WO2005077320A2 - Method of increasing working time ttcp - Google Patents

Method of increasing working time ttcp Download PDF

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Publication number
WO2005077320A2
WO2005077320A2 PCT/US2005/004025 US2005004025W WO2005077320A2 WO 2005077320 A2 WO2005077320 A2 WO 2005077320A2 US 2005004025 W US2005004025 W US 2005004025W WO 2005077320 A2 WO2005077320 A2 WO 2005077320A2
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WIPO (PCT)
Prior art keywords
ttcp
powder
calcium phosphate
whiskers
solution
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PCT/US2005/004025
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French (fr)
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WO2005077320A3 (en
Inventor
Jiin-Huey Chern Lin
Chien-Ping Ju
Wen-Cheng Chen
Kuan-Liang Lin
I-Chang Wang
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Calcitec, Inc.
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Priority claimed from US10/773,701 external-priority patent/US7169373B2/en
Application filed by Calcitec, Inc. filed Critical Calcitec, Inc.
Priority to CA002555240A priority Critical patent/CA2555240A1/en
Priority to EP05713163A priority patent/EP1711155A2/en
Publication of WO2005077320A2 publication Critical patent/WO2005077320A2/en
Publication of WO2005077320A3 publication Critical patent/WO2005077320A3/en

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    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B28/00—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements
    • C04B28/34—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements containing cold phosphate binders
    • C04B28/344—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements containing cold phosphate binders the phosphate binder being present in the starting composition solely as one or more phosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
    • A61K6/849—Preparations for artificial teeth, for filling teeth or for capping teeth comprising inorganic cements
    • A61K6/864—Phosphate cements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B12/00—Cements not provided for in groups C04B7/00 - C04B11/00
    • C04B12/02—Phosphate cements
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B28/00—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements
    • C04B28/34—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements containing cold phosphate binders
    • C04B28/346—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements containing cold phosphate binders the phosphate binder being present in the starting composition as a mixture of free acid and one or more phosphates
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
    • C04B2111/00034—Physico-chemical characteristics of the mixtures
    • C04B2111/00086—Mixtures with prolonged pot-life
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
    • C04B2111/00474—Uses not provided for elsewhere in C04B2111/00
    • C04B2111/00836—Uses not provided for elsewhere in C04B2111/00 for medical or dental applications

Definitions

  • the present invention relates to a tetracalcium phosphate (TTCP) for producing bioresorbable calcium phosphate cements (CPC), and in particular, to a tetracalcium phosphate having whiskers on the surface thereof for producing bioresorbable CPC having a high initial strength.
  • TTCP tetracalcium phosphate
  • CPC bioresorbable calcium phosphate cements
  • U.S. Pat. No. 6,379,453B1 which is commonly assigned with the present invention discloses a process for producing a fast-setting, bioresorbable calcium phosphate cement comprising the following steps: obtaining a powder mixture from at least one calcium phosphate selected from the group consisting of Ca 4 (P0 ) 2 0,
  • the invention accomplishes the above object by providing a tetracalcium phosphate (Ca 4 (P0 4 ) 2 0, TTCP) particle having basic calcium phosphate whiskers on a surface of said TTCP particle; said basic calcium phosphate whiskers having a length up to about 5000 nm and a width up to about 500 nm, and preferably, a length from about 1 nrn to about 2000 nm and a width from about 1 nm to about 200 nm.
  • Said basic calcium phosphate whiskers have a Ca/P molar ratio greater than 1.33, and preferably greater than 1.35 and less than 4.0.
  • Said basic calcium phosphate whiskers have a non-stoichiometric chemical composition.
  • said basic calcium phosphate whiskers are substantially free of a hydroxyapatite phase, and comprises TTCP as a major phase.
  • a method for significantly increasing working/setting time of a TTCP cement is disclosed. Furthermore, under certain conditions this method can also increase the compressive strength of the cement.
  • the method for increasing working time of monolithic tetracalcium phosphate (TTCP) cement paste formed by mixing a TTCP powder with an aqueous solution according to the present invention comprises heating said TTCP powder, prior to said mixing, so that said TTCP powder is maintained at a temperature of 50-350 °C for a period of time which is greater than one minute, so that that a TTCP cement paste formed by mixing the resulting heated TTCP powder with said aqueous solution has a prolonged working time in comparison with that formed by mixing TTCP powder that has not been subjected to said heating with said aqueous solution.
  • TTCP monolithic tetracalcium phosphate
  • Figs. 1A to 1C are related to microstructure and diffraction pattern of calcium phosphate whiskers grown on TTCP surface according to the present invention, wherein (a) bright field image of whiskers; (b) electron diffraction pattern of whiskers; and (c) inte ⁇ retation of the diffraction pattern.
  • Fig. 2 shows XRD patterns, wherein (a) TTCP without whisker treatment; (b) TTCP with whisker treatment in (NH )2HP0 4 for 5 minutes; and (c) CPC prepared from whisker-treated TTCP powder immersed in Hanks' solution for 24 hours.
  • the present invention discloses a process for preparing a tetracalcium phosphate (TTCP) powder comprising TTCP particles comprising basic calcium phosphate whiskers on surfaces of said TTCP particles, said process comprising the following steps: a) mixing a TTCP powder with a whisker-inducing solution so that basic calcium phosphate whiskers start to grow on surfaces of TTCP particles of said TTCP powder; b) terminating the growth of said calcium phosphate whiskers by drying the whisker-inducing solution in the mixture, so that said calcium phosphate whiskers have a length up to about 5000 nm and a width up to about 500 nm, and preferably, a length from about 1 nm to about 2000 nm and a width from about 1 nm to about 200 rim, said basic calcium phosphate whiskers have a Ca/P molar ratio greater than 1.33, preferably greater than 1.35 and less than 4.0, and said basic calcium calcium phosphate whiskers have a Ca/P
  • At least one additive selected from the group consisting of sodium phosphate (Na 3 P0 4 ), disodium hydrogen phosphate (Na 2 HP0 4 ), sodium dihydrogen phosphate (NaH 2 P0 4 ), disodium hydrogen phosphate dodecahydrate (Na 2 HP0 4 .12H 2 0), disodium hydrogen phosphate heptahydrate (Na 2 HP0 4 .7H 2 0), sodium phosphate dodecahydrate (Na 3 P0 4 .12H 2 0), orthophosphoric acid (H 3 P0 4 ), calcium sulfate (CaS0 4 ), Ca 4 (P0 ) 2 0, CaHP0 4 .2H 2 0, CaHP0 4 , Ca 8 H 2 (P0 4 ) 6 .5H 2 0, alpha-Ca 3 (P0 4 )2, beta-Ca 3 (P0 4 ) 2 , Ca 2 P 2 0 7 , and Ca 2 H 2 P 2 0 8 , (NH 4 phosphat
  • said drying instep b) is carried out by heating the mixture resulting from step a) at a temperature less than about 1000°C.
  • said drying instep b) comprises separating the mixture resulting from step a), and heating the separated powder at a temperature of about 50 to 500°C.
  • the heating includes (but not limited to) the conventional oven/furnace heating, resistance heating, infrared heating, microwave heating, electron beam heating, ion beam heating, laser beam heating and plasma heating.
  • said heating is conducted in vacuum, inert atmosphere or air atmosphere.
  • the whisker-inducing solution instep a) maybe an acidic aqueous solution, a basic aqueous solution, an organic solvent or a substantially pure water.
  • the acidic aqueous solution may contain at least one Ca or P source, or is free from Ca and P.
  • the acidic aqueous solution can be selected from the group consisting of nitric acid (HN0 3 ), hydrochloric acid (HC1), phosphoric acid (H 3 P0 4 ), carbonic acid (H 2 C0 3 ), sodium dihydrogen phosphate (NaH 2 P0 ), sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate (KH 2 P0 4 ), ammonium dihydrogen.phosphate (NEUH ⁇ PO ⁇ , malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.
  • the basic aqueous solution for use as the whisker-inducing solution in the method of the present invention may contain at least one Ca or P source, or is substantially free from Ca and P.
  • the basic aqueous solution may be selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na 2 HP0 4 ), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na 3 P0 4 ' 12H 2 0), dipotassium hydrogen phosphate (K 2 HP0 4 ), potassium phosphate tribasic (K 3 P0 4 ), diammonium hydrogen phosphate ((NH 4 ) 2 HP0 )- ammonium phosphate trihydrate ((NH 4 ) 3 P04.3H 2 0), sodium bicarbonate (NaHC0 3 ), and their mixture.
