Injectable carrier formulations of hyaluronic acid derivatives for delivery of osteogenic proteins

• US 7,189,392 B1
• Filed: 10/13/2000
• Issued: 03/13/2007
• Est. Priority Date: 10/15/1999
• Status: Expired due to Fees

• Current Assignee: Fidia Advanced Biopolymers S.R.L. (Anika Therapeutics Incorporated), Genetics Institute LLC (Pfizer Inc.)
• Original Assignee: Fidia Advanced Biopolymers S.R.L. (Anika Therapeutics Incorporated), Genetics Institute LLC (Pfizer Inc.)
• Inventors: Kim, Hyun, Callegaro, Lanfranco, Pavesio, Alessandra, Li, Rebecca, Seeherman, Howard, Wozney, John
• Primary Examiner(s): Tate; Christopher R.
• Assistant Examiner(s): HARLE, JENNIFER I
• Application Number:
  US09/687,281
• Time in Patent Office: 2,342 Days
• Field of Search: 514/21, 514/23, 424/423, 424/94.1
• US Class Current: 424/94.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61L 27/46 with phosphorus-containing inorganic fillers
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

An injectable formulation is disclosed for delivery of osteogenic proteins. The formulation comprises a pharmaceutically acceptable admixture of an osteogenic protein; and formulations comprising osteogenic protein, hyaluronic acid derivatives and tricalcium phosphate are also disclosed. Methods for formulating porous injectable gels and pastes from hyaluronic acid are also disclosed.

Claims

1. A composition for injectable delivery of osteogenic proteins to a patient comprising

(a) an osteogenic protein;

(b) an injectable hyaluronic acid ester; and

(c) a pore former selected from a liquid pore former or sodium bicarbonate,

wherein the composition is injectable through the skin of a patient.

4. The composition of any one of claims 1 to 3, wherein the hyaluronic acid ester is at least 50% esterified.

5. The composition of any one of claims 1 to 3, wherein the hyaluronic acid ester is at least 60% esterified.

6. The composition of any one of claims 1 to 3, wherein the hyaluronic acid is at least 65% esterified.

7. The composition of any one of claims 1 to 3, wherein the hyaluronic acid is at least 75% esterified.

8. The composition of any one of claims 1 to 3, wherein the hyaluronic acid is at least 80% esterified.

9. The composition of any one of claims 1 to 3, wherein the hyaluronic acid is 100% esterified.

10. The composition of any one of claims 1 to 3, wherein the liquid pore former is polyethylene glycol.

11. The composition of any one of claims 1 to 3, wherein the hyaluronic acid ester is solubilized in an organic solvent.

12. The composition of any one of claims 1 to 3, wherein the hyaluronic acid ester is solubilized in an aqueous buffer.

13. The composition of any one of claims 1 to 3, further comprising TCP.

14. The composition of any one of claims 1 to 3, wherein the osteogenic protein is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, and BMP-12.

15. The composition of any one of claims 1 to 3, wherein the hyaluronic acid ester is Hyaff11.

16. The composition of claim 15, wherein the liquid pore former is polyethylene glycol.

17. The composition of claim 15, wherein the hyaluronic acid ester is solubilized in an organic solvent.

18. The composition of claim 15, further comprising TCP.

19. The composition of claim 15, wherein the osteogenic protein is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, and BMP-12.

20. The composition of any one of claims 1 to 3, wherein the hyaluronic acid ester is Hyaff11p80.

21. The composition of claim 20, wherein the liquid pore former is polyethylene glycol.

22. The composition of claim 20, wherein the hyaluronic acid ester is solubilized in an organic solvent.

23. The composition of claim 20, further comprising TCP.

24. The composition of claim 20, wherein the osteogenic protein Is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, and BMP-12.

2. A composition for injectable delivery of osteogenic proteins to a patient comprising

(a) an osteogenic protein;

(b) an injectable hyaluronic acid ester; and

(c) a pore former selected from a liquid pore former or sodium bicarbonate,

wherein the composition is injectable through the skin of a patient, and upon injection the osteogenic protein and hyaluronic acid ester form a porous precipitate.

3. A composition for injectable delivery of osteogenic proteins to a patient comprising

(a) an osteogenic protein;

(b) an injectable hyaluronic acid ester; and

(c) a pore former selected from a liquid pore former or sodium bicarbonate,

wherein the composition is injectable through the skin of a patient, and upon injection the pore former is extracted from the osteogenic protein and hyaluronic acid ester by solubilization in situ.

25. A composition for delivery of osteogenic proteins to a patient comprising an osteogenic protein and Hyaff11p65, wherein the composition is injectable through the skin of the patient.

26. The composition of claim 25, wherein the osteogenic protein is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, and BMP-12.

27. The composition of claim 25, wherein the Hyaff11p65 is solubilized in aqueous buffer.

28. The composition of claim 25, further comprising TCP.

29. A composition for delivery of osteogenic proteins to a patient comprising BMP-12 and Hyaff11p65, wherein the composition is injectable through the skin of the patient.