Treatment of pain using protein solutions

• US 10,143,725 B2
• Filed: 03/15/2013
• Issued: 12/04/2018
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Biomet Manufacturing, LLC (Zimmer Biomet Holdings, Inc.)
• Original Assignee: Biomet Biologics LLC (Zimmer Biomet Holdings, Inc.)
• Inventors: O'Shaughnessey, Krista, Woodell-May, Jennifer E., Higgins, Joel C., Leach, Michael D.
• Primary Examiner(s): Hama, Joanne
• Assistant Examiner(s): LOCKARD, JON MCCLELLAND
• Application Number:
  US13/837,480
• Publication Number:
  US 20140271870A1
• Time in Patent Office: 2,090 Days
• Field of Search: None
• CPC Class Codes: A61K 35/14 Blood; Artificial blood perfluorocarbons A61K31/02; umbilical cord blood A61K35/51; haemoglobin A61K38/42
• CPC Class Codes: A61K 35/16 Blood plasma; Blood serum umbilical cord blood A61K35/51
• CPC Class Codes: A61K 38/1703 from vertebrates
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 38/19 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

Methods for treating pain using a protein solution comprising two or more of IL1-ra, sTNF-R1, sTNF-RII, IGF-I, EGF, HGF, PDGF-AB, PDGF-BB, VEGF, TGF-β1, and sIL-1RII, Compositions may also contain white blood cells and platelets.

Claims

1. A method for treating osteoarthritis pain in a mammalian subject, comprising locally administering to or near a site of osteoarthritis pain in the subject a composition comprising interleukin-1receptor antagonist (IL-1ra) at a concentration of at least 10,000 pg/ml, soluble tumor necrosis factor-receptor I (sTNF-RI) at a concentration of at least 1,200 pg/ml, soluble interleukin-1 receptor II (sIL-1RII) at a concentration of at least 15,000 pg/ml, and at least two proteins selected from the group consisting of epidermal growth factor (EGF) at a concentration of at least 800 pg/ml, hepatocyte growth factor (HGF) at a concentration of at least 1,000 pg/ml, platelet-derived growth factor BB (PDGF-BB) at a concentration of at least 10,000 pg/ml, soluble tumor necrosis factor-receptor II (sTNF-RII) at a concentration of at least 3,000 pg/ml, platelet-derived growth factor-AB (PDGF-AB) at a concentration of at least 35,00 pg/ml, vascular endothelial growth factor (VEGF) at a concentration of at least 500 pg/ml, and transforming growth factor-β

1 (TGF-β

1) at a concentration of at least 100,000 pg/ml, wherein treating pain includes reducing pain or eliminating pain at or near the site of administration of the composition.

2. The method according to claim 1, wherein the composition is autologous to the subject.

3. The method according to claim 1, wherein the composition further comprises:

white blood cells at a concentration of at least 15,000/μ

l.

4. A method for treating osteoarthritis pain, comprising topically administering a composition to or near a site of osteoarthritis pain in a subject, the composition comprising:

at least 10,000 pg/ml interleukin-1 receptor antagonist (IL-1ra);

at least 1,200 pg/ml soluble tumor necrosis factor-receptor I (sTNF-RI);

at least 15,000 pg/ml soluble interleukin-1 receptor II (sIL-1RII); and

at least 3,000 pg/ml soluble tumor necrosis factor-receptor II (sTNF-RII);

wherein treating pain includes reducing pain or eliminating pain at or near the site of administration of the composition.

5. The method according to claim 4, wherein the composition further comprises a supplemental protein selected from the group consisting of insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), hepatocyte growth factor (HGF), platelet-derived growth factor AB (PDGF-AB), platelet-derived growth factor-BB (PDGF-BB), vascular endothelial growth factor (VEGF), and transforming growth factor-β

1(TGF-β

1), wherein the concentration of the selected supplemental protein in the composition is greater than the concentration of the selected supplemental protein in normal blood.

6. The method according to claim 4, wherein the composition further comprises at white blood cells at a concentration of at least 30,000/μ

l.

7. A method for treating pain associated with osteoarthritis in a mammalian subject, comprising:

obtaining a cytokine-cell suspension from the subject;

processing the suspension to produce an protein solution comprising soluble interleukin-1receptor antagonist (IL-1ra) at a concentration of at least 10,000 pg/ml, soluble interleukin-1receptor II (sIL-1RII) at a concentration of at least 15,000 pg/ml, soluble tumor necrosis factor-receptor II (sTNF-RII) at a concentration of at least 3,000 pg/ml, and white blood cells at a concentration of at least 15,000/μ

l; and

administering the protein solution directly to or near a site of osteoarthritis pain in the subject, wherein treating pain includes reducing pain or eliminating pain at or near the site of administration of the protein solution.

8. The method according to claim 7, wherein the cytokine-cell suspension is obtained from one or more of blood, bone marrow aspirate, adipose tissue, or urine.

9. The method according to claim 7, wherein the cytokine-cell suspension comprises platelet rich plasma, bone marrow aspirate, or a combination thereof.

10. The method according to claim 7, wherein the protein solution has a IL-1ra:

interleukin-1β

concentration ratio greater than 1,500, a white blood cell concentration of at least about 30,000/μ

l, or both.

11. The method according to claim 7, wherein processing comprises concentrating the cytokine-cell suspension to produce the protein solution.

12. The method according to claim 7, wherein processing comprises contacting the cytokine cell suspension with a solid extraction material to produce the protein solution and

separating the solid extraction material from the protein solution.

13. The method according to claim 12, wherein the solid extraction material comprises corundum, quartz, titanium, dextran, agarose, polyacrylamide, polystyrene, polyethylene, polyvinyl chloride, polypropylene, or a combination thereof.

14. The method according to claim 13, wherein the solid extraction material comprises polyacrylamide.

15. The method according to claim 12, wherein the solid extraction material comprises a bead, fiber, powder, porous material, or a combination thereof.

16. The method according to claim 7, further comprising:

obtaining bone marrow aspirate from the subject;

concentrating the bone marrow aspirate to produce a concentrated bone marrow aspirate (cBMA); and

administering the cBMA to the subject.

17. The method according to claim 7, wherein processing includes mixing a bone marrow aspirate with the cytokine-cell suspension.

18. The method according to claim 7, further comprising administering to the subject a concomitant therapy.

19. The method according to claim 18, wherein the concomitant therapy comprises administering to the site of osteoarthritis pain a composition comprising hyaluronic acid, collagen, an ant-infective agent, or a combination thereof.

20. The method according to claim 18, wherein the concomitant therapy comprises off loader braces, electrical stimulation, or a combination thereof.

21. The method according to claim 7, wherein administering includes injecting the protein solution into a joint.

22. The method according to claim 7, wherein administering includes injecting the protein solution at or near the site of osteoarthritis pain.

23. The method according to claim 7, wherein administering includes topically delivering the protein solution to a muscle at or near a joint.

24. The method according to claim 7, wherein processing the cytokine-cell suspension provides a dosage for administering to the subject.

25. The method according to claim 7, wherein the osteoarthritis pain is associated with back pain.

26. The method according to claim 7, wherein the cytokine-cell suspension comprises about 55 mls to about 120 mls of the subject'"'"'s whole blood.