  • said whisker-inducing solution in step a) is a basic aqueous solution.
  • said basic aqueous solution is a diammonium hydrogen phosphate ((NH 4 ) 2 HP0 ), Na 2 HP0 , or K 2 HP0 aqueous solution.
  • a suitable diammonium hydrogen phosphate ((NH 4 ) 2 HP0 4 ) aqueous solution has a concentration of at least 5 wt ⁇ %, preferably 10-60 wt%, based on the weight of said solution, and the mixing of said TTCP powder with this diammonium hydrogen phosphate ((NH ) 2 HP0 4 ) aqueous solution in step a) is in a ratio of less than about 10 g powder per ml solution, preferably less than about 5 g powder per ml solution. In one of the preferred embodiment of the present invention, said concentration is about 33 wt%, and the mixing ratio is about 1 gm TTCP per 13 ml solution.
  • the present invention also discloses a calcium phosphate cement (CPC) powder comprising the TTCP powder of the present invention.
  • a method of preparing a monolithic tetracalcium phosphate (TTCP) cement paste having a prolonged working time includes heating a TTCP powder at a temperature of from 50-350 ° C for a period of time which is greater than one minute, and then mixing the heated TTCP powder with an aqueous solution to form a TTCP cement paste, said paste having a prolonged working time in comparison with a TTCP cement paste formed by mixing TTCP powder that has not been subjected to such heating prior to mixing with the aqueous solution.
  • said temperature is 100-300 °C, and said period of time is greater than 15 minutes. More preferably, said temperature is 150-250 °C, and said period of time is 30 to 120 minutes.
  • the heating of the TTCP powder can be conducted under conditions selected from in air, in vacuum, and in an inert atmosphere.
  • a suitable TTCP powder for use in the method of the present invention has particle sizes ranging from 0.05 to 100 microns, preferably 0.5 to 50 microns, and particles of said TTCP powder have whiskers on their surfaces having a width ranging from I to 200 nm, preferably I to 100 rim, and a length ranging from 1 to 2000 nm, preferably 1 to 1000 nm.
  • Said calcium phosphate whiskers preferably have a non-stoichiometric chemical composition, more preferably said calcium phosphate whiskers have a Ca/P molar ratio from about 1.35 to about 4.0, and most preferably from about 1.5 to about 2.5.
  • Said calcium phosphate whiskers generally comprise TTCP as a major phase, and are substantially free of a hydroxyapatite phase.
  • a suitable process for preparing the TTCP powder having whiskers on the surfaces of the particle thereof comprises: a) mixing a TTCP powder with a whisker-inducing solution so that basic calcium phosphate whiskers start to grow on surfaces of TTCP particles of said TTCP powder; and b) terminating the growth of said calcium phosphate whiskers by drying the whisker-inducing solution in the mixture, so that said calcium phosphate whiskers have a width ranging from I to 200 nm and a length ranging from I to 2000 nm. Further details of the process can be found in U.S. Patent Application No. 10/773,701, filed February 6,
  • TTCP preparation The TTCP powder was fabricated in-house from the reaction of dicalcium pyrophosphate (Ca 2 P 2 0 7 ) (Sigma Chem. Co., St. Louis, MO, USA) and calcium carbonate (CaC0 3 ) (Katayama Che . Co., Tokyo, Japan) in a weight ratio of 1:1.27.
  • the powders were mixed uniformly in ethanol for 12 hours, followed by heating in an oven to let the powders dry.
  • the dried powder mixture was then heated to 1400 ° C to allow two powders to react to form TTCP [Brown and Epstein [Journal of Research of the National Bureau of Standards- A Physics and Chemistry 6 (1965) 69A 12].
  • EXAMPLE 1 WHISKER-INDUCING TREATMENT OF TTCP PARTICLES TREATED IN PHOSPHATE-CONTAINING BASIC SOLUTION Ca (P0 4 ) 2 0 (TTCP) powder as synthesized was sieved with a #325 mesh. The sieved powder has an average particle size of about 10 gm.
  • An aqueous solution of diammonium hydrogen phosphate was prepared by dissolving 20 g of diammonium hydrogen phosphate, (NH ) 2 HP0 4 , in 40 ml deionized water. The resulting solution had a pH value of 8.02.
  • To the TTCP powder the basic aqueous solution of diammonium hydrogen phosphate was added according to the ratio of 1 gm TTCP/13 ml solution. The TTCP powder was immersed in the basic aqueous solution for various periods of time of 1 minute, 5 minutes and 10 minutes, and filtered rapidly with a vacuum pump again. The resulting powder cake was dried in an oven at 50°C. The dried powder was dispersed in ethanol with supersonication.
  • FIG. 1 represents a typical microstructure of the calcium phosphate whiskers grown on TTCP surface under such condition.
  • FIG. IA is a bright-field image showing the whiskers are substantially radial-oriented and the majority of which have lengths ⁇ 300nm and widths ⁇ 100nm;
  • FIG. IB is a typical electron diffraction pattern of such whiskers.
  • the dotted-ring pattern is a direct result of the diffraction of numerous nano-sized whiskers;
  • FIG. 1 C is the indexing/inte ⁇ retation of the diffraction pattern, which clearly shows that every ring matches a certain crystallographic plane of TTCP phase, indicating the whiskers have a TTCP crystal structure.
  • EXAMPLE 3 WHISKER-INDUCING TREATMENT OF TTCP PARTICLES TREATED IN PHOSPHATE-FREE BASIC SOLUTION The procedures of Example 1 were repeated except that the basic aqueous solution was changed to a basic aqueous NaOH solution having a pH of 10.66 and the immersion time was changed to 30 seconds and 24 hours. For the specimens treated for 30 seconds no whisker was observed on TTCP surface. The results for the treat time of 24 hours are shown in Table 3.
  • EXAMPLE 4 WHISKER-INDUCING TREATMENT OF TTCP PARTICLES TREATED IN PHOSPHATE-FREE ACIDIC SOLUTION The procedures of Example 1 were repeated except that the basic aqueous solution was changed to 0.16M HC1 aqueous solution having a pH of 0.8 and the immersion time was changed to 30 seconds, 10 minutes, one hour and 24 hours. For the specimens treated for 30 seconds no whisker was observed on TTCP surface. The results for the remaining treat times are shown in Table 4.
  • EXAMPLE 5 COMPRESSIVE STRENGTH OF CPC PREPARED FROM THE WHISKER-GROWN TTCP PARTICLES
  • Ca 4 (P0 4 ) 2 0 (TTCP) powder as synthesized was sieved with a #325 mesh and has an average particle size of about 10 pm.
  • a HC1 aqueous solution having a pH of 0.8 was added according to the ratio of 1 gm TTCP/13ml solution.
  • the sieved TTCP powder was immersed in the HC1 solution for 12 hours, filtered rapidly and washed with deionized water, and filtered rapidly with a vacuum pump again. The resulting powder cake was dried in an oven at 50°C.
  • a setting solution of diammonium hydrogen phosphate was prepared by dissolving 20 g of diammonium hydrogen phosphate, (NH ) 2 HP0 4 , in 40 ml deionized water. 100 g off the mixed ground powder and 35 ml of the setting solution were well mixed to form a paste, which was then filled in molds to form specimens for compression test. The specimens were removed from the molds 15 minutes after the mixing, and soaked in a Hanks' solution. The soaked specimens were removed from the Hanks' solution at various periods of soaking time, and were immediately subjected to the compression test without drying. The compression test was conducted according to a method commonly used in the literature. The cylindrical samples have a diameter of 6 mm and a length of 12 mm. Results: compressive strength is 27.4 MPa for the soaking time of 20 minutes, and 48 MPa for one-day soaking time.
  • EXAMPLE 6 COMPRESSIVE STRENGTH OF CPC PREPARED FROM THE WHISKER-GROWN TTCP PARTICLES
  • Ca (P0 4 ) 2 0 (TTCP) powder as synthesized was sieved with a #325 mesh and has an average particle size of about 10 ⁇ m.
  • To the sieved TTCP powder the aqueous (NH 4 ) 2 HP0 solution prepared in Example 1 was added according to the ratio of 1 gm TTCP/13ml solution.
