Processes for treating coral and coating an object

• US 20040091547A1
• Filed: 12/29/2003
• Published: 05/13/2004
• Est. Priority Date: 11/16/2000
• Status: Active Grant

• Current Assignee: Biotomo Pty., Ltd.
• Original Assignee: University of Technology at Sydney
• Inventors: Milev, Adriyan S, Kannangara, G S Kamall, Gillot, Edit, Conway, Robert M, Russell, Jennifer, Trefry, Clifford, Ben-Nissan, Besim, Hu, Ji, Green, Douglas Drysdal
• Granted Patent: US 7,258,898 B2
• Time in Patent Office: Days
• US Class Current: 424/602
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: C01B 25/32 Phosphates of magnesium, calcium, strontium, or barium
• CPC Class Codes: C07F 9/1417 Compounds containing the structure P-O-C(=X)- (X = O, S, Se)
• CPC Class Codes: C07F 9/4093 Compounds containing the structure P(=X)-X-C(=X)- (X = O, S, Se)

Abstract

The present invention generally relates to an improved process for the hydrothermal conversion of coral into hydroxyapatite, a process for coating an object with hydroxyapatite, a process for coating an object with a divalent metal phosphate and uses of objects prepared by these processes. Following the processes according to the present invention, the resultant hydroxyapatite has greater strength and bioactivity than that of the coral prior to its conversion.

Claims

11. A process for preparing hydroxyapatite material by means of hydrothermal conversion, the process comprising the steps of:

(a) providing a sample of coral;

(b) shaping the sample;

(c) applying a series of pre-conversion steps to the sample, the pre-conversion steps including;

(I) treating the sample with a series of cleansing steps to remove impurities the cleansing steps including;

(i) treating the sample with boiling water;

(ii) rinsing the sample with water

(iii) treating the sample with a solution of about 5% NaClO for about 24 hours;

(v) drying the sample at about 70°

C. for about 12 hours; and

(II) heating the sample at about 300°

C. for about 12 hours; and

(III) washing the heated sample in boiling water, and then drying the heated sample; and

(d) applying a series of hydrothermal conversion steps to the sample, the hydrothermal conversion steps including;

(I) treating the sample with a supersaturated solution of (NH₄)₂HPO₄ (1M) to attain a Ca/P mol ratio of about 10/20 at a temperature of about 250°

C. and at a pressure of about 3.8 MPa for about 24 hours; and

(II) washing the sample and then drying the sample at about 70°

C. for about 12 hours.

14. A phosphonate compound according to formula (1):

R—

C(O)—

O—

P(O)R¹—

O—

C(O)—

R² 

 

(1)

wherein R, R¹ and R², which may be the same or different, are selected from the group consisting of hydrogen, substituted alkyl groups and unsubstituted alkyl groups.

15. The phosphonate compound according to claim 14 wherein, R and R² are CH₃.

16. The phosphonate compound according to claim 14 or 15 wherein R¹ is hydrogen.

17. A divalent metal phosphonate complex wherein a divalent metal is coordinated to the phosphonate compound according to any one of claims 14 to 16.

18. The divalent metal phosphonate complex according to claim 17 wherein the divalent metal is selected from the group consisting of calcium, magnesium, strontium, copper, manganese and zinc.

19. The divalent metal phosphonate complex according to claim 17 or 18 wherein the divalent metal is calcium.

20. The divalent metal phosphonate complex according to any one of claims 17 to 19 wherein the divalent metal is coordinated with a carbonyl and/or phosphoryl oxygen of the phosphonate.

21. The divalent metal phosphonate complex according to any one of claims 17 to 20 wherein, the divalent metal phosphonate is a six-membered chelate ring according to formula (2) and/or (3).

22. The divalent metal phosphonate complex according to any one of claims 17 to 21 having a structure according to formula (4) and/or (5),

23. A method of preparing a phosphonate compound according to any one of claims 14 to 16 the method including reacting a phosphonate according to formula (6)

R³—

O—

P(O)R¹—

O—

R⁴ 

 

(6)

with an acid R⁵—

C(O)—

OH for a time and at a temperature sufficient to effect conversion to the phosphonate (1),

wherein R¹, R³, R⁴ and R⁵ which may be the same or different, are selected from the group consisting of hydrogen, substituted alkyl groups and unsubstituted ally groups.

24. The method according to claim 23 wherein R¹ and R⁴ are alkyl groups and R¹ is hydrogen such that the phosphonate according to formula (6) is a dialkyl hydrogen phoshonate.

