Injectable solid hyaluronic acid carriers for delivery of osteogenic proteins

Abstract

An injectable or implantable rod-shaped formulation is disclosed for delivery of osteogenic proteins. The formulation comprises hyaluronic acid derivatives and osteogenic proteins, and optional excipients and active ingredients such as a bone resorption inhibitor. Methods of making injectable rod-shaped pharmaceutical compositions and methods of using the osteogenic compositions to treat osteoporotic and / or osteopenic bone are also disclosed.

Description

FIELD OF THE INVENTION [0001] The subject invention relates to the field of osteogenic proteins and pharmaceutical formulations thereof. More particularly, the subject invention involves injectable or implantable solid pharmaceutical formulations comprising hyaluronic acid derivatives and osteogenic proteins. BACKGROUND OF THE INVENTION [0002] Idiopathic osteoporosis is a disease of unknown etiology characterized by progressive loss of bone mass and increased fragility, resulting in a marked increase in susceptibility to fractures. Osteoporosis is among the most prevalent of all musculoskeletal disorders, afflicting fifty-six percent of women over 45 years of age. Praemer et al., Musculoskeletal Conditions in the United States, American Academy of Orthopaedic Surgeons, Park Ridge, Ill. (1992). Because its incidence increases with age and the percentage of elderly in the population is increasing, osteoporosis will become more common with time. Osteoporosis is difficult to treat local...

AI Technical Summary

Benefits of technology

[0006] The present invention provides injectable or implantable solid, rod-shaped compositions for intraosseous delivery of osteogenic proteins. In one embodiment, the composition comprises the osteogenic protein and hyaluronic acid esters. In another embodiment, the composition may further comprise a bone resorption inhibitor such as a bisphosphonate. In yet another embodiment, the composition may further comprise one or more excipients, such as a pharmaceutically acceptable salt, polysaccharide, peptide, protein, amino acid, synthetic polymer, natural polymers, or surfactant. The solid, rod-shaped injectable or implantable compositions of the invention provide prolonged retention of the osteoinductive agent at the site of administration.

[0007] The present invention further provides methods and compositions for increasing bone mass and quality, and for minimizing or reducing the incidence or severity of osteoporosis-related fractures. Accordingly, the present invention provides methods and compositions useful for decreasing the incidence of fractures of osteoporotic or osteopenic bone. In particular, the present invention comprises methods of treating patients with osteoporosis, or with other evidence of osteoporosis or osteopenic condition. Preferred embodiments where the present invention may prove particularly useful include treatment of metaphyseal bone, including proximal femur (hip), proximal humerus (upper arm), distal radius (wrist), and vertebral bodies (spine), particularly the vertebral body.

[0008] The method comprises administering to a site of osteopenic or osteoporotic bone, or a site of low bone mass or density, a solid rod-shaped composition comprising an effective amount of at least one active agent that is capable of inducing growth of bone or increasing the formation of bone tissue or reducing bone loss at the site. Bone mass is commonly designated “bone mineral content” or “BMC” and is measured in grams. Bone density is commonly designated “bone mineral density” or “BMD” and is expressed as grams per unit area or grams per unit volume. In a particular embodiment, the mode of administration is by intraosseous injection. In illustrative embodiments, the active agent is one or more proteins selected from the group of proteins known as the transforming growth factors-beta (“TGF-β”) superfamily of proteins, preferably selected from the bone morphogenetic proteins (“BMPs”), the growth and differentiation factors (“GDFs”), as well as otherproteins, as described more fully herein. The methods and compositions of the present invention are advantageous in that they provide a localized treatment for osteoporosis or osteopenic bone, rather than systemic treatment. The present invention is further advantageous in that it utilizes as active agents osteogenic proteins, which may be produced via recombinant DNA technology, and therefore are of potentially unlimited supply. The methods and compositions of the present invention are further advantageous in that regeneration of the bone tissue increases the bone mass / density, increase the bone strength, and thereby reduce the severity of osteoporosis or incidence of osteoporotic lesions, ultimately lessening the incidence of bone fractures.

[0010] The present invention further provides a methods for increasing bone mass and quality, and for minimizing or reducing the incidence or severity of osteoporosis-related fractures, by administering an injectable rod-shaped composition comprising at least one osteogenic protein and a second composition comprising an effective amount of a bone resorption inhibitor. The second composition comprising the bone resorption inhibitor may be administered prior to, after, or substantially simultaneously with the osteogenic composition.

Problems solved by technology

Osteoporosis is difficult to treat locally, and there is presently no known cure.

Finally, and most significantly, osteoporosis is associated with a substantial morbidity and mortality.

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