  • the sieved TTCP powder was immersed in the (N ⁇ 4 ) 2 HP0 4 solution for 5 minutes, filtered rapidly and washed with deionized water, and filtered rapidly with a vacuum pump again.
  • Example 5 The resulting powder cake was dried in an oven at 50°C. The dried powder was ground 120 minutes to obtain a powder A. The procedures in Example 5 were repeated to obtain a powder B except that the dried powder was ground only for a period of 300 minutes. A mixed powder of A and Bin a ratio of 1:1 ratio was subjected to the compression tests following the procedures recited in Example 5. Results: compressive strength is 26 MPa for the soaking time of 20 minutes, and 42.8 MPa for one-day soaking time.
  • EXAMPLE 7 COMPRESSIVE STRENGTH OF CPC PREPARED FROM THE WHISKER-GROWN TTCP PARTICLES The procedures in Example 5 were repeated except that the HC1 solution was changed to the aqueous (NH4)2HP0 solution prepared in Example 1 and the soaking time was changed to 5 minutes. Results: compressive strength is 18.6 MPa for the soaking time of 20 minutes, and 48.8 MPa for one-day soaking time.
  • EXAMPLE 8 COMPRESSIVE STRENGTH OF CPC PREPARED FROM THE WHISKER-GROWN TTCP PARTICLES
  • Ca (P0 ) 2 0 (TTCP) powder as synthesized was sieved with a #325 mesh and ground for two hours.
  • To the ground TTCP powder the powder B prepared in Example 5 was added and mixed in a ratio of 1:1.
  • the resulting mixed powder was subjected to the compression tests following the procedures recited in Example 5.
  • EXAMPLE 9 X-RAY DIFFRACTION OF WHISKER-TREATED TTCP POWDER AND IMMERSED CPC PREPARED FROM SUCH TTCP
  • a TTCP powder was whisker-treated for 5 minutes according to the process described in Example 1.
  • X-ray diffraction (XRD) was performed using an X-ray diffractometer (Rigaku D-max 11 IV, Tokyo, Japan) with Ni- filtered CuKa radiation operated at 30 kV and 20 mA at a scanning speed of 17min. The phases were identified by matching each characteristic XRD peak with that compiled in JCPDS files.
  • the XRD pattern of the whisker-treated TTCP powder (b) is substantially identical to that of TTCP as synthesized (a).
  • the perfect match of every XRD peak position (diffraction angle) with the JCPDS data indicates that there is no additional phase formed during the whisker treatment.
  • the setting solution was prepared by dissolving 20 g (NH ) 2 HP0 in 40 ml deionized water.
  • the CPC paste was filled in a cylindrical mold (12 mm in height and 6 mm in diameter), allowing hardening of the paste to occur within the mold.
  • the hardened CPC sample was removed from the mold and immersed in a 37°C Hanks' solution for 24 hours. After removing from the Hanks' solution and drying, the CPC sample was ready for XRD analysis. After immersion in Hanks' solution for 24 hours, the XRD pattern (c) of the CPC shows a large amount of HA phase which has replaced TTCP as the dominant phase. At this time only a small amount of TTCP remains. The result suggests that the CPC prepared from the whisker- treated TTCP powder of the invention can quickly transform into HA (the major component of human bone), once implanted.
  • HA the major component of human bone
  • EXAMPLE 10 SETTING SOLUTION PREPARED FROM (NH 4 )H 2 P0 4 AND KOH
  • a TTCP powder was whisker-treated for 5 minutes according to the process described in Example 1. The resulting powder cake was dried in an oven at 50°C. The dried powder was ground for 120 minutes.
  • a setting solution was prepared by dissolving 13.2 g (NH 4 )H 2 P0 in 40 ml deionized water to obtain an initial solution having a pH value of 3.72, and adding KOH to the initial solution so that the pH value was adjusted to 7.5. 100 g of the ground powder and 35 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5. Results: compressive strength is 9.6 MPa for the soaking time of 20 min.
  • EXAMPLE 11 SETTING SOLUTION PREPARED FROM (NH 4 )H 2 P0 4 AND NaOH The procedures in Example 10 were repeated except that the KOH was changed to NaOH and the final pH value of the setting solution was 7.8, and 20 ml of the setting solution was mixed with 100 g of the ground powder. Results: compressive strength is 10.3 MPa for the soaking time of 20 min.
  • EXAMPLE 12 SETTING SOLUTION PREPARED FROM (NH 4 ) 2 HP04, NaH 2 P0 4 2H 2 0 AND K 2 HP0 4
  • a TTCP powder was prepared following the procedures recited in Example 10.
  • a setting solution was prepared by dissolving 7.5 g (NH 4 ) 2 HP0 4 , 2.5 g NaH 2 P0 4 2H 2 0 and 5 g K 2 HP0 4 in 40ml deionized water. The final pH value of the setting solution was 7.56. 100 g of the ground powder and 30 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5. Results: compressive strength is 18.0 MPa for the soaking time of 20 min.
  • EXAMPLE 13 SETTING SOLUTION PREPARED FROM Na 2 HP0 4 12H 2 0, NaH 2 P0 4 2H 2 0 AND (NH 4 ) 2 HP0 4
  • a TTCP powder was prepared following the procedures recited in Example 10.
  • a setting solution was prepared by dissolving 3 g Na 2 HP0 4 12H 2 0, 3 g NaH 2 P0 4 '2H 2 0 and 7.5g (NH 4 ) 2 HP0 4 in 40ml deionized water. The final pH value of the setting solution was 7.38. 100 g of the ground powder and 30 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5. Results: compressive strength is 20.8 MPa for the soaldng time of 20 min.
  • EXAMPLE 14 SETTING SOLUTION PREPARED FROM PHOSPHORIC ACID AND AMMONIA SOLUTION A TTCP powder was prepared following the procedures recited in Example 10.
  • a setting solution was prepared by mixing 37.68 ml of 85 wt% phosphoric acid and 100 ml deionized water, and then 73.8 ml of 28 wt% ammonia solution.
  • the final pH value of the setting solution was 7.0.
  • 100 g of the ground powder and 30 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5.
  • EXAMPLE 15 HEAT-TREATMENT EFFECT ON THE WORKING/SETTING TIME OF WHISKER- TREATED TTCP POWDER
  • the whisker-treated TTCP powder was heat-treated in an air furnace (N 7/H, Nabertheijn ® , Geiinany). Different heat-treatment temperatures (140-400 ° C) and times (30 and 120 min) were used for the study.
  • the TTCP powder was mixed with 3M diammonium hydrogenphosphate ((N ⁇ ) 2 HP0 4 ) hardening solution with a pH value of 8.6 and liquid/powder ratio of 0.3 ml/gm. After mixing for one minute, the cement paste was uniformly packed in a stainless steel mold under a popularly-used pressure of 0.7 MPa.
  • This mold has an opening of 6 mm in diameter and 12 mm in depth (ASTM F 451-99a) for the preparation of samples for compressive strength testing.
  • the TTCP cement samples were removed from the mold and immersed in 20 ml Hanks' physiological solution (Mears 1977) at 37 ° C. Since short term (typically within 20-30 minutes after implantation) and long teini strengths are both important for TTCP cement (especially for load-bearing applications), the compressive strengths of TTCP cement immersed in Hanks' solution for 20 minutes, 1 day and 7 days were measured.
  • the working time of the TTCP cement paste was determined as the duration for which the paste was no longer moldable, while setting time was measured according to ISO 1566 standard method. .
  • the compressive strength was measured using a desktop mechanical tester (Shimadzu AGS-500D, Tokyo, Japan) at a crosshead speed of 1.0 mm/min.
  • X-ray diffraction (XRD) was carried out to help identify the phase changes of TTCP cement during immersion.
  • a Rigaku D-MAX B X-ray diffractometer (Tokyo, Japan) with Ni-filtered CuKa radiation operated at 30 kV and 20 mA at a scanning speed of 0.25° /min was used for the study.
  • the various phases were identified by matching each characteristic XRD peak with that compiled in JCPDS files.
  • FTIR Fourier transform infrared spectroscopy
  • the growth rate of a basic whisker is also sensitive to such process parameters as the type, pH, temperature and ion concentrations of the solution, to name a few.
