Method of manufacturing hydroxyapatite and uses therefor in delivery of nucleic acids 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO03088925 A2 2003-10-30 [WO200388925]WO03088925 A3 2003-12-11 [WO200388925] / 2003-10-302003-12-11
申请号/申请日
2003WO-US08450 / 2003-03-19
发明人
KUMTA PRASHANT N;SFEIR CHARLES;HOLLINGER JEFFREY;CHOI DAIWON;WEISS LEE;CAMPBELL PHIL;
申请人
CARNEGIE MELLON UNIVERSITY;
主分类号
IPC分类号
A61L-027/12A61L-027/54C01B-025/32C12N-015/87
摘要
(WO200388925) Provided is a method for production of nanocrystalline hydroxyapatite particles, and nanocrystalline hydroxyapatite particles produced according to the method.  The nanocrystalline hydroxyapatite particles exhibit substantially superior cell transformation abilities as compared to known and commercially-available calcium phosphate kits.  The nanocrystalline hydroxyapatite particles also find use in tissue engineering applications, for example bone and tooth engineering and repair applications.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2002US-60373494 2002-04-18
主权利要求
(WO200388925) We claim: 1. A method for making hydroxyapatite, comprising the step of reacting calcium ions with phosphate ions in the presence of hydroxyl ions, wherein the ratio of calcium ions to phosphate ions is greater than 1.67. 2. The method of claim 1 , wherein the ratio of calcium ions to phosphate ions is greater than about 16.7. 3. The method of claim 1 , wherein the reacting step comprises the step of mixing a calcium ion-containing solution with a solution comprising trisodium phosphate. 4. The method of claim 1, wherein the reacting step comprises the step of mixing a calcium chloride solution with a solution containing phosphate ions. 5. The method of claim 1 , wherein the hydroxyapatite is prepared according to the formula: n(CaCl2) + 6(Na3PO4) + 2NaOH → Ca10(PO4)6(OH)2+ 20NaCl + (n-10)CaCl2, wherein n is greater than 10. 6. The method of claim 5, wherein n is greater than about 100. 7. The method of claim 5, wherein the calcium phosphate is precipitated by mixing a solution of calcium chloride with a solution of NaCl, KCl, Na3PO4, a sugar and a buffer adjusted to pH 7.5 with NaOH. 8. The method of claim 7, wherein the calcium phosphate is precipitated by mixing a solution of calcium chloride with a solution of about 280 mM NaCl, about 10 mM KCl, about 1.5 mM Na3PO4, about 12 mM dextrose and about 50 mM HEPES adjusted to pH 7.5 with NaOH. 9. The method of claim 1 , wherein the calcium phosphate is precipitated in the presence of a biomolecule. 10. The method of claim 9, wherein the biomolecule is a nucleic acid. 11. The method of claim 9, wherein the biomolecule is DNA. 12. The method of claim 11 , wherein the DNA comprises a bone morphogenetic protein gene. 13. The method of claim 11 , wherein the DNA comprises a gene selected from the group consisting of rhBMP-2, NEGF, EGF, ΝGF, TGF-β, FGF, .PDGF, IGF, Runx2, Osx and BMP-7. 14. The method of claim 11 , wherein the DΝA comprises a gene. 15. The method of claim 9, wherein the biomolecule is plasmid DΝA. 16. The method of claim 9, wherein the biomolecule is RΝA. 17. The method of claim 16, wherein the RΝA is one of an antisense RΝA and an interfering RΝA. 18. The method of claim 1 , further comprising the step of associating the calcium phosphate with a substrate. 19. The method of claim 18, wherein the substrate is a polymer matrix. 20. The method of claim 19, wherein the polymer matrix comprises a natural polymer. 21. The method of claim 20, wherein the natural polymer is selected from the group consisting of fibrin, carrageenan, chitosan, hyaluronic acid, alginate and collagen. 22. The method of claim 19, wherein the polymer matrix comprises a synthetic polymer. 23. The method of claim 22, wherein the synthetic polymer is selected from the group consisting of PLA, PLGA, PGA, polyurethanes, poly caprolactone, PMMA, poly-L-lysine, polyethyleneimine, poly-anhydrides, polypropylene-fumarate, hydrogels, dendrimers, polymeric micellular stractures and combinations thereof. 24. The method of claim 18, wherein the substrate is configured as a biomimetic extracellular matrix. 25. The method of claim 1 , further comprising the step of depositing the calcium phosphate onto a substrate. 26. The method of claim 25, wherein the substrate is configured as a biomimetic extracellular matrix. 27. The method of claim 25, wherein the substrate is a ceramic. 28. The method of claim 25, wherein the substrate is a metal. 29. The method of claim 25, wherein the substrate is a semiconductor. 30. The method of claim 25, wherein the substrate is selected from the group consisting of porous metal, porous ceramic, porous semiconductor, amorphous carbon, pyrolytic graphite and carbon nanotubes. 