25. The method according to claim 23 or 24 wherein R⁶ is a methyl group, R¹ is hydrogen and R³ and R⁴ are ethyl groups, such that the phosphonate according to formula (6) is diethyl hydrogen phosphonate.

26. The method according to any one of claims 23 to 25 wherein the method is carried out in the presence of one or more divalent metal precursors.

27. The method according to claim 26, wherein the divalent metal precursor is selected from calcium, magnesium, strontium, copper, manganese and zinc metal precursors.

28. The method according to claim 27 wherein the divalent metal precursor is a calcium precursor.

29. The method according to any one of claims 26 to 28 wherein the divalent metal precursor is selected from one or more divalent metal salts of a carboxylic acid and/or one or more metal alkoxides.

30. The method according to any one of claims 26 to 29 wherein the divalent metal precursor is calcium diethoxide.

31. The method according to any one of claims 23 to 30 wherein the phosphonate (6) is reacted with the acid in one or more solvents selected from the group consisting of ethylene glycol, ethanol and methanol.

32. The method according to claim 31 wherein the ratio of solvent/acid ranges from 4:

1 to 1;

3,

33. The method according to claim 32 wherein the ratio of solvent/acid is about 1:

1.

34. The method according to any one of claims 23 to 33 wherein the reaction is carried out at a temperature between about 15°

C. to about 100°

C.

35. The method according to claim 34, wherein the reaction is carried out at a temperature of about 70°

C.

36. The method according to any one of claims 26 to 35 wherein a Ca/P mol ratio for reactants is between about 1:

1 to 3;

1.

37. The method according to claim 36 wherein the Ca/P mol ratio is about 1.67:

1.

39. A process of forming a divalent metal phosphonate complex according to any one of claims 17 to 22 wherein the phosphonate compound according to formula (1) is heated to a temperature sufficient to allow the divalent metal to coordinate to the carbonyl and/or phosphoryl oxygen to form the divalent metal phosphonate complex.

40. The process according to claim 39 wherein a solution of the phosphonate compound according to formula (I) is prepared according to the any one of claims 23 to 38.

41. The process according to claim 39 or 40 wherein the phosphonate compound according to formula (1) is heated between about 25°

C. and about 150°

C. for a time of about 10 to about 1000 h.

43. A process of preparing a crystalline monophasic and/or bone-like divalent metal phosphate wherein the divalent metal phosphonate complex according to any one of claims 17 to 22 is fired to a temperature sufficient to allow formation of the crystalline monophasic and/or bone-like divalent metal phosphate.

44. The process according to claim 43 wherein the divalent metal phosphonate complex is fired to form crystalline monophasic and/or bone-like hydroxyapatite.

45. The process according to claim 43 or 44 wherein the divalent metal phosphonate complex is prepared using the method according to any one of claims 39 to 42.

46. The process according to any one of claims 43 to 45 wherein the divalent metal phosphonate about 0.1 to about 1000 h.

47. The process according to claim 46 wherein the divalent metal phosphonate complex is heated between about 500°

C. and about 800°

C. for a time of about 2 h.

48. The process according to any one of claims 43 to 47 wherein the crystalline monophasic and/or bone-like divalent metal phosphate is obtained as a nanocrystalline powder.

50. A process of forming a sintered monolithic product, the process including shaping and sintering one or more divalent metal phosphates prepared according to any one of claims 43 to 49.

51. The process according to claim 50 wherein the divalent metal phosphates are selected from hydroxyapatite and/or tri-calcium phosphate.

52. The process according to claim 50 or 51 wherein the sintered monolithic product comprises one or more pharmaceutically active compounds.

53. A prosthetic implant formed from a sintered monolithic product produced using the process as defined in any one of claims 50 to 52.

54. The prosthetic implant of claim 53 wherein the prosthetic implant is selected from the group consisting of dental implants, orthopaedic implants, craniofacial and ocular implants.

55. A process for coating an object with a divalent metal phosphate, the process comprising the steps of:

(a) preparing a sol containing the divalent metal phosphonate complex according to any one of claims 17 to 22;

(b) dipping the object into the sol;

(c) heating the dipped object in order to remove any solvent; and

(d) firing the heated object to allow conversion of the divalent metal phosphonate complex into the divalent metal phosphate.

57. The process according to claim 55 or 56 wherein the divalent metal phosphonate complex is prepared according to the process of any one of claims 39 to 42.

58. The process according to any one of claims 55 to 57 wherein in step (c) the object is heated between about 20°

C. and 200°

C.