  • the working/setting time of the present monolithic TTCP-derived CPC can be significantly changed by applying a heat-treatment to the TTCP powder. As can be seen from Table 1, all the investigated heat-treatment conditions caused the working/setting time to become longer than that without heat-treatment. Specifically, when the TTCP powder was heat-treated at a temperature of 300 °C or lower, the working and setting times of the CPC increased respectively from 8 and 9.5 minutes to respectively 12-14 minutes (by 50-75%) and 15-17 minutes (by 60-80%), which are ideal for most applications.
  • the TTCP powder When the TTCP powder was heat-treated to 400 °C for 30 minutes, the working and setting times greatly increased to a surgically inconvenient level. When the TTCP powder was heat- treated to 400 °C for 120 minutes, the cement paste was hardly set.
  • the compressive strength of the TTCP cement can also be modified by heat-treating the TTCP powder. As indicated in Table 2, when the TTCP powder was heat-treated at 140 °C for 30 min, the compressive strengths of CPC immersed in Hanks' solution for 20 minutes and 7 days both largely decreased from 49.2 and 70.5 MPa to 17.5 and 38.8 MPa, respectively, although its 1-day-strength did not change much.
  • XRD XRD was performed on all heat-treated TTCP powders.
  • the XRD pattern of non-heat-treated TTCP powder showed a typical TTCP crystal structure, except the heat- treatment conditions of 300 °C/120 minutes and 400 °C, the XRD patterns of all heat-treated TTCP powders remained essentially the same as that of non-heat-treated powder.
  • the TTCP powder was heat-treated to 300 °C for 120 minutes or to 400 °C for 30 minutes, apatite peaks were observed, indicating that a phase transition from TTCP to apatite had occurred under such heat treatment conditions.
  • the powder was treated to 400 °C for 120 minutes, apatite became the dominant phase.

Abstract

A tetracalcium phosphate (TTCP) particle for use in preparing a fast-setting, bioresorbable calcium phosphate cement is disclosed. The TTCP particle has a basic calcium phosphate whiskers on a surface thereof; the basic calcium phosphate whiskers having a Ca/P molar ratio greater than 1.33, and having a length up to about 5000 nm and a width up to about 500 nm. The basic calcium phosphate whiskers are substantially free of a hydroxyapatite phase and mainly composed of TTCP phase.

Description

METHOD OF INCREASING WORKING TIME OF TETRACAI-CIUM PHOSPHATE CEMENT PASTE
BACKGROUND OF THE INVENTION FIELD OF THE INVENTION
The present invention relates to a tetracalcium phosphate (TTCP) for producing bioresorbable calcium phosphate cements (CPC), and in particular, to a tetracalcium phosphate having whiskers on the surface thereof for producing bioresorbable CPC having a high initial strength.
DESCRIPTION OF THE RELATED ART
U.S. Pat. No. 6,379,453B1 which is commonly assigned with the present invention discloses a process for producing a fast-setting, bioresorbable calcium phosphate cement comprising the following steps: obtaining a powder mixture from at least one calcium phosphate selected from the group consisting of Ca4(P0 )20,
CaHP04.2H20, CaHP04, Ca8H2(P04)6.5H2O, alpha-Ca3(P04)2, beta-Ca3(P04)2, Ca2P207, Ca2H2P208, wherein the molar ratio of Ca to P in the mixture is roughly between 1 and 2; mixing the powder mixture in a phosphate- containing solution to obtain a powder/solution mixture having a concentration of less than 4 g powder mixture per ml solution; immediately heating the powder/solution mixture to a temperature of roughly 50°C-350°C to obtain a powder containing uniformly distributed submicron-sized apatite crystals; and mixing the apatite crystal-containing powder in a phosphate ion-containing solution to obtain a fast-setting, bioresorbable calcium phosphate cement.
In our earlier U.S. Patent No. 6,648,960 Bl, "Method of shortening a working and setting time of a CPC paste," a heat-treatment method to effectively shorten working/setting time of TTCP/DCPA-based CPC paste was disclosed. Without such treatment, the working /setting time of this TTCP/DCPA-based CPC paste would be inconveniently long.
Continued study led to further development of a monolithic TTCP-based CPC with nano-sized whiskers grown on its surface, which composition demonstrates excellent mechanical properties and biological responses and bioresoφtion behavior. This newly-developed monolithic TTCP cement, however, displays a working/setting time that is too short for certain surgical applications, such as the rather complicated orthopedic and spinal surgeries.
SUMMARY OF THE INVENTION An extensive study on the preparation of the fast-setting, bioresorbable calcium phosphate cement disclosed in U.S. Pat. No. 6,379,453131 has been conducted by the same inventors and their co-workers, and found that a fast- setting, bioresorbable CPC having a high initial strength can be prepared from a unique calcium phosphate, tetracalcium phosphate (Ca4(P04)2θ, TTCP) particle having basic whiskers or fine crystals on the surface thereof, wherein said basic whiskers or fine crystals have a Ca/P ratio greater than 1.33. Therefore an object of the invention is to provide such a unique TTCP particle. Another object of the present invention is to provide a process for preparing said unique TTCP particle. A further object of the present invention is to provide a fast-setting, bioresorbable CPC calcium phosphate cement prepared from said unique TTCP particle.
The invention accomplishes the above object by providing a tetracalcium phosphate (Ca4(P04)20, TTCP) particle having basic calcium phosphate whiskers on a surface of said TTCP particle; said basic calcium phosphate whiskers having a length up to about 5000 nm and a width up to about 500 nm, and preferably, a length from about 1 nrn to about 2000 nm and a width from about 1 nm to about 200 nm. Said basic calcium phosphate whiskers have a Ca/P molar ratio greater than 1.33, and preferably greater than 1.35 and less than 4.0. Said basic calcium phosphate whiskers have a non-stoichiometric chemical composition. Further, said basic calcium phosphate whiskers are substantially free of a hydroxyapatite phase, and comprises TTCP as a major phase.
In another embodiment, a method for significantly increasing working/setting time of a TTCP cement is disclosed. Furthermore, under certain conditions this method can also increase the compressive strength of the cement. The method for increasing working time of monolithic tetracalcium phosphate (TTCP) cement paste formed by mixing a TTCP powder with an aqueous solution according to the present invention comprises heating said TTCP powder, prior to said mixing, so that said TTCP powder is maintained at a temperature of 50-350 °C for a period of time which is greater than one minute, so that that a TTCP cement paste formed by mixing the resulting heated TTCP powder with said aqueous solution has a prolonged working time in comparison with that formed by mixing TTCP powder that has not been subjected to said heating with said aqueous solution.
BRTEF DESCRIPTION OF THE DRAWINGS Figs. 1A to 1C are related to microstructure and diffraction pattern of calcium phosphate whiskers grown on TTCP surface according to the present invention, wherein (a) bright field image of whiskers; (b) electron diffraction pattern of whiskers; and (c) inteφretation of the diffraction pattern.
Fig. 2 shows XRD patterns, wherein (a) TTCP without whisker treatment; (b) TTCP with whisker treatment in (NH )2HP04 for 5 minutes; and (c) CPC prepared from whisker-treated TTCP powder immersed in Hanks' solution for 24 hours.