31. The method of claim 25, wherein the substrate is a polymer. 32. The method of claim 1, further comprising the step of incorporating the calcium phosphate into a pharmaceutically acceptable dosage form. 33. The method of claim 32, wherein the dosage form is a transdermal form. 34. The method of claim 32, wherein the dosage form is an aerosol form. 35. The method of claim 32, wherein the dosage form is a parenteral form. 36. The method of claim 32, wherein the dosage form is an oral form. 37. A composition, comprising hydroxyapatite prepared by a method comprising the step of reacting calcium ions with phosphate ions, at a calcium ion to phosphate ion ratio of greater than about 1.67, in the presence of hydroxyl ions. 38. The composition of claim 37, wherein the hydroxyapatite is prepared according to the formula: n(CaCl2) + 6(Na3PO4) + 2NaOH → Caι0(PO4)6(OH)2+ 20NaCl + (n-10)CaCl2, wherein n is greater than 10. 39. The composition of claim 38, wherein n is greater than about 100. 40. A product, comprising hydroxyapatite prepared according to the step of reacting calcium ions with phosphate ions in the presence of hydroxyl ions, at a calcium ion to phosphate ion ratio of greater than 1.67, in which the hydroxyapatite is associated with a substrate. 41. The product of claim 40, wherein the hydroxyapatite is prepared according to the formula: n(CaCl2) + 6(Na3PO4) + 2NaOH → Caι0(PO4)6(OH)2+ 20NaCl + (n-10)CaCl2, wherein n is greater than 10. 42. The product of claim 40, wherein the substrate is selected from the group consisting of a cell growth support or matrix, a cell growth medium, and a medical implant. 43. The product of claim 40, wherein the substrate is a stent. 44. The product of claim 40, wherein the substrate comprises a metal. 45. The product of claim 40, wherein the substrate comprises a ceramic. 46. The product of claim 40, wherein the substrate comprises a semiconductor. 47. The product of claim 40, wherein the substrate comprises an amorphous form of carbon. 48. The product of claim 47, wherein the amorphous form of carbon is one of pyrolitic graphite and carbon nanotubes. 49. The product of claim 40, wherein the substrate comprises one of a porous metal, a porous ceramic and a porous semiconductor. 50. The product of claim 40, wherein the substrate comprises a polymer. 51. The product of claim 50, wherein the polymer is a hydrogel and the composition is contained within the hydrogel. 52. The product of claim 51 , wherein the hydrogel is contained within a cell-culture vessel. 53. The product of claim 50, wherein the polymer is a natural polymer. 54. The product of claim 53, wherein the natural polymer is selected from the group consisting of fibrin, carrageenan, chitosan, hyaluronic acid, alginate and collagen. 55. The product of claim 50, wherein the polymer is a synthetic polymer. 56. The product of claim 55, wherein the synthetic polymer is selected from the group consisting of PLA, PLGA, PGA, polyurethane, polycaprolactone, PMMA, poly-L-lysine, polyethyleneimine, poly-anhydrides, polypropylene-fumarate, hydrogels, dendrimers, polymeric micellular structures and combinations thereof. 57. The product of claim 50, wherein the polymer is porous. 58. The product of claim 57, wherein the porous polymer comprises polymer fibers. 59. The product of claim 57, wherein the porous polymer comprises an expanded polymer. 60. The product of claim 57, wherein the porous polymer is a biomimetic extracellular matrix. 61. The product of claim 40, wherein the substrate is a woven or non- woven mesh. 62. The product of claim 40, wherein the substrate is an aqueous reservoir for a transdermal drag delivery device. 63. The product of claim 40, wherein the substrate comprises a pharmaceutically acceptable filler or excipient. 64. Hydroxyapatite prepared according to the step of reacting calcium ions with phosphate ions in the presence of hydroxyl ions, at a calcium ion to phosphate ion ratio of greater than 1.67, wherein the hydroxyapatite is prepared according to the formula: n(CaCl2) + 6(Na3PO4) + 2NaOH → Caι0(PO4)6(OH)2+ 20NaCl + (n-10)CaCl2, wherein n is greater than 10. 65. The hydroxyapatite of claim 64, further comprising a nucleic acid complexed with the hydroxyapatite. 66. The hydroxyapatite of claim 65, wherein the calcium is precipitated from an aqueous phase in the presence of the nucleic acid. 67. The hydroxyapatite of claim 64, wherein n is greater than about 100. 68. A method for introducing a biomolecule into a cell, comprising the step of contacting a cell with a composition comprising hydroxyapatite prepared according to the step of reacting calcium ions with phosphate ions in the presence of a biomolecule and hydroxyl ions, at a calcium ion to phosphate ion ratio of greater than 1.67. 