Bone Morphogenetic Protein Compositions

Abstract

The present invention relates to compositions of bone morphogenetic proteins, particularly solid and liquid formulations of such proteins comprising one or more stabilizing excipients. The invention further provides methods of producing the compositions, kits comprising the compositions and methods of using the compositions in the treatment of diseases of skeletal and non-skeletal tissues.

Description

RELATED APPLICATIONS[0001]This application is a continuation-in-part of International Application No. PCT / US2008 / 006144, which designated the United States and was filed on May 14, 2008, published in English, which claims the benefit of U.S. Provisional Application No. 60 / 930,219, filed on May 15, 2007. The entire teachings of the above applications are incorporated herein by reference.FIELD OF THE INVENTION[0002]The invention relates to preparations of bone morphogenetic proteins having enhanced stability and, in certain embodiments, highly concentrated aqueous solutions of such proteins.BACKGROUND OF THE INVENTION[0003]Protein-based therapeutics have proven highly effective for a variety of disorders, injuries and diseases. Apart from the performance challenges associated with protein-based therapeutics, numerous other types of challenges arise during the development of such therapeutics, including protein processing considerations such as ease and cost of manufacturing, stability...

AI Technical Summary

Benefits of technology

[0006]The present invention is based on the discovery that formulations of bone morphogenetic proteins having enhanced stability can be prepared using a suitable combination of excipients, such as bulking agents, and acidic buffers. In one embodiment, the invention provides buffered aqueous solutions comprising a bone morphogenetic protein at a concentration of at least about 0.1 mg / mL and one or more stabilizing excipients. In another embodiment, the invention provides heretofore undescribed aqueous preparations of proteins which are highly concentrated, i.e., at least about two- to about five-fold, preferably about three-fold, more concentrated than those known in the art, can be readily accomplished using the methods and reagents disclosed herein. Briefly, aqueous protein solutions of at least about 4 mg / mL, can be accomplished using a specified combination of ionic strength, pH and buffering systems; and, this solubility matrix of specific solubilization conditions results in highly efficient manufacture of such protein preparations with a high rate of recovery. Of particular significance, the present invention's highly concentrated protein preparations permit the clinician to administer locally or systemically effective doses of proteins in minimal administration volumes, thereby allowing administration to physiologically-constrained sites such as intrajoint or intra-intervertebral disc sites.

[0015]Preferred embodiments can effectively treat a skeletal tissue disorder, injury or disease selected from the group consisting of metabolic bone disease, osteoarthritis, osteochondral disease, rheumatoid arthritis, osteoporosis, bone fractures, Paget's disease, periodontitis, and dentinogenesis. Other preferred embodiments can effectively treat a non-mineralized skeletal tissue disorder, injury or disease selected from the group consisting of osteoarthritis, osteochondral disease or defect, chondral disease or defect, rheumatoid arthritis, trauma-induced and inflammation-induced cartilage degeneration, age-related cartilage degeneration, articular cartilage injuries and diseases, full thickness cartilage defects, superficial cartilage defects, sequelae of systemic lupus erythematosis, sequelae of scleroderma, periodontal tissue regeneration, hierniation and rupture of intervertebral discs, degenerative diseases of the intervertebral disc (for example, degenerative disc disease), osteochondrosis, and injuries and diseases of ligament, tendon, synovial capsule, synovial membrane and meniscal tissues.

[0016]Certain other preferred embodiments can effectively treat tissue injury selected from the group consisting of: trauma-induced and inflammation-induced cartilage degeneration, articular cartilage injuries, full thickness cartilage defects, superficial cartilage defects, hierniation and rupture of intervertebral discs, degeneration of intervertebral discs due to an injury(s), and injuries of ligament, tendon, synovial capsule, synovial membrane and meniscal tissues.

Problems solved by technology

Apart from the performance challenges associated with protein-based therapeutics, numerous other types of challenges arise during the development of such therapeutics, including protein processing considerations such as ease and cost of manufacturing, stability and shelf-life, as well as modes of administration, dosages and form of effective dosage, to name but a few.

Certain therapeutically significant proteins are particularly difficult to formulate because of their inherent insolubility under physiological conditions, such as but not limited to physiological pH.

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