DETAILED DESCRIPTION OF THE INVENTION The present invention discloses a process for preparing a tetracalcium phosphate (TTCP) powder comprising TTCP particles comprising basic calcium phosphate whiskers on surfaces of said TTCP particles, said process comprising the following steps: a) mixing a TTCP powder with a whisker-inducing solution so that basic calcium phosphate whiskers start to grow on surfaces of TTCP particles of said TTCP powder; b) terminating the growth of said calcium phosphate whiskers by drying the whisker-inducing solution in the mixture, so that said calcium phosphate whiskers have a length up to about 5000 nm and a width up to about 500 nm, and preferably, a length from about 1 nm to about 2000 nm and a width from about 1 nm to about 200 rim, said basic calcium phosphate whiskers have a Ca/P molar ratio greater than 1.33, preferably greater than 1.35 and less than 4.0, and said basic calcium phosphate whiskers have a non-stoichiometric chemical composition, preferably said basic calcium phosphate whiskers are substantially free of a hydroxyapatite phase, and comprises TTCP as a major phase. Optionally, at least one additive selected from the group consisting of sodium phosphate (Na3P04), disodium hydrogen phosphate (Na2HP04), sodium dihydrogen phosphate (NaH2P04), disodium hydrogen phosphate dodecahydrate (Na2HP04.12H20), disodium hydrogen phosphate heptahydrate (Na2HP04.7H20), sodium phosphate dodecahydrate (Na3P04.12H20), orthophosphoric acid (H3P04), calcium sulfate (CaS04), Ca4(P0 )20, CaHP04.2H20, CaHP04, Ca8H2(P04)6.5H20, alpha-Ca3(P04)2, beta-Ca3(P04)2, Ca2P207, and Ca2H2P208, (NH4)3P04, (NH4)2HP04, and (NH4)H2P04 together with said TTCP particles are mixed with the whisker-inducing solution in step a). Optionally, said drying instep b) is carried out by heating the mixture resulting from step a) at a temperature less than about 1000°C. Preferably, said drying instep b) comprises separating the mixture resulting from step a), and heating the separated powder at a temperature of about 50 to 500°C. The heating includes (but not limited to) the conventional oven/furnace heating, resistance heating, infrared heating, microwave heating, electron beam heating, ion beam heating, laser beam heating and plasma heating. Preferably said heating is conducted in vacuum, inert atmosphere or air atmosphere. The whisker-inducing solution instep a) maybe an acidic aqueous solution, a basic aqueous solution, an organic solvent or a substantially pure water. The acidic aqueous solution may contain at least one Ca or P source, or is free from Ca and P. The acidic aqueous solution can be selected from the group consisting of nitric acid (HN03), hydrochloric acid (HC1), phosphoric acid (H3P04), carbonic acid (H2C03), sodium dihydrogen phosphate (NaH2P0 ), sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate (KH2P04), ammonium dihydrogen.phosphate (NEUH^PO^, malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture. The basic aqueous solution for use as the whisker-inducing solution in the method of the present invention may contain at least one Ca or P source, or is substantially free from Ca and P. The basic aqueous solution may be selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na2HP04), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na3P04 '12H20), dipotassium hydrogen phosphate (K2HP04), potassium phosphate tribasic (K3P04), diammonium hydrogen phosphate ((NH4)2HP0 )- ammonium phosphate trihydrate ((NH4)3P04.3H20), sodium bicarbonate (NaHC03), and their mixture. Preferably, said whisker-inducing solution in step a) is a basic aqueous solution. More preferably, said basic aqueous solution is a diammonium hydrogen phosphate ((NH4)2HP0 ), Na2HP0 , or K2HP0 aqueous solution. A suitable diammonium hydrogen phosphate ((NH4)2HP04) aqueous solution has a concentration of at least 5 wt<%, preferably 10-60 wt%, based on the weight of said solution, and the mixing of said TTCP powder with this diammonium hydrogen phosphate ((NH )2HP04) aqueous solution in step a) is in a ratio of less than about 10 g powder per ml solution, preferably less than about 5 g powder per ml solution. In one of the preferred embodiment of the present invention, said concentration is about 33 wt%, and the mixing ratio is about 1 gm TTCP per 13 ml solution. The present invention also discloses a calcium phosphate cement (CPC) powder comprising the TTCP powder of the present invention. In another embodiment, a method of preparing a monolithic tetracalcium phosphate (TTCP) cement paste having a prolonged working time, includes heating a TTCP powder at a temperature of from 50-350 ° C for a period of time which is greater than one minute, and then mixing the heated TTCP powder with an aqueous solution to form a TTCP cement paste, said paste having a prolonged working time in comparison with a TTCP cement paste formed by mixing TTCP powder that has not been subjected to such heating prior to mixing with the aqueous solution. Preferably, said temperature is 100-300 °C, and said period of time is greater than 15 minutes. More preferably, said temperature is 150-250 °C, and said period of time is 30 to 120 minutes. The heating of the TTCP powder can be conducted under conditions selected from in air, in vacuum, and in an inert atmosphere. A suitable TTCP powder for use in the method of the present invention has particle sizes ranging from 0.05 to 100 microns, preferably 0.5 to 50 microns, and particles of said TTCP powder have whiskers on their surfaces having a width ranging from I to 200 nm, preferably I to 100 rim, and a length ranging from 1 to 2000 nm, preferably 1 to 1000 nm. Said calcium phosphate whiskers preferably have a non-stoichiometric chemical composition, more preferably said calcium phosphate whiskers have a Ca/P molar ratio from about 1.35 to about 4.0, and most preferably from about 1.5 to about 2.5. Said calcium phosphate whiskers generally comprise TTCP as a major phase, and are substantially free of a hydroxyapatite phase. A suitable process for preparing the TTCP powder having whiskers on the surfaces of the particle thereof comprises: a) mixing a TTCP powder with a whisker-inducing solution so that basic calcium phosphate whiskers start to grow on surfaces of TTCP particles of said TTCP powder; and b) terminating the growth of said calcium phosphate whiskers by drying the whisker-inducing solution in the mixture, so that said calcium phosphate whiskers have a width ranging from I to 200 nm and a length ranging from I to 2000 nm. Further details of the process can be found in U.S. Patent Application No. 10/773,701, filed February 6,
2004, and U.S. Patent Application Serial Number 10/607,023, filed June 27, 2003.
The following examples are intended to demonstrate the invention more fully without acting as a limitation upon its scope, since numerous modifications and variations will be apparent to those skilled in this art.
TTCP preparation The TTCP powder was fabricated in-house from the reaction of dicalcium pyrophosphate (Ca2P207) (Sigma Chem. Co., St. Louis, MO, USA) and calcium carbonate (CaC03) (Katayama Che . Co., Tokyo, Japan) in a weight ratio of 1:1.27. The powders were mixed uniformly in ethanol for 12 hours, followed by heating in an oven to let the powders dry. The dried powder mixture was then heated to 1400 ° C to allow two powders to react to form TTCP [Brown and Epstein [Journal of Research of the National Bureau of Standards- A Physics and Chemistry 6 (1965) 69A 12].
TEM examination
A Hitachi Model-HF2000 200kV field emission transmission electron microscope (TEM) equipped with a Noran Vayager Model 1000 energy dispersive spectroscopy (EDS) system was used for the study. The aperture size for microchemical analysis (Ca/P ratio) is 15nm. EXAMPLE 1: WHISKER-INDUCING TREATMENT OF TTCP PARTICLES TREATED IN PHOSPHATE-CONTAINING BASIC SOLUTION Ca (P04)20 (TTCP) powder as synthesized was sieved with a #325 mesh. The sieved powder has an average particle size of about 10 gm. An aqueous solution of diammonium hydrogen phosphate was prepared by dissolving 20 g of diammonium hydrogen phosphate, (NH )2HP04, in 40 ml deionized water. The resulting solution had a pH value of 8.02. To the TTCP powder the basic aqueous solution of diammonium hydrogen phosphate was added according to the ratio of 1 gm TTCP/13 ml solution. The TTCP powder was immersed in the basic aqueous solution for various periods of time of 1 minute, 5 minutes and 10 minutes, and filtered rapidly with a vacuum pump again. The resulting powder cake was dried in an oven at 50°C. The dried powder was dispersed in ethanol with supersonication. A drop of the dispersion was dripped on a single-side carbon sieve of #325 mesh having a diameter of 3 mm, and left dry to obtain a specimen coated with a thin carbon film for electrical conductivity for TEM examination. The microchemical analysis (Ca/P ratio) results of ten specimens (PI to P10) for each treat time are shown in Table 1.
Figure imgf000006_0001
FIG. 1 represents a typical microstructure of the calcium phosphate whiskers grown on TTCP surface under such condition. FIG. IA is a bright-field image showing the whiskers are substantially radial-oriented and the majority of which have lengths <300nm and widths <100nm; FIG. IB is a typical electron diffraction pattern of such whiskers. The dotted-ring pattern is a direct result of the diffraction of numerous nano-sized whiskers; FIG. 1 C is the indexing/inteφretation of the diffraction pattern, which clearly shows that every ring matches a certain crystallographic plane of TTCP phase, indicating the whiskers have a TTCP crystal structure. The absence of hydroxyapatite (HA) phase (100) ring (d = 0.817 run) in the diffraction pattern excludes the possibility for the whiskers to have an apatite crystal structure under this whisker treatment condition. It also can be seen from Table 1 that basic calcium phosphate whiskers have a Ca/P ratio other than 1.67, i.e. a non-stoichiometric chemical composition. The Ca/P ratio of hydroxyapatite (HA) is 1.67. The results show that Ca/P ratio is sensitive to the process condition (in this case, treating time).
