(12) United States Patent (10) Patent No.: US 7,393,405 B2 Bohner (45) Date of Patent: Jul

USOO7393405B2

(12) United States Patent (10) Patent No.: US 7,393,405 B2 Bohner (45) Date of Patent: Jul. 1, 2008

(54) HYDRAULIC CEMENT BASED ON CALCIUM 4,619,655 A 10, 1986 Hanker et al. PHOSPHATE FOR SURGICAL USE 4,880,610 A 11/1989 Constantz 5,338,356 A 8, 1994 Hirano et al. (75) Inventor: Marc Bohner, Aarau (CH) 5,605,713 A 2/1997 Boltong 5,954,867 A 9, 1999 Chow et al. (73) Assignee: H.C. Robert Mathys Stiftung, Bettlach 6,206,957 B1 3/2001 Driessens et al. (CH) *) NotOt1Ce: Subjubject to anyy d1Sclaimer,disclai theh term off thithis FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 JP 2000-159564 * 6, 2000 U.S.C. 154(b) by 311 days. WO WO 01/41824 * 6, 2001 (21) Appl. No.: 10/517,166 WO WO O2/O87649 * 11 2002

(22) PCT Filed: May 13, 2003 OTHER PUBLICATIONS (86). PCT No.: PCT/CHO3FOO3O4. WO 91/00252, Calcium Sulfate Hemihydrate Composition Having Utility in the Presence of Blood, Publication Date: Jan. 10, 1991. S371 (c)(1), WO 02/05861. A Composition for an Injectable Bone Mineral Sub (2), (4) Date: Dec. 7, 2004 stitute Material, Publication Date: Jan. 24, 2002. Mirichi AA et al: “Calcium Phosphate Cements: Action of Setting (87) PCT Pub. No.: WO04/000374 Regulators on the Properties of the -Tricalcium Phosphate Monoalcium Phosphate Cements' Biomaterials. . . . . PCT Pub. Date: Dec. 31, 2003 Nilsson M. Fernández E. Sarda S. Lidgren L. Planell JA., Character ization of a novel calcium phosphate? Sulphate bone cement, Journal (65) Prior Publication Data of Biomedical Materials Research (2002); pp. 600-607, vol. 61. Wiley Periodicals, Inc. US 2005/0241535A1 Nov. 3, 2005 * cited by examiner (30) Foreign Application Priority Data Primary Examiner C. Melissa Koslow Jun. 19, 2002 (WO) ...... PCT CHO2/OO332 (74) Attorney, Agent, or Firm Rankin, Hill & Clark LLP (51) Int. Cl. (57) ABSTRACT A6 IF 2/28 (2006.01) C04B 12/02 (2006.01) A hydraulic cement is based on calcium phosphate for Surgi (52) U.S. Cl...... 106/690; 106/691; 623/23.62: cal use, and includes three components. The first component 623/23.61; 623/23.56; 424/602 includes C.-tricalcium phosphate powder particles. The sec (58) Field of Classification Search ...... 424/602; ond, component includes calcium Sulphate dehydrate. The 623/23.62. 23.61, 23.56; 106/690, 691 third component includes water. Furthermore the hydraulic See application file for complete search history. cement does not contain more calcium sulfate hemihydrate (56) References Cited (CSH) than 10% of the total amount of the calcium sulphate dihydrate (CSD). U.S. PATENT DOCUMENTS 4,518.430 A 5, 1985 Brown et al. 51 Claims, No Drawings US 7,393,405 B2 1. 2 HYDRAULC CEMENT BASED ON CALCUM pH-value is not desirable due to the adverse effect on the PHOSPHATE FOR SURGICAL USE tissue cells which leads to a low compatibility of such a Cement. This invention concerns a hydraulic cement based on cal From U.S. Pat. No. 6,206,957 a “biocement paste compris cium phosphate for Surgical use. ing (a) tricalcium phosphate (b) at least one further calcium Calcium phosphate cements (CPC) are mixtures of one or phosphate-containing compound, (c) a cohesion promoter several calcium phosphate powders that react with water to and (d) a setting accelerator, wherein components (a) and (b) form a new calcium phosphate compound, generally an apa form a cement powder, and components (c) and (d) are in an tite. Through these chemical reactions, there is hardening of aqueous Solution, wherein said cement powders . . . . is the aqueous paste. In vivo studies have shown that CPC are 10 known. In this patent, not only one, but two calcium phos generally biocompatible, osteoconductive and somehow phate compounds were used, one being O-TCP. However, no bioresorbable. Therefore, CPC have been the subject of a mention of CSD is made. large and growing interest of the medical community. Several In the scientific literature, Nilsson et al. (Key Eng. Mater, products have been introduced on the market. However, all of vols. 218-220 (2202) pp. 365-368) described the effects of these products have some drawbacks 15 mixing C-TCP with CSH. But again, the use of CSD is not From the U.S. Pat. No. 4,880,610 a mixture of an aqueous mentioned. Although some of the CSH is hydrolysed in CSD solution, C.