Patent Grant
7066999
The present invention relates to a process for producing fast-setting, bioresorbable calcium phosphate cements (CPC), and in particular, to a process including a pre-heat treatment step to generate whiskers or fine crystals on surfaces of the CPC particles.
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(PO4)2O, CaHPO4.2H2O, CaHPO4, Ca8H2(PO4)6.5H2O, alpha-Ca3(PO4)2, beta-Ca3(PO4)2, Ca2P2O7, Ca2H2P2O8, 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.
An extensive study on the preparation of the fast-setting, bioresorbable calcium phosphate cement disclosed in U.S. Pat. No. 6,379,453B1 has been conducted by the same inventors and their co-workers, and found that the fast-setting, bioresorbable calcium phosphate cement can be prepared under various conditions. Therefore an object of the invention is to provide a more comprehensive process for producing a fast-setting, bioresorbable calcium phosphate cement.
The invention accomplishes the above object by providing a process which can be carried out with a heat treatment up to 1000° C. on a mixture of a wetting solution and a calcium phosphate powder having a Ca to P molar ratio of 0.5–2.5. The wetting solution suitable for use in the process of the present invention includes water, an organic solvent, an acidic and basic solution, not limited to the phosphate-containing solution. A setting solution for mixing with the heated powder to form the fast-setting, bioresorbable calcium phosphate cement may be an acidic solution, a basic solution or substantially pure water according to the process of the present invention.
The preferred embodiments of the present invention include (but not limited to) the following:
1) A process for producing a fast-setting, bioresorbable calcium phosphate cement, comprising the following steps:
(a) obtaining a calcium phosphate powder comprising at least one calcium phosphate selected from the group consisting of Ca4(PO4)2O, CaHPO4.2H2O, CaHPO4, Ca8H2(PO4)6.5H2O, alpha-Ca3(PO4)2, beta-Ca3(PO4)2, Ca2P2O7, Ca2H2P2O8, wherein the molar ratio of Ca to P in said calcium phosphate powder is between about 0.5 and 2.5;
(b) mixing said calcium phosphate powder obtained from step (a) with a wetting solution to obtain a powder/solution mixture in a ratio of less than about 10 g powder per ml solution;
(c) heating the powder/solution mixture resulting from step (b) to a temperature up to about 1000° C.; and
(d) mixing the resulting dried powder from step (c) in a setting solution to obtain the fast-setting, bioresorbable calcium phosphate cement.
2) The process as set forth in item 1), wherein said Ca/P molar ratio in step (a) is between 1.0 and 2.0.
3) The process as set forth in item 2), wherein in step (d) the resulting dried powder from step (c) together with at least one additive selected from the group of sodium phosphate (Na3PO4), disodium hydrogen phosphate (Na2HPO4), sodium dihydrogen phosphate (NaH2PO4), disodium hydrogen phosphate dodecahydrate (Na2HPO4.12H2O), disodium hydrogen phosphate heptahydrate (Na2HPO4.7H2O), sodium phosphate dodecahydrate (Na3PO4.12H2O), orthophosphoric acid (H3PO4), calcium sulfate (CaSO4), Ca4(PO4)2O, CaHPO4.2H2O, CaHPO4, Ca8H2(PO4)6.5H2O, alpha-Ca3(PO4)2, Ca2P2O7, and Ca2H2P2O8, are mixed with the setting solution to obtain the fast-setting, bioresorbable calcium phosphate cement.
4) The process as set forth in item 3), wherein said wetting solution in step (b) is an acidic aqueous solution, a basic aqueous solution, an organic solvent, or substantially pure water.
5) The process as set forth in item 4), wherein the organic solvent is ethanol.
6) The process as set forth in item 1), wherein the mixing ratio in step (b) is less than about 5 g powder per ml solution.
7) The process as set forth in item 1), wherein the heating temperature in step (c) is up to about 500° C.
8) The process as set forth in item 1), wherein the setting solution in step (d) is an acidic aqueous solution, a basic aqueous solution, or a substantially pure water.
9) The process as set forth in item 4) or 8), wherein the acidic aqueous solution is selected from the group consisting of nitric acid-3-(HNO3), hydrochloric acid (HCl), phosphoric acid (H3PO4), carbonic acid (H2CO3), sodium dihydrogen phosphate (NaH2PO4), sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate (KH2PO4), ammonium dihydrogen.phosphate (NH4H2PO4), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.