EXAMPLE 2: WHISKER-INDUCING TREATMENT OF TTCP PARTICLES TREATED IN PHOSPHATE-CONTAINING ACIDIC SOLUTION The procedures of Example 1 were repeated except that the basic aqueous solution was changed to 1M phosphorus acid aqueous solution having a pH of 0.8 and the immersion time was changed to 30 seconds. The results are shown in Table 2.
Figure imgf000007_0002
SD= standard deviation
EXAMPLE 3: WHISKER-INDUCING TREATMENT OF TTCP PARTICLES TREATED IN PHOSPHATE-FREE BASIC SOLUTION The procedures of Example 1 were repeated except that the basic aqueous solution was changed to a basic aqueous NaOH solution having a pH of 10.66 and the immersion time was changed to 30 seconds and 24 hours. For the specimens treated for 30 seconds no whisker was observed on TTCP surface. The results for the treat time of 24 hours are shown in Table 3.
Figure imgf000007_0001
= stan ar ev a t on
EXAMPLE 4: WHISKER-INDUCING TREATMENT OF TTCP PARTICLES TREATED IN PHOSPHATE-FREE ACIDIC SOLUTION The procedures of Example 1 were repeated except that the basic aqueous solution was changed to 0.16M HC1 aqueous solution having a pH of 0.8 and the immersion time was changed to 30 seconds, 10 minutes, one hour and 24 hours. For the specimens treated for 30 seconds no whisker was observed on TTCP surface. The results for the remaining treat times are shown in Table 4.
Figure imgf000007_0003
SD= standard deviation
EXAMPLE 5: COMPRESSIVE STRENGTH OF CPC PREPARED FROM THE WHISKER-GROWN TTCP PARTICLES Ca4(P04)20 (TTCP) powder as synthesized was sieved with a #325 mesh and has an average particle size of about 10 pm. To the sieved TTCP powder a HC1 aqueous solution having a pH of 0.8 was added according to the ratio of 1 gm TTCP/13ml solution. The sieved TTCP powder was immersed in the HC1 solution for 12 hours, filtered rapidly and washed with deionized water, and filtered rapidly with a vacuum pump again. The resulting powder cake was dried in an oven at 50°C. The dried powder was divided into halves, ground for 20 minutes and 120 minutes separately, and combined. A setting solution of diammonium hydrogen phosphate was prepared by dissolving 20 g of diammonium hydrogen phosphate, (NH )2HP04, in 40 ml deionized water. 100 g off the mixed ground powder and 35 ml of the setting solution were well mixed to form a paste, which was then filled in molds to form specimens for compression test. The specimens were removed from the molds 15 minutes after the mixing, and soaked in a Hanks' solution. The soaked specimens were removed from the Hanks' solution at various periods of soaking time, and were immediately subjected to the compression test without drying. The compression test was conducted according to a method commonly used in the literature. The cylindrical samples have a diameter of 6 mm and a length of 12 mm. Results: compressive strength is 27.4 MPa for the soaking time of 20 minutes, and 48 MPa for one-day soaking time.
EXAMPLE 6: COMPRESSIVE STRENGTH OF CPC PREPARED FROM THE WHISKER-GROWN TTCP PARTICLES Ca (P04)20 (TTCP) powder as synthesized was sieved with a #325 mesh and has an average particle size of about 10 μm. To the sieved TTCP powder the aqueous (NH4)2HP0 solution prepared in Example 1 was added according to the ratio of 1 gm TTCP/13ml solution. The sieved TTCP powder was immersed in the (NΗ4)2HP04 solution for 5 minutes, filtered rapidly and washed with deionized water, and filtered rapidly with a vacuum pump again. The resulting powder cake was dried in an oven at 50°C. The dried powder was ground 120 minutes to obtain a powder A. The procedures in Example 5 were repeated to obtain a powder B except that the dried powder was ground only for a period of 300 minutes. A mixed powder of A and Bin a ratio of 1:1 ratio was subjected to the compression tests following the procedures recited in Example 5. Results: compressive strength is 26 MPa for the soaking time of 20 minutes, and 42.8 MPa for one-day soaking time.
EXAMPLE 7: COMPRESSIVE STRENGTH OF CPC PREPARED FROM THE WHISKER-GROWN TTCP PARTICLES The procedures in Example 5 were repeated except that the HC1 solution was changed to the aqueous (NH4)2HP0 solution prepared in Example 1 and the soaking time was changed to 5 minutes. Results: compressive strength is 18.6 MPa for the soaking time of 20 minutes, and 48.8 MPa for one-day soaking time.
EXAMPLE 8: COMPRESSIVE STRENGTH OF CPC PREPARED FROM THE WHISKER-GROWN TTCP PARTICLES Ca (P0 )20 (TTCP) powder as synthesized was sieved with a #325 mesh and ground for two hours. To the ground TTCP powder the powder B prepared in Example 5 was added and mixed in a ratio of 1:1. The resulting mixed powder was subjected to the compression tests following the procedures recited in Example 5. -Results: compressive strength is 19.7 MPa for the soaking time of 20 minutes, and 43.6 MPa for one-day soaking time.
EXAMPLE 9: X-RAY DIFFRACTION OF WHISKER-TREATED TTCP POWDER AND IMMERSED CPC PREPARED FROM SUCH TTCP A TTCP powder was whisker-treated for 5 minutes according to the process described in Example 1. X-ray diffraction (XRD) was performed using an X-ray diffractometer (Rigaku D-max 11 IV, Tokyo, Japan) with Ni- filtered CuKa radiation operated at 30 kV and 20 mA at a scanning speed of 17min. The phases were identified by matching each characteristic XRD peak with that compiled in JCPDS files.
[0029] Results: As indicated in Fig. 2, the XRD pattern of the whisker-treated TTCP powder (b) is substantially identical to that of TTCP as synthesized (a). The perfect match of every XRD peak position (diffraction angle) with the JCPDS data indicates that there is no additional phase formed during the whisker treatment. 0.7 g whisker-treated TTCP powder with 0.25 ml setting solution to form a CPC paste. The setting solution was prepared by dissolving 20 g (NH )2HP0 in 40 ml deionized water. The CPC paste was filled in a cylindrical mold (12 mm in height and 6 mm in diameter), allowing hardening of the paste to occur within the mold. After 15 minutes the hardened CPC sample was removed from the mold and immersed in a 37°C Hanks' solution for 24 hours. After removing from the Hanks' solution and drying, the CPC sample was ready for XRD analysis. After immersion in Hanks' solution for 24 hours, the XRD pattern (c) of the CPC shows a large amount of HA phase which has replaced TTCP as the dominant phase. At this time only a small amount of TTCP remains. The result suggests that the CPC prepared from the whisker- treated TTCP powder of the invention can quickly transform into HA (the major component of human bone), once implanted.
EXAMPLE 10: SETTING SOLUTION PREPARED FROM (NH4)H2P04 AND KOH A TTCP powder was whisker-treated for 5 minutes according to the process described in Example 1. The resulting powder cake was dried in an oven at 50°C. The dried powder was ground for 120 minutes. A setting solution was prepared by dissolving 13.2 g (NH4)H2P0 in 40 ml deionized water to obtain an initial solution having a pH value of 3.72, and adding KOH to the initial solution so that the pH value was adjusted to 7.5. 100 g of the ground powder and 35 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5. Results: compressive strength is 9.6 MPa for the soaking time of 20 min.
EXAMPLE 11: SETTING SOLUTION PREPARED FROM (NH4)H2P04 AND NaOH The procedures in Example 10 were repeated except that the KOH was changed to NaOH and the final pH value of the setting solution was 7.8, and 20 ml of the setting solution was mixed with 100 g of the ground powder. Results: compressive strength is 10.3 MPa for the soaking time of 20 min.
EXAMPLE 12: SETTING SOLUTION PREPARED FROM (NH4)2HP04, NaH2P042H20 AND K2HP04
A TTCP powder was prepared following the procedures recited in Example 10. A setting solution was prepared by dissolving 7.5 g (NH4)2HP04, 2.5 g NaH2P042H20 and 5 g K2HP04 in 40ml deionized water. The final pH value of the setting solution was 7.56. 100 g of the ground powder and 30 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5. Results: compressive strength is 18.0 MPa for the soaking time of 20 min. EXAMPLE 13: SETTING SOLUTION PREPARED FROM Na2HP0412H20, NaH2P042H20 AND (NH4)2HP04 A TTCP powder was prepared following the procedures recited in Example 10. A setting solution was prepared by dissolving 3 g Na2HP0412H20, 3 g NaH2P04'2H20 and 7.5g (NH4)2HP04 in 40ml deionized water. The final pH value of the setting solution was 7.38. 100 g of the ground powder and 30 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5. Results: compressive strength is 20.8 MPa for the soaldng time of 20 min.