-tricalcium phosphate (O-TCP, Ca(PO)). in the presence of water so that entanglement of CSD crystals monocalcium phosphate monohydrate (MCPM; Ca(H. can take place this reaction has to compete with a second PO). HO), and calcium carbonate (CC; CaCO) is known. reaction taking place simultaneously and which is the Due to the presence of MCPM, the paste is initially acid. hydrolysis of C-TCP and entanglement of apatite crystals. Therefore, dicalcium phosphate dehydrate (DCPD; The occurrence of two competing parallel reactions compli CaHPO.2H2O) crystals form during the initial seconds of the cates the setting reaction and leads to interactions between the setting reaction, hence rendering the paste hard. These crys two competing setting reactions, hence leading to inadequate tals have to be broken down to be able to keep a paste con rheological properties of the cement paste. “Inadequate sistency and to be able to fill the bone defect with the cement 25 meaning that the paste requires more water to be a paste, paste. Hardening of the paste occurs in a second step via the which has a negative effect on the injectability of the cement formation of carbonated apatite. Due to the fact that the paste paste and the final mechanical properties of the cement. hardens in two steps, the cement cannot be mixed with a From WOO2/05861 LIDGREN a cement composition is pestle and a spatula: it requires the use of a mixing machine known which is based on an aqueous liquid, calcium Sulfate providing large mechanical forces (to break DCPD crystals). 30 hemihydrate (CSH) as a first reaction component, calcium For the Surgeon, this is obviously a disadvantage. phosphate as a second reaction component and an accelerator From the U.S. Pat. No. 5,338,356 a mixture of an aqueous for the reaction of CSH with water. Therefore, as with the solution, O-TCP tetracalcium phosphate (TTCP: Ca(PO) mixture of Nilsson, there are two simultaneous setting reac O), dicalcium phosphate (DCP: CaHPO) and hydroxyapa tions taking place, namely the hydrolysis of CSH and of the tite (HA, Cas (PO).OH) is known. This paste sets via one 35 calcium phosphate, which leads to inadequate rheological single setting reaction to form an apatite. As a result, the properties of the cement paste (bad injectability) and a hard mixing procedure is very simple. However, the presence of a ened cement with poor mechanical properties. very basic calcium phosphate (TTCP) decreases the biore It would be desirable therefore to provide a calcium phos sorbability of the set cement 4, which might be undesirable. phate cement which overcomes or alleviates in part or all of 40 the above mentioned drawbacks. Additionally, the cement formulation is rather complicated According to a broad aspect, the present invention solves with its four different powder components. the problem of providing a hydraulic cement based on cal From the U.S. Pat. No. 4,518.430 a mixture of an aqueous cium phosphate for Surgical use which has not a very basic solution, TTCP and DCP is known. As for the cement accord component such as TTCP, consists of a limited amount of ing to U.S. Pat. No. 5,338,356, the use of a basic calcium 45 components, sets fast, and is easy to mix. phosphate (TTCP) reduces the bioresorbability of the CSH has a solubility roughly 10 times larger than that of cement. Moreover, the setting reaction is slow and must occur CSD. Therefore, small amounts of CSH can have a very large in the absence of blood flow. impact on the cement. It is therefore very important to limit From U.S. Pat. No. 4,619,655 it is known to use plaster of the CSH amount to a minimum, namely at least 10 times Paris (calcium sulphate hemihydrate, CSH; CaSO.1/ 50 lower than the CSD amount. But it is preferable to lower this 2H2O) in combination with a calcium phosphate ceramic, amount down to 1-2% and more preferably to 0%. Thus, a such as a "calcium triphosphate'. However, these mixtures do hydraulic cement according to the invention does not contain not contain CSD. Additionally, the calcium phosphate more calcium sulfate hemihydrate (CSH) than 10% of a total ceramic is not added as a powder but as particles. Particles amount of said calcium sulphate dihydrate (CSD). Preferably, larger than 20 um are not reactive enough. Therefore, the 55 the amount of calcium sulfate sulfate hemihydrate (CSH) of setting reaction that could result from the hydrolysis of O-tri the cement is lower than 5%, or more preferably 2%, of said calcium phosphate particles would take a few hours which is calcium sulphate dihydrate (CSD). far too long for a medical use. The cement according to the invention comprises a first From U.S. Pat. No. 5,605,713 a mixture of “three to four component comprising O-TCP powder particles, a second calcium phosphates', in particular C-TCP is known, but none 60 component comprising calcium Sulphate dihydrate (CSD; of the mentioned calcium compounds is CSD. CaSO4.2H2O) and a third component comprising water. From U.S. Pat. No. 5,954,867 a method is known for “mak O-TCP acts as the setting component whereas CSD is simul ing a calcium phosphate cement which self-sets at ambient taneously a lubricant and enables an adequate control of the temperatures comprising combining a calcium phosphate salt Ca/P molar ratio. In