Delayed-Setting Calcium Phosphate Pastes

• US 20080028992A1
• Filed: 04/14/2005
• Published: 02/07/2008
• Est. Priority Date: 04/15/2004
• Status: Active Grant

• Current Assignee: Etex Corporation (Zimmer Biomet Holdings, Inc.)
• Original Assignee: Etex Corporation (Zimmer Biomet Holdings, Inc.)
• Inventors: Rosenberg, Aron, Lee, Dosuk, Lee, Youngmi, Gilles De Pelichy, Laurent, Sutaria, Manish, Tofighi, Aliassghar
• Granted Patent: US 8,216,359 B2
• Time in Patent Office: Days
• US Class Current: 106/690
• CPC Class Codes: A61F 2/30767 Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
• CPC Class Codes: A61F 2310/00293 containing a phosphorus-containing compound, e.g. apatite
• CPC Class Codes: A61F 2310/00796 Coating or prosthesis-covering structure made of a phosphorus-containing compound, e.g. hydroxy(l)apatite
• CPC Class Codes: A61L 2300/256 Antibodies, e.g. immunoglobulins, vaccines
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/432 Inhibitors, antagonists A61L2300/402 - A61L2300/43 take precedence
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 24/02 containing inorganic materials
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: G06Q 99/00 Subject matter not provided for in other groups of this subclass

Abstract

The invention features delayed-setting calcium phosphate pastes which are useful for the preparation of delivery vehicles for biologically active agents, useful for the treatment of orthopedic conditions and can be stored for long periods without prematurely setting.

Claims

1. A paste comprising a calcium phosphate material and a liquid, wherein said liquid comprises less than 5% (w/w) water and said paste forms a hardened calcium phosphate material when placed in a moist environment.

2. The paste of claim 1, said paste comprising at least 30% (w/w) calcium phosphate material and at least 5% (w/w) liquid, wherein said liquid comprises less than 1% (w/w) water.

3. The paste of claim 2, said paste comprising at least 50% (w/w) calcium phosphate material and at least 10% (w/w) liquid.

4. The paste of claim 1, wherein said calcium phosphate material is calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium phosphate, tricalcium phosphate dihydrate, crystalline hydroxyapatite (HA), poorly crystalline calcium phosphate (PCA), calcium pyroposphate, monetite, octacalcium phosphate, amorphous calcium phosphate, or mixtures thereof.

5. The paste of claim 4, wherein said calcium phosphate material comprises a poorly crystalline calcium phosphate.

6. The paste of claim 4, wherein said calcium phosphate material comprises amorphous calcium phosphate.

7. The paste of claim 6, said paste comprising at least 50% (w/w) calcium phosphate material and at least 20% (w/w) liquid, wherein said liquid comprises less than 1% (w/w) water.

8. The paste of claim 1, wherein said liquid comprises dimethyl sulfoxide, N-methyl 2-pyrrolidone, glycofurol, ethyl lactate, ethanol, propylene glycol, 1,2-dimethoxyethane, diglyme, dimethyl isosorbide, Solketal®

, tetrahydrofurfuryl alcohol, glycerol, triacetin, propylene carbonate, polyethylene glycol, lecithin, or combinations thereof.

9. The paste of claim 8, wherein said liquid comprises N-methyl 2-pyrrolidone.

10. The paste of claim 1, further comprising a supplementary material.

11. The paste of claim 10, wherein said supplementary material comprises a bioerodible polymer selected from the group consisting of a polysaccharide, nucleic acid, carbohydrate, protein, polypeptide, poly(a-hydroxy acid), poly(lactone), poly(amino acid), poly(anhydride), poly(orthoester), poly (anhydride-co-imide), poly(orthocarbonate), poly(α

-hydroxy alkanoate), poly(dioxanone), and poly(phosphoester), and mixtures thereof.

