Patent EA-000309-B1 (EA)
Title: Bone substitution material and a method of its manufacture
Inventor: LEE DOSUK D
IPC: A61L27/42
Filed: 1996-05-20
Abstract: 1. A reactive amorphous calcium phosphate material having at least 90% percent amorphous character and characterized in that, when prepared 1:1 as a mixture with dicalcium diphosphate in water at 37 degree C, the mixture hardens within about 10 to about 60 minutes. 2. The reactive amorphous calcium phosphate material according to Claim 1, characterized in that, when prepared 1:1 as a mixture with dicalcium diphosphate in water at 37 degree C, the mixture is injectable for a time greater than about 60 minutes at about 22 degree C. 3. The reactive amorphous calcium phosphate material having at least 90 percent amorphous character obtained by removal of a carbonate pre-component of an amorphous calcium phosphate by thermal decomposition of the pre-component into gaseous or vaporous by-products. 4. The reactive amorphous calcium phosphate material according to Claim 3, characterized in that the reaction is substantially complete within about 75 minutes. 5. The reactive amorphous calcium phosphate material having at least 90 percent amorphous character and characterized in that, when prepared 1:1 as a mixture with dicalcium diphosphate in water at 37  degree C, the reaction is substantially complete mixture within about 40 minutes. 6. The reactive amorphous calcium phosphate according to any of 1, 3, or 5 Claims, characterized in that the calcium to phosphate ratio is in the range of about 1.1 to about 1.9. 7. The reactive amorphous calcium phosphate according to any of 1, 3, or 5 Claims he Ca/P ratio is about 1.58. 8. A method of preparing a reactive amorphous calcium phosphate, according to any of 1, 3, or 5 Claims comprising reacting calcium ions, phosphate ions and a third ion, so as to obtain an amorphous calcium phosphate; and removing at least a portion of the third ion in the amorphous calcium phosphate. 9. The method according to Claim 8, characterized in that the third ion comprises a carbonate ion 10. The method according to Claim 8, characterized in that the step of reacting calcium ions, phosphate ions and a third ion comprises precipitating the amorphous calcium phosphate from an solution comprising the calcium, phosphate and third ions. 11 The method according to Claim 8, characterized in that the solution is an aqueous solution, and the removal step comprises removing a portion of residual water from the amorphous calcium phosphate. 12. The method according to Claim 8, characterized in that the reactive amorphous calcium phosphate has a calcium to phosphate ratio in the range of about 1.1 to about 1.9. 13. The method according to Claim 8, characterized in that the third ion is selected to alter the calcium to phosphate ratio in the product reactive amorphous calcium phosphate. 14. The method according to Claim 8, characterized in that the third ion is selected to stabilize the amorphous character of the amorphous calcium phosphate. 15. The method according to Claim 8, characterized in that further comprising the step of drying the amorphous calcium phosphate prior to removal of the third ion under conditions selected to maintain the amorphous character of the calcium phosphate. 16. The method according to Claim 8, characterized in that the step of removing third ion comprises the step of heating under conditions selected to maintain the amorphous character of the calcium phosphate. 17. The method according to Claim 8, characterized in that the step of removing third ion comprises the step of decomposing the third ion. 18. The method according to Claim 8, characterized in that the step of removing third ion comprises dissolving the third ion from the amorphous calcium phosphate. 19. The method according to Claim 9, characterized in that the step of removing carbonate comprises removing up to about 60 % of the amorphous calcium phosphate carbonate content. 20. The method according to Claim 8, characterized in that reactive vacant sites are introduced into the amorphous calcium phosphate during the removal step. 21. The method according to Claim 8, characterized in that farther comprising adding a bone regenerative protein or an antibiotic to the amorphous carbonated calcium phosphate prior drying. 22. A method of preparing a poorly crystalline hydroxyapatite, comprising: reacting the reactive amorphous calcium phosphate according to any of Claims 1. 3 or 5 with a second calcium phosphate, the second calcium phosphate and the reactive amorphous calcium phosphate in a proportion to form a hydroxyapatitic calcium phosphate. 23. The method according to Claim 22, characterized in that the poorly crystalline hydroxyapatitic calcium phosphate is bioresorbable. 24. The method according to Claim 22, characterized in that the reaction is carried out in a fluid, the fluid selected from the group consisting of water, a physiologically acceptable pH-buffered solution, saline solution, serum and tissue culture medium. 