EXAMPLE 14: SETTING SOLUTION PREPARED FROM PHOSPHORIC ACID AND AMMONIA SOLUTION A TTCP powder was prepared following the procedures recited in Example 10.
A setting solution was prepared by mixing 37.68 ml of 85 wt% phosphoric acid and 100 ml deionized water, and then 73.8 ml of 28 wt% ammonia solution. The final pH value of the setting solution was 7.0. 100 g of the ground powder and 30 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5. Results: compressive strength is 23.4 MPa for the soaking time of 20 min.
EXAMPLE 15: HEAT-TREATMENT EFFECT ON THE WORKING/SETTING TIME OF WHISKER- TREATED TTCP POWDER
To study the effect of heat treatment on working/setting time and compressive strength, the whisker-treated TTCP powder was heat-treated in an air furnace (N 7/H, Nabertheijn®, Geiinany). Different heat-treatment temperatures (140-400 ° C) and times (30 and 120 min) were used for the study. To fozni a TTCP cement paste, the TTCP powder was mixed with 3M diammonium hydrogenphosphate ((NΗ )2HP04) hardening solution with a pH value of 8.6 and liquid/powder ratio of 0.3 ml/gm. After mixing for one minute, the cement paste was uniformly packed in a stainless steel mold under a popularly-used pressure of 0.7 MPa. This mold has an opening of 6 mm in diameter and 12 mm in depth (ASTM F 451-99a) for the preparation of samples for compressive strength testing. At the time of 15 minutes after mixing, the TTCP cement samples were removed from the mold and immersed in 20 ml Hanks' physiological solution (Mears 1977) at 37 ° C. Since short term (typically within 20-30 minutes after implantation) and long teini strengths are both important for TTCP cement (especially for load-bearing applications), the compressive strengths of TTCP cement immersed in Hanks' solution for 20 minutes, 1 day and 7 days were measured. The working time of the TTCP cement paste was determined as the duration for which the paste was no longer moldable, while setting time was measured according to ISO 1566 standard method. . The compressive strength was measured using a desktop mechanical tester (Shimadzu AGS-500D, Tokyo, Japan) at a crosshead speed of 1.0 mm/min. X-ray diffraction (XRD) was carried out to help identify the phase changes of TTCP cement during immersion. A Rigaku D-MAX B X-ray diffractometer (Tokyo, Japan) with Ni-filtered CuKa radiation operated at 30 kV and 20 mA at a scanning speed of 0.25° /min was used for the study. The various phases were identified by matching each characteristic XRD peak with that compiled in JCPDS files. A Fourier transform infrared spectroscopy (FTIR) system (Jasco, FT/IR-460 Plus, UK) in transmission absoφtion mode with a spectral resolution of 2 cm" 1 was used to characterize the various functional groups of the TTCP powder under various heat-treatment conditions.
Results/Discussion Although a "basic" whisker can be grown on TTCP surface by immersion in a variety of solutions, the process should be carefully controlled. For example, when the solution contains a P source in the absence of Ca, the immersion time should be long enough to grow a basic whisker (an "acidic" whisker is grown at the early stage due to the excess P ions in the solution). Yet the immersion time should not be too long either to avoid the basic whisker's growing too large, that can largely deteriorate the CPC properties. On the other hand, when the solution does not contain P (e.g., HC1), acidic whisker is never grown on the surface of TTCP particles. All the observed whiskers on TTCP particles at all stages are basic in nature. [0037] In addition to Ca/P ratio, the growth rate of a basic whisker is also sensitive to such process parameters as the type, pH, temperature and ion concentrations of the solution, to name a few. The working/setting time of the present monolithic TTCP-derived CPC can be significantly changed by applying a heat-treatment to the TTCP powder. As can be seen from Table 1, all the investigated heat-treatment conditions caused the working/setting time to become longer than that without heat-treatment. Specifically, when the TTCP powder was heat-treated at a temperature of 300 °C or lower, the working and setting times of the CPC increased respectively from 8 and 9.5 minutes to respectively 12-14 minutes (by 50-75%) and 15-17 minutes (by 60-80%), which are ideal for most applications. When the TTCP powder was heat-treated to 400 °C for 30 minutes, the working and setting times greatly increased to a surgically inconvenient level. When the TTCP powder was heat- treated to 400 °C for 120 minutes, the cement paste was hardly set. The compressive strength of the TTCP cement can also be modified by heat-treating the TTCP powder. As indicated in Table 2, when the TTCP powder was heat-treated at 140 °C for 30 min, the compressive strengths of CPC immersed in Hanks' solution for 20 minutes and 7 days both largely decreased from 49.2 and 70.5 MPa to 17.5 and 38.8 MPa, respectively, although its 1-day-strength did not change much. When TTCP powder was heat-treated at 200 °C for 30 minutes, both 20 min and 7-day-compressive strengths of CPC significantly increased. Specifically, the CPC derived from such-treated powder had a 7-day-compressive strength (85.1 MPa) higher than that without treatment (70.5 MPa). When the powder was treated at 200 °C for 120 minutes, the 20-minute and 1-day-compressive strengths further increased to 65.9 and 96.0 MPa (the highest 1-day-strength), respectively. Its 7-day-strength, however, declined to 80.1 MPa. The heat-treatment at 250 °C for 30 minutes is also interesting in that the compressive strength of the TTCP cement continued to increase even after immersion for 7 days. While the heat-treatment at 300 °C for 30 minutes still showed relatively high 1-day and 7-day-strengths, the heat-treatment to 300 °C for 120 minutes or to 400 °C caused the compressive strength of the CPC to largely decline. From a practical point of view, among all heat-treatment conditions investigated in this study, the heat-treatment at about 200-300 °C for about 30- 120 min appears to be a suitable range for prolonging the working/setting time, while maintaining (in some cases even increasing) the compressive strength of the monolithic TTCP cement. TABLE 5
Working time (min) Setting time (min)
Non-heat-treated 8.0 9.5 140 °C 30 min 12.0 15.8 120min 12.3 15.3 200 °C 30 min 12.5 15.8 120 min 13.3 16.0 250 °C 30 min 12.0 14.3 120 min 12.0 14.0 300 °C 30 min 12.0 15.0 120 min 13.8 17.3 400 °C 30 min 16.5 23.0 120 min 45.0 Cement is hardly set
TABLE 6 Compressive strength (MPa)
20 min I d 7d Non-heat-treated 49.2 90.3 70.5 140 °C 30 min 17.5 86.5 38.8 120 min 18.0 72.6 69.6 200 °C 30 min 44.9 85.2 85.1 120 min 65.9 96.0 80.1 250 °C 30 min 41.7 66.7 86.5 120 min 42.8 88.6 58.5 300 °C 30 min 29.7 91.1 80.4 120 min 25.6 52.3 54.3 400 °C 30 min 16.1 28.5 36.2
To further understand the effect of heat treatment, XRD was performed on all heat-treated TTCP powders. The XRD pattern of non-heat-treated TTCP powder showed a typical TTCP crystal structure, except the heat- treatment conditions of 300 °C/120 minutes and 400 °C, the XRD patterns of all heat-treated TTCP powders remained essentially the same as that of non-heat-treated powder. When the TTCP powder was heat-treated to 300 °C for 120 minutes or to 400 °C for 30 minutes, apatite peaks were observed, indicating that a phase transition from TTCP to apatite had occurred under such heat treatment conditions. When the powder was treated to 400 °C for 120 minutes, apatite became the dominant phase. The formation of apatite under these heat-treatment conditions was reconfirmed by the presence of OH band at 3570 cm"' in FTIR spectra. Although the present invention has been described with reference to specific details of certain embodiments thereof, it is not intended that such details should be regarded as limitations upon the scope of the invention except as and to the extent that they are included in the accompanying claims. Many modifications and variations are possible in light of the above disclosure.