69. The method of claim 68, wherein the hydroxyapatite is prepared according to the formula: n(CaCl2) + 6(Na3PO4) + 2NaOH → Ca10(PO4)6(OH)2+ 20NaCl + (n-10)CaCl2, wherein n is greater than 10. 70. The method of claim 69, wherein the biomolecule is DNA. 71. The method of claim 70, wherein the DNA contains a gene. 72. The method of claim 70, wherein the DNA comprises a bone morphogenetic protein gene. 73. The method of claim 70, wherein the DNA comprises a gene selected from the group consisting of rhBMP-2, VEGF, EGF, NGF, TGF-β, FGF, .PDGF, IGF, Runx2, Osx and BMP-7. 74. A kit for use in preparing calcium chloride, comprising: (a) a first solution comprising calcium chloride in a first container; and (b) a second solution comprising trisodium phosphate and hydroxyl ions in a second container. 75. The kit of claim 74, further comprising a biomaterial in one of the first and second solutions. 76. The kit of claim 75, wherein the biomaterial is a nucleic acid. 77. The kit of claim 76, wherein the nucleic acid is DNA which comprises a bone morphogenetic protein gene. 78. The kit of claim 75, wherein the biomaterial is a plasmid DNA. 79. A method for treating a bone or tooth injury comprising the step of introducing into a site of injury in a bone or tooth a matrix containing a hydroxyapatite complex comprising hydroxyapatite complexed with a biomaterial, wherein the hydroxyapatite is prepared by reacting calcium ions with phosphate ions in the presence of hydroxyl ions, wherein the ratio of calcium ions to phosphate ions is greater than 1.67.
法律状态
(WO200388925) LEGAL DETAILS FOR WO03088925  Actual or expected expiration date=2005-10-18    Legal state=DEAD    Status=LAPSED     Event publication date=2003-03-19  Event code=WO/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=WO WOUS0308450  Application date=2003-03-19  Standardized application number=2003WO-US08450     Event publication date=2003-10-30  Event code=WO/A2  Event type=Examination events  International application published without international search report  Publication country=WO  Publication number=WO03088925  Publication stage Code=A2  Publication date=2003-10-30  Standardized publication number=WO200388925     Event publication date=2003-10-30  Event code=WO/AL  Event indicator=Pos  Event type=Designated states  Designated countries for regional patents GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG    Event publication date=2003-10-30  Event code=WO/AK  Event indicator=Pos  Event type=Designated states  Designated states AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG UZ VC VN YU ZA ZM ZW    Event publication date=2003-12-11  Event code=WO/A3  Event indicator=Pos  Event type=Examination events  Later publication of ISR with revised front page  Publication country=WO  Publication number=WO03088925  Publication stage Code=A3  Publication date=2003-12-11  Standardized publication number=WO200388925     Event publication date=2004-01-15  Event code=WO/DFPE  Event type=Examination events  Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)    Event publication date=2005-10-18  Event code=WO/EETL  Event type=Event indicating Not In Force  PCT Application validity period expired. LEGAL DETAILS FOR DESIGNATED STATE AU2003218271  Actual or expected expiration date=2005-01-13    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=AU Corresponding appl: AU2003218271  Application date in the designated or member state=2003-03-19   Application number in the designated or member state=2003AU-0218271 Corresponding cc:  Designated or member state=AU Corresponding pat: AU2003218271  Publication stage code in the designated or member state=A1  Publication date in the designated or member state=2003-11-03   Publication number in the designated or member state=AU2003218271    Event publication date=2005-01-13  Event code=AU/STCHG  Patent Status changed by the national office Corresponding cc:  Designated or member state=AU  LEGAL DETAILS FOR DESIGNATED STATE JP  Actual or expected expiration date=2006-06-29    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=JP     Event publication date=2006-06-29  Event code=WO/NENP  Event type=Event indicating Not In Force  Non-entry into the national phase in: Corresponding cc:  Designated or member state=JP     Event publication date=2006-06-29  Event code=WO/WWW  Event indicator=Neg  Event type=Event indicating Not In Force  Wipo information: withdrawn in national office Corresponding cc:  Designated or member state=JP
专利类型码
A2A3
国别省市代码
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