one embodiment, the cement consists of which is substantially free of TTCP with an additional source 65 a powder/liquid formulation to be mixed, whereby (a) a pow of calcium and an aqueous solution adjusted with a base to der comprises said first and second component, and (b) a maintain a pH of about 12.5 or above'. Such a high basic liquid comprises the third component. Component (a) can US 7,393,405 B2 3 4 additionally comprise water-soluble phosphate salts, and In a preferred embodiment at least one of the three cement component (b) can comprise a polymer. In another embodi components comprises a setting regulator; a setting regulator ment, the cement consists of a powder comprising said first being either a setting accelerator or a setting retarder. and second component, a first viscous Solution comprising The setting time can be controlled by the particle size of the said third component, and a second solution comprising a O-TCP powder: the smaller the particle size, the faster the contrasting agent. setting reaction. However, a decrease of the particle size can be difficult to achieve (especially for diameters below 1 um). CSD is a very biocompatible material. It is obtained by Therefore, other methods should be considered. A very effi mixing CSH with water. CSD has a solubility in water close cient way to accelerate the setting time is to have large con to 10 mM (in calcium ions), i.e. much larger than the concen 10 centrations of phosphate ions in the mixing solution. This can tration of calcium ions in the body. As a result, CSD happen via two ways: (i) a soluble phosphate salt is added as implanted in a human body disappears by passive dissolution. a powder in the cement formulation. Upon contact with the However, as CSD is much more soluble than the solubility of mixing Solution, the phosphate salt dissolves, and hence hydroxyapatite, and as the body contains a large amount of accelerate the chemical reaction (LeChatelier principle). (ii) a phosphate ions, hydroxyapatite can precipitate around CSD 15 soluble phosphate salt is pre-dissolved in the mixing liquid. implants. Precipitation can be enhanced if hydroxyapatite Examples of soluble phosphate salts are NaHPO, crystals are already present around CSD crystals. In the com NaH2PO, KHPO, KHPO. NHHPO. Typical concen positions described in this patent, O-TCP is transformed in an trations in the mixing liquid are in the range of 0.05 to 1.00M. apatitic compound. CSD crystals can therefore be trans Another way to accelerate the setting reaction is to add nuclei formed into hydroxyapatite: for apatite crystal growth, as the nucleation step of the setting reaction is a limiting factor. Typically, apatite crystals can be used, preferably a calcium-deficient hydroxyapatite or As a result, C.-TCP/CSD mixtures implanted in vivo hydroxyapatite powder. Small amounts (a few weight per becomes denser and stronger with the implantation time, until cents) are Sufficient to drastically reduce the setting time. all CSD is dissolved. Additionally, the precipitation of 25 When the setting time is too short, various setting additives hydroxyapatite provokes a slight acidification of the cement can be added to increase the setting time. Typical examples Surroundings, which is positive to keep a high bioresorbabil are compounds which inhibits the nucleation and/or growth ity. of apatite crystals. Common examples are pyrophosphate, Solubility data shows that the equilibrium pH between citrate, or magnesium ions. One particularly interesting com CSD and hydroxyapatite is close to pH 4. Therefore, if the 30 pound is calcium carbonate (CC; CaCO). Carbonate ions are cement was placed in pure water, the equilibrium pH should present in human bone. Additionally, carbonate ions are able tend towards this pH value. In vivo, the pH value in the cement to reduce the size of apatite crystals, probably via the inhibi pores will always tend to decrease to reach this low equilib tion of apatite crystal growth. rium pH value. However, the body fluids are buffered at a pH The Ca/P molar ratio of O-TCP is 1.5. Any addition ofCSD value close to 7.4. Therefore, there will always be a compe 35 will lead to an increase of the global Ca/P molar ratio. Simul tition between the latter two reactions: (a) acidification of the taneously, an addition of CSD will allow an additional pre cement to reach equilibrium and (b) buffering of the cement cipitation of apatite, hence leading to larger mechanical prop erties, and lower porosity. It is well-known that the by body fluids. bioresorbability of calcium phosphate cements depends on The use of CSD has also the advantage to promote the flow 40 the Ca/P molar ratio: an increase of the CafP molar ratio leads properties of the cement paste. This improvement is charac to a decrease