12. The paste of claim 10, wherein said supplementary material comprises a bioerodible material selected from the group consisting of collagen, glycogen, chitin, starch, keratins, silk, demineralized bone matrix, hyaluronic acid, poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide (PLGA), poly(L-lactide-co-D, L-lactide), poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB), poly(ε

-caprolactone), poly(δ

-valerolactone), poly(γ

-butyrolactone), and poly(caprolactone), and mixtures thereof.

13. The paste of claim 10, wherein said supplementary material comprises a non-erodible material selected from the group consisting of dextran, cellulose, polyethylene, polymethylmethacrylate, carbon fiber, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymer, and poly(ethylene terephthalate)polyamide, and mixtures thereof.

14. The paste of claim 13, wherein said cellulose is methylcellulose, carboxy methylcellulose, hydroxypropyl methylcellulose, or hydroxyethyl cellulose.

15. The paste of claim 1, further comprising a biologically active agent.

16. The paste of claim 15, wherein said biologically active agent is an osteogenic protein, antibiotic, polynucleotide, anti-cancer agent, growth factor, or vaccine.

17. The paste of claim 16, wherein said osteogenic protein is BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-1 1, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, or BMP-18.

18. The paste of claim 15, wherein said biologically active agent is an alkylating agent, platinum agent, antimetabolite, topoisomerase inhibitor, antitumor antibiotic, antimitotic agent, aromatase inhibitor, thymidylate synthase inhibitor, DNA antagonist, farnesyltransferase inhibitor, pump inhibitor, histone acetyltransferase inhibitor, metalloproteinase inhibitor, ribonucleoside reductase inhibitor, TNF alpha agonist, TNF alpha antagonist, endothelin A receptor antagonist, retinoic acid receptor agonist, immuno-modulator, hormonal agent, antihormonal agent, photodynamic agent, or tyrosine kinase inhibitor.

19. The paste of claim 1, further comprising an effervescent agent.

20. The paste of claim 18, wherein said effervescent is sodium bicarbonate.

21. The paste of claim 20, wherein said paste is from about 1 to about 40 percent (w/w) sodium bicarbonate.

28. A method of promoting bone growth at a site in need thereof, said method comprising applying to said site a paste of claim 1.

29. The method of claim 28, wherein said site is the surface of an orthopedic implant.

30. The method of claim 28, wherein said site is a bone fracture.

31. The method of claim 28, wherein said paste further comprises a biologically active agent.

32. A method of preparing a structural support for segmented bone, said method comprising contacting bone segments with a paste of claim 1.

33. The method of claim 32, further comprising contacting fixation hardware with said paste.

34. The method of claim 33, wherein said fixation hardware is selected form screws and plates.

35. A kit comprising:

(i) a paste of claim 1, and

(ii) instructions for implanting said paste into a mammal.

36. The kit of claim 35, wherein said paste further comprises a biologically active agent.

37. A method of promoting investment in a company conducting or planning in vivo studies on a paste of claim 1, said method comprising the step of disseminating information about the identity, therapeutic use, toxicity, efficacy, or projected date of governmental approval of said paste.

38. A method for promoting the use of a paste of claim 1, said method comprising the step of disseminating information about the identity or therapeutic use of said paste.

22. A method of preparing a vehicle for the delivery of a biologically active agent, comprising:

(i) preparing a paste comprising a calcium phosphate material, a biologically active agent, and a liquid, wherein said liquid comprises less than 5% (w/w) water, and

(ii) placing said paste in a moist environment until a hardened calcium phosphate material is formed.

23. The method of claim 22, wherein said paste further comprises a supplementary material.

24. The method of claim 22, wherein said moist environment is inside a mammal.

27. The method of claim 24, wherein said moist environment is inside a mammal.

25. A method of preparing an implant, comprising:

(i) preparing a paste comprising a calcium phosphate material and a liquid, wherein said liquid comprises less than 5% (w/w) water, and

(ii) placing said paste in a moist environment until a hardened calcium phosphate material is formed.

26. The method of claim 25, wherein said paste further comprises a supplementary material.