10) The process as set forth in item 4) or 8), wherein the basic aqueous solution is selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkaline earth hydroxide, disodium hydrogen phosphate (Na2HPO4), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na3PO2.12H2O), dipotassium hydrogen phosphate (K2HPO4), potassium phosphate tribasic (K3PO4), diammonium hydrogen phosphate ((NH4)2HPO4), ammonium phosphate trihydrate ((NH4)3PO4.3H2O), sodium bicarbonate (NaHCO3), and their mixture.
11) The process as set forth in item 1) further comprising grinding the resulting dried powder from step (c) between step (c) and step (d).
12) The process as set forth in item 1), wherein the fast-setting, bioresorbable calcium phosphate cement obtained from step (d) has a viscosity so that it can be injected by a syringe.
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.
To fabricate the CPC, the TTCP (Ca4(P04)20) powder was prepared from the reaction of dicalcium pyrophosphate (Ca2P207) (Sigma Chem. Co., St Louis, Mo., USA) and calcium carbonate (CaC03) (Katayama Chem. Co., Tokyo, Japan) using the method suggested by Brown and Epstein [Journal of Research of the National Bureau of Standards—A Physics and Chemistry 6 (1965) 69A 12], while the DCPA (CaHPO4) powder is a commercial product (Jassen Chemical Co., Japan).
5 g of a mixed powder of DCPA and TTCP in 1:1 molar ratio and 1.6 ml of a wetting solution of a phosphoric acid aqueous solution having a pH of 1.96 were mixed, and stirred for one minute. The resulting mixture was placed into an oven at 50° C. for 15 minutes, and the resulting dried mixture was mechanically ground for 20 minutes to fine particles after being removed from the oven. 1 g of the fine particles and 0.4 ml of phosphate aqueous solution (1.0 M, pH=6.0) were mixed to form a paste, which was tested every 30 seconds to determine the working time and the setting time. The setting time is the time required when a 1 mm diameter pin with a load of ¼ pounds can be inserted only 1 mm deep into the surface of the paste. The working time is the time after which the paste is too viscous to be stirred. The working time of the paste of this example is 6.5 minutes and the setting time thereof is 11.5 minutes.
The paste was placed in a relatively large amount of deionized water immediately following the formation thereof, and it was observed that the paste was non-dispersive in deionized water.
The procedures of Example 1 were repeated except that the heat treatment at 50° C. for 15 minutes was changed according to the conditions listed in Table 1. The performance is also listed in Table 1.
The procedures of Example 1 were repeated by using the calcium phosphate powders and the wetting solutions listed in Table 2. The performance is also listed in Table 2.
The procedures of Example 1 were repeated by using the wetting solutions having different pH values listed in Table 3. The performance is also listed in Table 3.
In the following examples, different setting solutions were used to verify the effect of the setting solution on the non-dispersive property of the calcium phosphate cement.
5 g of a mixed powder of DCPA and TTCP in 1:1 molar ratio and 1.6 ml of a wetting solution of 25 mM phosphoric acid aqueous solution were mixed, and stirred for one minute. The resulting mixture was placed into an oven at 50° C. for 15 minutes, and the resulting dried mixture was mechanically ground for 20 minutes to fine particles after being removed from the oven. 1 g of the fine particles and 0.4 ml of the setting solutions listed in Table 4 were mixed to form a past, which was tested every 30 seconds to determine the working time and the setting time as defined in Example 1. The results are shown in Table 4.
The procedures of Example 23 were repeated except that an additive as shown in Table 4 was added to the mixed powder of DCPA and TTCP in a weight ratio of 1:10 after the mixed powder was removed from the oven, and the setting solution used in these examples was deionized water. The results are shown in Table 4.
To 5 g TTCP powder which was used as synthesized 10 ml of 1M phosphoric acid aqueous solution was poured, and the mixture was filtered immediately. The filtered cake was placed into an oven at 150° C. for 10 minutes, and the resulting dried mixture was mechanically ground for 5 hours to fine particles. The resulting heat treated TTCP fine particles and the TTCP powder as synthesized (without heat treatment) were mixed in a weight ratio of 1:1. 1 g of the mixed TTCP powder and 0.4 ml of the setting solutions listed in Table 4 were mixed to form a paste, which was tested every 30 seconds to determine the working time and the setting time as defined in Example 1. The results are shown in Table 4.