59. The process according to claim 58 wherein the object is heated at about 130°

C.

60. The process according to any one of claims 55 to 59 wherein in step (d), the object is fired between about 400°

C. and about 1200°

C.

61. The process according to any one of claims 55 to 60 wherein the divalent metal phosphate is formed according to any one of claims 43 to 48.

89. A bone graft material formed from a coated object produced according to the process of any one of claims 55 to 73.

90. A bone graft material formed from a sintered product prepared according to the process of any one of claims 50 to 52 or 84 to 86.

92. The bone graft material of any one of claims 89 to 91 wherein the coated object, the sintered products and hydroxyapatite material, respectively, are used alone or incorporated with bone morphogenic proteins (BMP), collagen, growth factors (GF) and/or marrow stromal cells (MSC).

93. A scaffolding for soft tissue formed from the coated object produced according to the process of any one of claims 55 to 73.

94. A scaffolding for soft tissue formed from a sintered product prepared according to the process of any one of claims 50 to 52 or 84 to 86.

38. A method of preparing a solution or a sol containing diacetyl hydrogen phosphonate, the method including the steps of:

(i) dissolving calcium diethoxide or acetate in a 1;

1 mixture of ethylene glycol and acetic acid;

(ii) adding a stoichiometric amount of diethyl hydrogen phosphonate to attain a Ca/P ratio of about 1.67;

(iii) heating the solution at 70°

C. for up to 48 h to yield diacetyl hydrogen phosphonate.

42. A process of forming calcium diacetyl hydrogen phosphonate complex, wherein diacetyl hydrogen phosphonate undergoes heat treatment at approximately 130°

C. for approximately 48 h to form solid divalent metal phosphonate complexes according to formula (4) and/or (5);

49. A process for the formation of monophasic or bone-like hydroxyapatite, wherein a calcium complex of diacetyl hydrogen phosphonate is fired at a temperature between about 500-800°

C. for about 2 h to produce crystalline monophasic hydroxyapatite.

63. A process for coating an object with hydroxyapatite, the process comprising the steps of:

(a) preparing a sol containing a precursor of hydroxyapatite;

(b) dipping the object into the sol;

(c) heating the dipped object in order to hydrolyse the precursor of hydroxyapatite; and

(d) firing the heated object.

65. The process according to claim 63 or 64 wherein the sol is prepared by reacting calcium diethoxide with diethyl phosphite under an inert atmosphere.

66. The process according to claim 65 wherein calcium diethoxide is dissolved in one or more solvents selected from the group consisting of ethanol, methanol and ethylene glycol prior to reaction with diethyl phosphite.

67. The process according to any one of claims 63 to 66 wherein a Ca/P mol ratio of between about 1:

1 to about 3;

1 is obtained.

68. The process according to claim 67 wherein the Ca/P mol ratio is about 1.67:

1.

69. The process according to any one of claims 63 to 68 wherein the sol is prepared by reacting calcium acetate with diethyl phosphite in glycol and acetic acid.

70. The process according to claim 69 wherein the ratio of ethylene glycol/acetic acid ranges from 4:

1 to 1;

3.

71. The process according to any one of claims 63 to 70 wherein the object in step (c) is heated at a temperature of about 70°

C.

72. The process according to any one of claims 63 to 71 wherein in the object in step (d) is fired at a temperature of about 500°

C.

73. A process for coating an object with hydroxyapatite, the process comprising the steps of:

(a) preparing a sol containing a precursor of hydroxyapatite by reacting calcium diethoxide with diethyl phosphite in glycol under an inert atmosphere in an amount sufficient to achieve a Ca/P ratio of about 1.67;

(b) dipping the object into the sol;

(c) heating the dipped object to a temperature of about 70°

C. for a period of about 24 hours in order to hydrolyse the precursor of hydroxyapatite; and

(d) firing the heated object to a temperature of about 1000°

C.

74. A process for forming crystalline hydroxyapatite, the process comprising the steps of:

(a) preparing a sol containing a precursor of hydroxyapatite;

(b) heating the sol in order to hydrolyse the precursor of hydroxyapatite;

(c) firing the product obtained from step (b) to a temperature sufficient to form crystalline hydroxyapatite.

75. The process according to claim 74 wherein the sol is prepared by reacting calcium diethoxide with diethyl phosphite under an inert atmosphere.

76. The process according to claim 75 wherein calcium diethoxide is dissolved in one or more solvents selected from the group consisting of ethanol, methanol and ethylene glycol prior to reaction with diethyl phosphite.