Claims

What is claimed is:
1. A method for increasing working time of monolithic tetracalcium phosphate (TTCP) cement paste formed by mixing a TTCP powder with an aqueous solution, said method comprising heating said TTCP powder, prior to said mixing, so that said TTCP powder is maintained at a temperature of 50-350 °C for a period of time which is greater than one minute, and that a TTCP cement paste formed by mixing the resulting heated TTCP powder with said aqueous solution has a prolonged working time in comparison with that formed by mixing TTCP powder that has not been subjected to said heating with said aqueous solution.
2. The method according to claim 1, wherein said temperature is 100-300 °C, and said period of time is greater than 15 minutes.
3. The method according to claim 1, wherein said temperature is 150-250 °C, and said period of time is 30 to 120 minutes.
4. The method according to claim 1, wherein said heating is conducted in air, in vacuum, or in an inert atmosphere.
5. The method according to claim 1, wherein said TTCP powder has particle sizes ranging from 0.05 to 100 microns, and particles of said TTCP powder have whiskers on their surfaces having a width ranging from I to 200 nm and a length ranging from I to 2000 nm.
6. The method according to claim 5, wherein said TTCP powder has particle sizes ranging from 0.5 to 50 microns.
7. The method according to claim 6, wherein particles of said TTCP powder have whiskers on their surfaces having a width ranging from I to 100 nm and a length ranging from I to 1000 nm.
8. The method according to claim 5, wherein said calcium phosphate whiskers have a non-stoichiometric chemical composition.
9. The method according to claim 8, wherein said calcium phosphate whiskers have a Ca/P molar ratio from about 1.35 to about 4.0.
10. The method according to claim 9, wherein said calcium phosphate whiskers have an average Ca/P molar ratio from about 1.5 to about 2.5.
11. The method according to claim 10, wherein said calcium phosphate whiskers comprise TTCP as a major phase.
12. The method according to claim 11, wherein said calcium phosphate whiskers are substantially free of a hydroxyapatite phase.
13. A method for preparing a monolithic tetracalcium phosphate (TTCP) cement paste which comprises heating a TTCP powder at a temperature of from 50-350 °C for a period of time which is greater than one minute, and then mixing the heated TTCP powder with an aqueous solution to form a TTCP cement paste, said paste having a prolonged working time in comparison with a TTCP cement paste formed by mixing TTCP powder that has not been subjected to the heating prior to mixing with the aqueous solution.
14. The method according to claim 13, wherein said temperature is 100-300 °C, and said period of time is greater than 15 minutes.
15. The method according to claim 13, wherein said temperature is 150-250 °C, and said period of time is 30 to 120 minutes.
16. The method according to claim 13, wherein said heating is conducted in air, in vacuum, or in an inert atmosphere.
17. The method according to claim 13, wherein said TTCP powder has particle sizes ranging from 0.05 to 100 microns, and particles of said TTCP powder have whiskers on their surfaces having a width ranging from I to 200 nm and a length ranging from I to 2000 nm.
18. The method according to claim 17, wherein said TTCP powder has particle sizes ranging from 0.5 to 50 microns.
19. The method according to claim 18, wherein particles of said TTCP powder have whiskers on their surfaces having a width ranging from I to 100 nm and a length ranging from I to 1000 nm.
20. The method according to claim 17, wherein said calcium phosphate whiskers have a non-stoichiometric chemical composition.
21. The method according to claim 20, wherein said calcium phosphate whiskers have a Ca/P molar ratio from about 1.35 to about 4.0.
22. The method according to claim 21, wherein said calcium phosphate whiskers have an average Ca/P molar ratio from about 1.5 to about 2.5.
23. The method according to claim 22, wherein said calcium phosphate whiskers comprise TTCP as a major phase.
24. The method according to claim 17 further comprising, prior to said heating, a) mixing a TTCP powder with a whisker-inducing solution so that basic calcium phosphate whiskers start to grow on surfaces of TTCP particles of said TTCP powder; and b) terminating the growth of said calcium phosphate whiskers by drying the whisker-inducing solution in the mixture, so that said calcium phosphate whiskers have a width ranging from I to 200 nm and a length ranging from I to 2000 nm.
25. A tetracalcium phosphate (TTCP) particle comprising basic calcium phosphate whiskers on a surface of said TTCP particle; said basic calcium phosphate whiskers having a length up to about 5000 nm and a width up to about 500 nm, said basic calcium phosphate whiskers having a Ca/P molar ratio greater than 1.33, and said basic calcium phosphate whiskers having a non-stoichiometric chemical composition.
26. The tetracalcium phosphate as defined in claim 25, wherein basic calcium phosphate whiskers have a length from about 1 nm to about 2000 nm and a width from about 1 nm to about 200 nm.
27. The tetracalcium phosphate as defined in claim 25, wherein said basic calcium phosphate whiskers have a Ca/P molar ratio from about 1.35 to about 4.0.
28. The tetracalcium phosphate as defined in claim 25, wherein said basic calcium phosphate whiskers are substantially free of a hydroxyapatite phase.
29. The tetracalcium phosphate as defined in claim 28, wherein said basic calcium phosphate whiskers comprise tetracalcium phosphate as a major phase.
30. A process for preparing a tetracalcium phosphate (TTCP) powder comprising TTCP particles comprising basic calcium phosphate whiskers on surfaces of said TTCP particles, said process comprising the following steps: a) mixing a TTCP powder with a whisker-inducing solution so that basic calcium phosphate whiskers start to grow on surfaces of TTCP particles of said TTCP powder; b) terminating the growth of said calcium phosphate whiskers by drying the whisker-inducing solution in the mixture, so that said calcium phosphate whiskers have a length up to about 5000 nm and a width up to about 500 nm, said basic calcium phosphate whiskers have a Ca/P molar ratio greater than 1.33, and said basic calcium phosphate whiskers have a non-stoichiometric chemical composition.
31. The process as defined in claim 30, wherein basic calcium phosphate whiskers have a length from about 1 nm to about 2000 nm and a width from about 1 nm to about 200 nm.
32. The process as defined in claim 30, wherein said basic calcium phosphate whiskers have a Ca/P molar ratio from about 1.35 to about 4.0.
33. The process as defined in claim 30, wherein said basic calcium phosphate whiskers are substantially free of a hydroxyapatite phase.
34. The process as defined in claim 30, wherein said basic calcium phosphate whiskers comprise tetracalcium phosphate as a major phase.
35. The process as defined in claim 30, wherein said whisker-inducing solution in step a) is an acidic aqueous solution, a basic aqueous solution, an organic solvent, or substantially pure water.
36. The process as defined in claim 35, wherein said whisker-inducing solution in step a) is a basic aqueous solution.
37. The process as defined in claim 36, wherein said basic aqueous solution is a diammonium hydrogen phosphate, Na2HP0 , or K2HP0 aqueous solution.
38. The process as define in claim 37, wherein said basic aqueous solution is the diammonium hydrogen phosphate aqueous solution, and said diammonium hydrogen phosphate aqueous solution has a concentration of at least 5 wt%, based on the weight of said solution, and the mixing of said TTCP powder with said diammonium hydrogen phosphate aqueous solution in step a) is in a ratio of less than about 10 g powder per ml solution.
39. The process as defined in claim 38, wherein said concentration is 10-60 wt%, and the mixing ratio is less than about 5 g powder per ml solution.
40. The process as defined in claim 39, wherein said concentration is about 33 wt%, and the mixing ratio is about 1 gm TTCP per 13 ml solution.
41. The process as defined in claim 30, wherein said drying in step b) is carried out by heating the mixture resulting from step a) at a temperature less than about 1000°C.
42. The process as defined in claim 30, wherein said drying in step b) is carried out by separating the mixture resulting from step a) and heating the separated powder at a temperature of 50-500°C.
43. A method for increasing working time of monolithic tetracalcium phosphate (TTCP) cement paste formed by mixing a TTCP powder with an aqueous solution, said method comprising heating said TTCP powder, prior to said mixing, so that said TTCP powder is maintained at a temperature of greater than about 50 CC.
44. A tetracalcium phosphate (TTCP) particle comprising basic calcium phosphate whiskers on a surface of said TTCP particle.
45. A process for preparing a tetracalcium phosphate (TTCP) powder comprising TTCP particles comprising basic calcium phosphate whiskers on surfaces of said TTCP particles, said process comprising mixing a TTCP powder with a whisker-inducing solution.
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