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.
This application is a continuation U.S. application Ser. No. 10/328,019, filed Dec. 26, 2002 now U.S. Pat. No. 6,840,995, which is a continuation-in-part application of U.S. application Ser. No. 09/615,384 filed Jul. 13, 2000, now abandoned; and which is a continuation in part of U.S. application Ser. No. 09/351,912 filed Jul. 14,1999, now issued as U.S. Pat. No. 6,379,453. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3679360 | Rubin et al. | Jul 1972 | A |
| 4371484 | Inukai et al. | Feb 1983 | A |
| 4481175 | Iino et al. | Nov 1984 | A |
| 4518430 | Brown et al. | May 1985 | A |
| 4612053 | Brown et al. | Sep 1986 | A |
| 4623553 | Ries et al. | Nov 1986 | A |
| RE33161 | Brown et al. | Feb 1990 | E |
| RE33221 | Brown et al. | May 1990 | E |
| 4959104 | Iino et al. | Sep 1990 | A |
| 5017518 | Hirayama et al. | May 1991 | A |
| 5053212 | Constantz et al. | Oct 1991 | A |
| 5092888 | Iwamoto et al. | Mar 1992 | A |
| 5149368 | Liu et al. | Sep 1992 | A |
| 5164187 | Constantz et al. | Nov 1992 | A |
| 5180426 | Sumita | Jan 1993 | A |
| 5262166 | Liu et al. | Nov 1993 | A |
| 5336264 | Constanz et al. | Aug 1994 | A |
| 5338356 | Hirano et al. | Aug 1994 | A |
| 5342441 | Mandai et al. | Aug 1994 | A |
| 5409982 | Imura et al. | Apr 1995 | A |
| 5476647 | Chow et al. | Dec 1995 | A |
| 5492768 | Okimatsu et al. | Feb 1996 | A |
| 5496399 | Ison et al. | Mar 1996 | A |
| 5503164 | Friedman | Apr 1996 | A |
| 5522893 | Chow et al. | Jun 1996 | A |
| 5525148 | Chow et al. | Jun 1996 | A |
| 5536575 | Imura et al. | Jul 1996 | A |
| 5542973 | Chow et al. | Aug 1996 | A |
| 5545254 | Chow et al. | Aug 1996 | A |
| 5550172 | Regula et al. | Aug 1996 | A |
| 5569490 | Imura et al. | Oct 1996 | A |
| 5605713 | Boltong | Feb 1997 | A |
| 5607685 | Cimbollek et al. | Mar 1997 | A |
| 5652016 | Imura et al. | Jul 1997 | A |
| 5683461 | Lee et al. | Nov 1997 | A |
| 5683496 | Ison et al. | Nov 1997 | A |
| 5695729 | Chow et al. | Dec 1997 | A |
| 5697981 | Ison et al. | Dec 1997 | A |
| 5766669 | Pugh et al. | Jun 1998 | A |
| 5782971 | Constantz et al. | Jul 1998 | A |
| 5814681 | Hino et al. | Sep 1998 | A |
| 5820632 | Constantz et al. | Oct 1998 | A |
| 5846312 | Ison et al. | Dec 1998 | A |
| 5891448 | Chow et al. | Apr 1999 | A |
| 5899939 | Boyce et al. | May 1999 | A |
| 5954867 | Chow et al. | Sep 1999 | A |
| 5958430 | Campbell et al. | Sep 1999 | A |
| 5964932 | Ison et al. | Oct 1999 | A |
| 5976234 | Chow et al. | Nov 1999 | A |
| 5993535 | Sawamura et al. | Nov 1999 | A |
| 5997624 | Chow et al. | Dec 1999 | A |
| 6005162 | Constantz | Dec 1999 | A |
| 6013591 | Ying et al. | Jan 2000 | A |
| 6018095 | Lerch et al. | Jan 2000 | A |
| 6027742 | Lee et al. | Feb 2000 | A |
| 6117456 | Lee et al. | Sep 2000 | A |
| 6118043 | Nies et al. | Sep 2000 | A |
