Calcium phosphate delivery vehicles for osteoinductive proteins

• US 7,413,753 B2
• Filed: 05/31/2002
• Issued: 08/19/2008
• Est. Priority Date: 06/08/2001
• Status: Active Grant

• Current Assignee: Wyeth (Pfizer Inc.), Etex Corporation (Zimmer Biomet Holdings, Inc.)
• Original Assignee: Wyeth (Pfizer Inc.), Etex Corporation (Zimmer Biomet Holdings, Inc.)
• Inventors: Li, Rebecca H., Seeherman, Howard
• Primary Examiner(s): Henley, III; Raymond J.
• Application Number:
  US10/160,607
• Publication Number:
  US 20020187104A1
• Time in Patent Office: 2,272 Days
• Field of Search: 514/50
• US Class Current: 424/602
• 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 38/02 Peptides of undefined number of amino acids; Derivatives thereof
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61L 17/005 containing a biologically active substance, e.g. a medicament or a biocide
• CPC Class Codes: A61L 17/145 Coating
• CPC Class Codes: A61L 24/02 containing inorganic materials
• CPC Class Codes: A61L 24/108 Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

A composition for delivery of osteogenic proteins is disclosed. The composition comprises an osteogenic protein, a calcium phosphate material as a carrier, and an effective amount of an effervescent agent. Methods of making the compositions and methods of using the osteogenic compositions to treat osteoporotic and/or osteopenic bone are also disclosed.

Claims

1. A composition for delivery of osteogenic proteins, which comprises an osteogenic protein as a first biologically active agent, a calcium phosphate material as a carrier, and an effective amount of a material that liberates gas upon dissolution in vivo.

2. The composition of claim 1, wherein the osteogenic protein is selected from the group consisting of members of the bone morphogenic protein (BMP) family.

3. The composition of claim 2, wherein the osteogenic protein is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-10, BMP-12 and BMP-13, and combination thereof.

4. The composition of claim 2, wherein the osteogenic protein is BMP-2 or BMP-6, or a combination thereof.

5. The composition of claim 1, wherein the calcium phosphate material is selected from the group of calcium phosphates consisting of amorphous apatitic calcium phosphate, hydroxyapatite, tricalcium phosphate, and fluorapatite.

6. The composition of claim 1, wherein the calcium phosphate material is an amorphous apatitic calcium phosphate.

7. The composition of claim 1, wherein the calcium phosphate material is a poorly crystalline apatitic calcium phosphate.

8. The composition of claim 7, wherein the calcium phosphate has a calcium-to-phosphate ratio comparable to naturally occurring bone minerals.

9. The composition of claim 7, wherein the calcium phosphate material has a calcium-to-phosphate ratio of less than 1.50.

10. The composition of claim 7, wherein the calcium phosphate has a calcium-to-phosphate ratio of about 1.4.

11. The composition of claim 1, further comprising a supplementary material selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, and surfactants.

12. The composition of claim 1, further comprising a supplementary material selected from the group of solid structures consisting of sponges, meshes, films, fibers, gels, filaments, microparticles, and nanoparticles.

13. The composition of claim 1, further comprising a supplementary material selected from the group of bioerodible polymers consisting of collagen, glycogen, chitin, celluloses, starch, keratins, silk, nucleic acids, demineralized bone matrix, derivativized hyaluronic acid, polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid, and copolymers.

14. The composition of claim 1, further comprising a supplementary material selected from the group of polyesters consisting of α

-hydroxycarboxylic acids, such as poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly(D,L-lactide-co-trimethylene carbonate), and polyhydroxybutyrate (PHB), and polyanhydrides, and co-polymers.

15. The composition of claim 1, further comprising at least one supplementary material selected from the group consisting of SiO₂, Na₂O, CaO, P₂O₅, Al₂O₃ and CaF₂.

16. The composition of claim 1, further comprising a supplementary material selected from the group consisting of polysaccharides, peptides and fatty acids.

17. The composition of claim 1, further comprising a second active agent, wherein the second active agent is selected from the group consisting of Hedghog, Frazzled, Chordin, Noggin, Cerberus and Follistatin proteins.

18. A method of treating a bone defect in a mammal comprising administering to the site of the bone defect an effective amount of an osteogenic composition of claim 1.

19. The method of claim 18, wherein the osteogenic protein is selected from the group consisting of members of the bone morphogenic protein (BMP) family.

20. The method of claim 19, wherein the bone morphogenic protein is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-10, BMP-12 and BMP-13 and combinations thereof.

21. The method of claim 19, wherein the bone morphogenic protein is BMP-2 or BMP-6, or a combination thereof.

22. The method of claim 18, wherein the calcium phosphate material is selected from the group of calcium phosphates consisting of amorphous apatitic calcium phosphate, hydroxyapatite, tricalcium phosphate, and fluorapatite.

23. The method of claim 18, wherein the calcium phosphate material is an amorphous apatitic calcium phosphate.

24. The method of claim 18, wherein the calcium phosphate material is a poorly crystalline apatitic calcium phosphate.

25. The method of claim 24, wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio comparable to naturally occurring bone minerals.

26. The method of claim 24, wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of less than 1:

1.50.

27. The method of claim 24, wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of about 1:

1.40.

28. The composition of claim 2, wherein the osteogenic protein is a bone morphogenic protein (BMP) heterodimer.

29. The composition of claim 3, wherein the osteogenic protein is a bone morphogenic protein (BMP) heterodimer.

30. The composition of claim 4, wherein the osteogenic protein is a bone morphogenic protein (BMP) heterodimer.

31. The method of claim 19, wherein the osteogenic protein is a bone morphogenic protein (BMP) heterodimer.

32. The method of claim 20, wherein the osteogenic protein is a bone morphogenic protein (BMP) heterodimer.

33. The method of claim 21, wherein the osteogenic protein is a bone morphogenic protein (BMP) heterodimer.

34. A composition for delivery of osteogenic proteins, which comprises a bone morphogenic protein as a first biologically active agent, a calcium phosphate material as a carrier, and an effective amount of a gas that is dissolved under pressure, wherein the gas is selected from the group consisting of carbon dioxide, air, nitrogen, helium, oxygen, and argon, and wherein the gas is liberated upon exposure to physiological conditions.

35. A composition for delivery of osteogenic proteins, which comprises a bone morphogenic protein as a first biologically active agent, a calcium phosphate material as a carrier, and an effective amount of sodium bicarbonate.

36. The composition of claim 35, wherein the sodium bicarbonate is present at a concentration of between about 10 and about 40 percent (w/w).

37. The composition of claim 36, wherein the sodium bicarbonate is present at a concentration of about 20 percent (w/w).

38. A method of treating a bone defect in a mammal comprising administering to the site of the bone defect an effective amount of an osteogenic composition, wherein the osteogenic composition comprises a bone morphogenetic protein, a calcium phosphate material, and sodium bicarbonate.

39. The method of claim 38, wherein the sodium bicarbonate is added at a concentration of between about 10 and about 40 percent (w/w).

40. The method of claim 38, wherein the osteogenic composition further comprises a supplementary material selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, and surfactants.

41. The method of claim 38, wherein the osteogenic composition further comprises a supplementary material selected from the group of polyesters consisting of α

-hydroxycarboxylic acids, such as poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide (PLGA), poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB), polyanhydrides, and co-polymers thereof.

42. The method of claim 38, wherein the osteogenic composition further comprises at least one supplementary material selected from the group consisting of SiO₂, Na₂O, CaO, P₂O₅, Al₂O₃ and CaF₂.