77. The process according to any one of claims 74 to 76 wherein a Ca/P mol ratio of between about 1:

1 to about 3;

1 is obtained.

78. The process according to claim 77 wherein the Ca/P mol ratio is about 1.67:

1.

79. The process according to any one of claims 74 to 78 wherein the sol is prepared by reacting calcium acetate with diethyl phosphite in glycol and acetic acid.

80. The process according to claim 79 wherein the ratio of ethylene glycol/acetic acid ranges from 4:

1 to 1;

3.

81. The process according to any one of claims 74 to 80 wherein the sol in step (b) is heated to about 70°

C.

82. The process according to any one of claims 74 to 81 wherein the product obtained from step (b) is fired in step (c) at a temperature of about 1000°

C.

83. The process according to any one of claims 74 to 82 wherein a nanocrystalline powder is formed.

84. A process of forming a sintered monolithic product, the process including shaping and sintering crystalline hydroxyapatite prepared according to the process of any one of claims 74 to 83.

85. The process according to claim 84 wherein the sintered monolithic product further includes one or more other divalent metal phosphates.

86. The process according to claim 84 or 85 wherein the sintered monolithic product comprises one or more pharmaceutically active compounds.

87. A prosthetic implant formed from a sintered monolithic product prepared according to the process of claim 84 to 86.

88. The prosthetic implant of claim 87 wherein the prosthetic implant is selected from the group consisting of dental implants, orthopaedic implants, craniofacial and ocular implants.

96. A hydrothermally converted coral material coated with a divalent metal phosphate, the material having a three dimensional porous microstructure comprised of a plurality of macropores at least some of which are interconnected by one or more connecting channels defined by channel walls and a plurality of mesopores and nanopores within the channel walls wherein at least some of the mesopores and nanopores are substantially coated with the divalent metal phosphate.

97. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 96 wherein at least some of the mesopores and nanopores are substantially covered or filled with the divalent metal phosphate and the macropores remain substantially uncovered or unfilled.

98. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 96 or 97, wherein the divalent metal phosphate is selected from the group consisting of hydroxyapatite, tri-calcium phosphate, dicalcium phosphate, octacalcium phosphate and amorphous calcium phosphate.

99. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 96-98, wherein the material has a biaxial strength greater than that of corresponding coral material not hydrothermally converted or corresponding coral material hydrothermally converted but not coated with hydroxyapatite.

100. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 96-99, wherein the coral material is hydrothermally converted by a process comprising the steps of:

(a) pre-treating the coral material to substantially remove impurities; and

(b) heating the pretreated coral material in the presence of phosphate ions to convert carbonate present in the coral material to phosphate to form an hydrothermally converted coral material.

101. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 100, wherein in step (a) the coral material is treated with water at a temperature between about 70°

C. and about 100°

C. for a period of between about 3 minutes and several hours to remove impurities.

102. The hydrothermally converted coral material coated with hydroxyapatite according to any one of claims 99-101, wherein in step (a) the coral material is treated with a solution of NaClO to remove impurities.

103. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 101 or 102, wherein the coral material is treated with a solution of about 1% to about 15% NaClO for a period of between about 1 hour and several days.

104. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 100-103, wherein in step a) the coral material is pretreated further by a process comprising the steps of:

(i) heating the treated sample to a temperature of at least about 50°

C. for at least about 3 hours; and

(ii) washing the heated sample, and then drying the sample.

105. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 104, wherein ill step (a)(i) the sample is heated to a temperature of between about 50°

C. and about 600°

C.

106. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 100-105, wherein in step b) the hydrothermally converted coral material is formed by a process comprising the steps of:

(i) treating that sample with a solution of (NH₄)₂HPO₄, at a temperature of at least about 150°

C. and at a pressure of at least about 1 MPa for at least about 12 hours; and

(ii) washing the sample, and then drying the sample.

107. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 106, wherein in step (b)(i) the sample is treated with a supersaturated solution of (NH₄)₂HPO₄ to attain a Ca/P mol ratio of between about 1.40 and about 1.75.

108. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 106 or 107, wherein in step (b)(i) the temperature ranges from anywhere between about 200°

C. and about 300°

C. and the pressure ranges from anywhere between about 2 MPa and about 8.5 MPa.

109. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 106-108 wherein in step (b)(i) the sample is treated for anywhere between about 16 hours and about 32 hours.

110. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 100-109, wherein the coral material is selected from the genus Goniopora, Alveopora or Arcopora.

111. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 100-110, wherein the coral material undergoes shaping at any time throughout the process.

112. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 96-99 wherein the coral material is coated by a process comprising the steps of:

a) preparing a sol containing a divalent metal phosphonate complex in which a divalent metal is coordinated to a phosphonate compound according to formula 1;

R—

C(O)—

O—

P(O)R¹—

O—

C(O)—

R² 

 

(1)

wherein R, R¹ and R², which may be the same or different, are selected from the group consisting of hydrogen, substituted alkyl groups and unsubstituted alkyl groups;

b) dipping the coral material into the sol;

c) heating the dipped object in order to remove any solvent; and

d) firing the heated object to allow conversion of the divalent metal phosphonate complex into a divalent metal phosphate.

113. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 112, wherein in formula (1), R and R² are CH₃.

114. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 112 or 113, wherein in formula (1) R¹ is hydrogen.

115. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 112-114, wherein the divalent metal is selected from the group consisting of calcium, magnesium, strontium, copper, manganese and zinc.

116. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 115, wherein the divalent metal is calcium.

117. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 112-116, wherein the divalent metal is coordinated with a carbonyl and/or phosphoryl oxygen of the phosphonate compound according to formula (I).

118. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 112-117, wherein, the divalent metal phosphonate complex is a six-membered chelate ring according to formula (2) and/or (3).

119. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 112-118, wherein the divalent metal phosphonate complex has a structure according to formula (4) and/or (5).

120. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 112-119, wherein in step (c) the object is heated between about 20°

C. and 200°

C.

121. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 112-120 wherein in step c) the object is heated at about 130°

C.

122. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 112-121, wherein in step (d), the object is fired between about 400°

C. and about 1200°

C.

123. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 96-99, wherein the coral material is coated by a process comprising the steps of:

(a) preparing a sol containing a precursor of hydroxyapatite;

(b) dipping the object into the sol;

(c) heating the dipped object in order to hydrolyse the precursor of hydroxyapatite; and

(d) firing the heated object.

124. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 123, wherein the sol is prepared by reacting calcium diethoxide with diethyl phosphite under an inert atmosphere.

125. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 124, wherein calcium diethoxide is dissolved in one or more solvents selected from the group consisting of ethanol, methanol and ethylene glycol prior to reaction with diethyl phosphite.

126. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 123-125, wherein a Ca/P mol ratio of between about 1.5 to about 1.75 is obtained.

127. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 126, wherein the CG/P mol ratio is about 1.67.

128. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 123 to 127, wherein the sol is prepared by reacting calcium acetate with diethyl phosphite in glycol and acetic acid.

129. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 128, wherein the ratio of ethylene glycol/acetic acid ranges from 4:

1 to 1;

3.

130. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 123-129, wherein the object in step (c) is heated at a temperature of about 70°

C.

131. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 123-130, wherein the object in step (d) is fired at a temperature of about 500°

C.

132. The hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 98-130, wherein the biaxial strength is at least approximately 50% greater than corresponding coral hydrothermally converted but not coated with hydroxyapatite.

133. The hydrothermally converted coral material coated with a divalent metal phosphate according to claim 132, wherein the biaxial strength is approximately 100-120% greater than corresponding coral hydrothermally converted but not coated with hydroxyapatite.

134. A prosthetic implant formed from the hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 96-133.

135. A scaffolding formed from the hydrothermally converted coral material coated with a divalent metal phosphate according to any one of claims 96-133.

136. A process of forming a sintered monolithic product, the process including shaping and sintering the hydrothermally converted coral material in powder form according to any one of claims 96-133.

137. The process according to claim 136, wherein the sintered monolithic product further includes one or more other divalent metal phosphates.

138. The process according to claim 136 or 137 wherein the sintered monolithic product comprises one or more pharmaceutically active compounds.

139. A prosthetic implant formed from a sintered monolithic product prepared according to the process of any one of claim 136 to 138.

140. The prosthetic implant of claim 139 wherein the prosthetic implant is selected from the group consisting of dental implants, orthopaedic implants, craniofacial and ocular implants.

141. A bone graft material formed from the hydrothermally converted coral material according to any one of claims 96 to 133.

142. A bone graft material formed from a sintered product prepared according to the process of any one of claims 136-138.

143. The bone graft material of material of claims 141 or 142 wherein the hydrothermally converted coral material and the sintered products, respectively, are used alone or incorporated with bone morphogenic proteins (BMP), collagen, growth factors (GF) and/or marrow stromal cells (MSC).

144-1. A hydrothermally converted coral material coated with a divalent metal phosphate produced by the method according to claim 144.