| 6123731 | Boyce et al. | Sep 2000 | A |
| 6132463 | Lee et al. | Oct 2000 | A |
| 6149688 | Brosnahan et al. | Nov 2000 | A |
| 6162258 | Scarborough et al. | Dec 2000 | A |
| 6277149 | Boyle et al. | Aug 2001 | B1 |
| 6294041 | Boyce et al. | Sep 2001 | B1 |
| 6294187 | Boyce et al. | Sep 2001 | B1 |
| 6323146 | Pugh et al. | Nov 2001 | B1 |
| 6325987 | Sapieszko et al. | Dec 2001 | B1 |
| 6325992 | Chow et al. | Dec 2001 | B1 |
| 6332779 | Boyce et al. | Dec 2001 | B1 |
| 6340648 | Imura et al. | Jan 2002 | B1 |
| 6379453 | Lin et al. | Apr 2002 | B1 |
| 6440444 | Boyce et al. | Aug 2002 | B1 |
| 6478825 | Winterbottom et al. | Nov 2002 | B1 |
| 6495156 | Wenz et al. | Dec 2002 | B1 |
| 6530955 | Boyle et al. | Mar 2003 | B1 |
| 6547866 | Edwards et al. | Apr 2003 | B1 |
| 6569489 | Li | May 2003 | B1 |
| 6585992 | Pugh et al. | Jul 2003 | B1 |
| 6616742 | Lin et al. | Sep 2003 | B1 |
| 6648960 | Lin et al. | Nov 2003 | B1 |
| 6670293 | Edwards et al. | Dec 2003 | B1 |
| 6696073 | Boyce et al. | Feb 2004 | B1 |
| 6719989 | Matsushima et al. | Apr 2004 | B1 |
| 6752831 | Sybert et al. | Jun 2004 | B1 |
| 6793725 | Chow et al. | Sep 2004 | B1 |
| 6808561 | Genge et al. | Oct 2004 | B1 |
| 6808585 | Boyce et al. | Oct 2004 | B1 |
| 6840995 | Lin et al. | Jan 2005 | B1 |
| 20020019635 | Wenstrom, Jr. et al. | Feb 2002 | A1 |
| 20020073894 | Genge et al. | Jun 2002 | A1 |
| 20020137812 | Chow et al. | Sep 2002 | A1 |
| 20030019396 | Edwards et al. | Jan 2003 | A1 |
| 20030031698 | Roeder et al. | Feb 2003 | A1 |
| 20030039676 | Boyce et al. | Feb 2003 | A1 |
| 20030055512 | Genin et al. | Mar 2003 | A1 |
| 20030078317 | Lin et al. | Apr 2003 | A1 |
| 20030121450 | Lin et al. | Jul 2003 | A1 |
| 20030167093 | Xu et al. | Sep 2003 | A1 |
| 20030216777 | Tien et al. | Nov 2003 | A1 |
| 20040003757 | Chern Lin et al. | Jan 2004 | A1 |
| 20040022825 | Lagow | Feb 2004 | A1 |
| 20040031420 | Lin et al. | Feb 2004 | A1 |
| 20040076685 | Tas | Apr 2004 | A1 |
| 20040137032 | Wang | Jul 2004 | A1 |
| 20040175320 | Lin et al. | Sep 2004 | A1 |
| 20040180091 | Lin | Sep 2004 | A1 |
| 20040185181 | Matsumoto | Sep 2004 | A1 |
| 20040186481 | Lin et al. | Sep 2004 | A1 |
| 20050008759 | Nie et al. | Jan 2005 | A1 |
| 20050076813 | Lin et al. | Apr 2005 | A1 |
| 20050101964 | Lin et al. | May 2005 | A1 |
| 20050184417 | Lin et al. | Aug 2005 | A1 |
| 20050186354 | Lin et al. | Aug 2005 | A1 |
| Number | Date | Country |
|---|---|---|
| 0267624 | May 1988 | EP |
| 06-228011 | Aug 1994 | JP |
| WO 03055418 | Jul 2003 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20050076813 A1 | Apr 2005 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10328019 | Dec 2002 | US |
| Child | 10944278 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 09615384 | Jul 2000 | US |
| Child | 10328019 | US | |
| Parent | 09351912 | Jul 1999 | US |
| Child | 09615384 | US |