25. The method according to Claim 22, characterized in that the step of reacting comprises mixing the amorphous calcium phosphate and the second calcium phosphate and adding an aqueous solution to the mixture in an amount sufficient to initiate the reaction. 26. The method according to Claim 22, characterized in that the reactive amorphous calcium phosphate material is obtained by reacting calcium ions, phosphate ions and a third ion, so as to obtain an amorphous calcium phosphate; and removing at least a portion of the third ion in the amorphous calcium phosphate so as to obtain a reactive amorphous calcium phosphate. 27. The method according to Claim 22, characterized in that in the Ca/P ratio of the poorly crystalline hydroxy apatite is less than about 1.5. 28. The method according to Claim 22, characterized in that the second calcium phosphate is amorphous or microcrystalline. 29. The method according to Claim 22, characterized in that further comprising: adding a bone regenerative protein or an antibiotic to the mixture. 30. A method of preparing a poorly crystalline hydroxyapatite, comprising reacting the reactive amorphous calcium phosphate according to one of Claims 1, 3 or 5 with a promoter, the promoter selected to convert the reactive amorphous calcium phosphate into a hydroxyapatitic calcium phosphate. 31. The method according to Claim 30, characterized in that the promoter comprises amorphous calcium phosphate. 32. The method according to Claim 30, characterized in that the poorly crystalline hydroxyapatitic calcium phosphate is bioresorbable. 33. The method according to Claim 30, characterized in that the reaction is carried out in a fluid, the fluid selected from the group consisting of water, a physiologically acceptable pH-buffered solution, saline solution, serum and tissue culture medium. 34. The method according to Claim 30, characterized in that the reactive amorphous calcium phosphate material is obtained by reacting calcium ions, phosphate ions and a third ion, so as to obtain an amorphous calcium phosphate; and removing at least a portion of the third ion in the amorphous calcium phosphate so as to obtain a reactive amorphous calcium phosphate. 35. The method according to Claim 30, characterized in that in the Ca/P ratio of the poorly crystalline hydroxy apatite is less than about 1.5. 36. The method according to Claim 30, characterized in that further comprising: adding a bone regenerative protein or an antibiotic to the mixture. 37. A resorbable bone substitute material comprising a poorly crystalline hydroxy apatite having an X-ray diffraction pattern substantially as shown in Fig. 7d. 38. A resorbable bone substitute material comprising a poorly crystalline hydroxyapatite having an X-ray diffraction pattern comprising broad peaks at 2 _0_ (2 Teta) values of 26 degree , 28.5 degree , 32 degree  and 33 degree . 39. A resorbable bone substitute material comprising a poorly crystalline hydroxyapatite, characterized in that, when placed in a rat intramuscular site, resorption of at least 100 mg of the bone substitute material is complete within one month. 40. The resorbable bone substitute material according to Claim 39, wherein resorption of at least 300 mg of the bone substitute material is complete within one month. 41. The resorbable bone substitute material according to any of Claims 37-39, characterized in that, when prepared from a reaction of amorphous calcium phosphate and a second phosphate in a fluid, the reaction mixture hardens after a time greater than 60 minutes at about 22 degree C, and the reaction mixture hardens within about 10 to 60 minutes at 37 degree C. 42. The resorbable bone substitute material according to Claim 41, characterized in that the mixture is injectable for a time greater than about 60 minutes at about 22 degree C. 43. The resorbable bone substitute material according to 41, characterized in that wherein the mixture is formable for a time greater than about 60 minutes at about 22 degree C. 44. The resorbable bone substitute material according to any of Claims 37-39 characterized in that the calcium to phosphorous ratio is in the range of about 1.1 to 1.9. 45. The resorbable bone substitute material according to any of Claims 37-39, characterized in that the calcium to phosphorous ratio is in the range of about 1.3 to 1.5. 46. A formable paste, suitable for use as a resorbable bone substitution material, comprising a mixture of the reactive amorphous calcium phosphate according to one of Claims 1, 3 or 5 and a second calcium phosphate powder; and an amount of a fluid sufficient to provide the desired consistency, said mixture capable of hardening at about 22 degree C. 47. The paste according to Claim 46, characterized in that the mixture hardens after a time greater than 60 minutes at about 22 degree C, and the mixture hardens within about 10 to 60 minutes at about 37 degree C. 48. The paste according to Claim 47, characterized in that the mixture is injectable for a time greater than about 60 minutes at about 22 degree C. 49. The paste accord