Injectable solid hyaluronic acid carriers for delivery of osteogenic proteins

a technology of hyaluronic acid carriers and osteogenic proteins, which is applied in the direction of phosphorous compound active ingredients, prosthesis, metabolic disorders, etc., can solve the problems of osteoporosis that is difficult to treat and is associated with a substantial morbidity and mortality, and achieve the effect of prolonging the retention of the osteoinductive agen

Inactive Publication Date: 2005-12-29
WYETH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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 embo

Problems solved by technology

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

Method used

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  • Injectable solid hyaluronic acid carriers for delivery of osteogenic proteins

Examples

Experimental program
Comparison scheme
Effect test

example 1

Formulation of Hyaff-11 Rods

[0056] Injectable 100% esterified Hyaff-11 rod-shaped compositions (1 mm in diameter) were prepared and evaluated for recombinant human bone morphogenetic protein-2 (rhBMP-2) retention and bone formation efficacy. The rod-shaped compositions comprised Hyaff-11® hyaluronan-based material as carrier, two doses (see Table 1) of rhBMP-2 as active ingredient, and varying amounts of excipients for modulation of release kinetics. Excipients used in this example consisted of dry powder forms of either glutamic acid or buffer salts. Buffer salts contained 0.5% sucrose, 2.5% glycine, 5 mM L-glutamic acid, 5 mM NaCl, and 0.01% polysorbate 80. The Hyaff-11® based compositions were formed into rod shapes using a phase inversion process. Briefly, rhBMP-2 and excipients (glutamate and buffer salts) were mixed into pre-solubilized Hyaff-11® particulates. (10% w / v) in organic solvent N-methylpyrrolidone (NMP), extruded into excess ethanol (nonsolvent) using a syringe and...

example 2

Formulation of Hyaff-11p65® Rods

[0057] Injectable 65% esterified Hyaff-11p65 rod-shaped compositions (1 mm in diameter) were prepared and evaluated for rhBMP-2 retention and bone formation efficacy. The rod-shaped compositions comprised Hyaff-11p65® hyaluronan-based material as carrier and two doses (see Table 1) of rhBMP-2 as active ingredient. Hyaff-11p65®-based compositions comprising 20% (w / w) rhBMP-2 (i.e., 80 / 20 (w / w) Hyaff-11p65® / rhBMP-2) or 40% (w / w) rhBMP-2 (i.e., 60 / 40 (w / w) Hyaff-11p65® / rhBMP-2) were prepared by mixing desalted rhBMP-2 and Hyaff-11p65® non-woven pads in dry forms, followed by hydrating to 18.75% (w / v) of the weight of the non-woven pad, mixing to a white paste-like consistency, transferring to a syringe, extruding through a catheter (e.g., 16-gauge), and drying. A variation of this method consists of extruding the paste through a catheter to a rod form, freezing the rod (in −80° C. or liquid nitrogen), inserting into a slightly larger diameter tubing (e....

example 3

In Vitro Characterization

[0058] All rod-shaped compositions were rigid, straight, handleable, and injectable through a 16-gauge needle. Scanning electron micrographs (SEM) of Hyaff-11® rod compositions were typically solid, dense, and smooth, while those of Hyaff-11p65® rod compositions were densely packed with short, fibrillar segments of the native non-woven fibers. Bioactivity of rhBMP-2 in the rod-shaped compositions was obtained after extracting rhBMP-2 from the compositions and testing its ability to induce alkaline phosphatase (a bone marker) expression in mouse W-20-17 stromal cells. The rhBMP-2 from Hyaff-11® and Hyaff-11p65® rod compositions were bioactive.

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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...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K31/663A61K31/728A61L27/00A61K38/17A61K38/18A61K38/48A61K45/00A61K47/36A61L27/20A61L27/22A61L27/26A61L27/50A61P19/00A61P19/10C07K14/51
CPCA61K9/0024A61K31/663C07K14/51A61L27/50A61L27/26A61L27/227A61L27/20A61K47/36A61K38/1875A61K31/728A61K2300/00C08L5/08C08L89/00A61P19/00A61P19/08A61P19/10A61P3/14A61P5/00
Inventor LI, REBECCA H.KIM, HYUN D.
Owner WYETH
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