptide endothelin-1 affects osteoblast growth and function. Accordingly, there has been speculation that these proteins as well as numerous other isolated compounds may play a role in bone and cartilage repair. 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 and almost all the studies reporting bone formation were done in vivo (Mark and Miller, 1993). 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 endothelin 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 endothelin, 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 endothelin, 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 endothelin 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 “endothelin” is intended to include any of the related family members of native endothelin proteins isolated from human or other warm-blooded vertebrates, naturally occurring isoforms of endothelin, recombinant protein produced from endothelin encoding nucleic acid sequences, and protein fragments/peptides of endothelin proteins. An endothelin gene is defined herein to include any nucleic acid sequence encoding for endothelin, including the native gene sequences isolated from human or other warm-blooded vertebrates, any nucleic acid sequence encoding active fragments of endothelin, 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” refers to degree of absence of contaminants and the like.
The compositions of the present invention can be used in a method for inducing the repair of damaged or defective tissues of a warm-blooded vertebrate. More particularly, endothelin 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
Glancy Todd P.
Nousek-Goebl Nancy
Peterson Dale R.
Barnes & Thornburg
DePuy Orthopaedics
Martin Alice O.
McQueeney P. E.
Page Thurman K.
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