of the bioresorption rate. Therefore, the resorb terised by the fact that the amount of mixing liquid can be ability of the cement can be controlled by the fraction of CSD reduced when the amount of CSD is increased. used in the cement composition. For a low resorbability, a Preferably, in cement according to the invention, the first Ca/P molar ratio larger than 2 is ideal. Thus, in a cement and second components are in the form of particles having an 45 according to the invention, the Ca/P molar ratio of the cement average diameter larger than 0.1 Lum. In a preferred embodi is greater than 1.5. Preferably the Ca/P molar ration of a ment the powder particles of said first component have an cement according to the invention is greater than or equal to average diameter inferior to 20 um and preferably inferior to 1.667, and more preferably is greater than or equal to 2.0. 10 um. Typically the average particle diameter is chosen to be In recent years, the occurrence of osteoporotic fractures 1 um. The specific surface area (SSA) of the powderparticles 50 has dramatically increased. Considering the lack of adequate of said first component is in the range of 0.05 to 10.000 m/g, cure and the increasing number of elderly people, this trend is or more preferably within the range of 1 to 2 m/g. expected to continue. Osteoporotic fractures are often very The setting time of the cement is an important property of difficult to repair, because the bone is very weak. It is there the cement. If the setting time is too fast, the Surgeon does not fore not possible to insert screws to hold osteosynthesis have time to use the cement before it is hard. If the setting time 55 plates. A way to solve the problem is to inject a calcium is too long, the Surgeon must wait until he/she can close the phosphate cement into the osteoporotic bone to reinforce it. In wound. Therefore, an intermediate setting time is desirable. order to prevent any extravasation of the cement into the Values comprised between 1 and 20 minutes are in a good tissues Surrounding bone, it is very important to visualise the range. Preferable values are in the range of 2 to 15 minutes, in cement. The easiest way is to increase the radio-opacity of the more details in the range of 5 to 12 minutes. Thus a setting 60 cement, for example by means of contrasting agents. Metallic time of a cement paste according to the invention, which is powders oftantalum, titanium ortungsten (among others) can obtained by mixing a first component comprising O-trical be used. However, it might not be desirable to use such pow cium phosphate powderparticles, a second component com ders in partially bioresorbable cements. It is preferable to use prising calcium Sulphate dihydrate (CSD) and a third com liquid agents, such as iodine compounds. Examples are iopa ponent comprising water at 37° C., is between 1 and 20 65 midol, iohexol and iotrolan. minutes, or preferably between 2 and 15 minutes, or more The injection of a CPC into an osteoporotic bone is only preferably between 5 and 12 minutes. possible if the cement is well injectable. Often, CPC are not US 7,393,405 B2 5 6 well injectable. The reason is a too large average particle size docusate Sodium (CoH7NaOS), sodium lauryl Sulphate and a too low viscosity of the mixing liquid, leading to so (CHNaOS), stearic acid (CHCOOH), alkyldimethyl called filter pressing: when a pressure is applied on the (phenylmethyl)ammonium chloride CAS registry number cement paste (e.g. during cement injection), the liquid and 8001-54-5, benzethonium chloride (CHCINO), cetrim Solid phases are separated. The easiest way to solve the prob ide (CHBrN), glycerin monooleate (CHO), polysor lem is to increase the Viscosity of the mixing liquid, for bate 20 (CssH4O2), polysorbate 21 (C2H5oCo), polysor example by adding Small amounts of polysaccharides into the bate 40 (CH2O), polysorbate 60 (CH2O). mixing liquid. Typical polymers that can be used are polysac polysorbate 61 (Cs2H2Oo), polysorbate 65 (CooHoOs). charide derivatives comprising hyaluronic acid or salt, chon polysorbate 80 (CHO), polysorbate 81 (CHO). droitin Sulphate, dermantan Sulphate, heparan Sulphate, hep 10 polysorbate 85 (CooHssOs), polysorbate 120 arin, dextran, alginate, keratan Sulphate, (CHO), polyvinyl alcohol ((CHO)), Sorbitan hydroxypropylmethyl cellulose, chitosan, Xanthan gum, guar di-isostearate (CHsO4), Sorbitan dioleate (CHO), Sor gum, carrageenan. The most interesting compounds are those bitan monoisoStearate (CHO), Sorbitan monolaurate already certified for medical applications, such as hyalur (CHO). Sorbitan monooleate (CHO), Sorbitan onate compounds. Typical concentrations are around 1% 15 monopalmitate (CHO), Sorbitan monostearate w/w. The additive used to control the cement rheology can be (CHO). Sorbitan Sesqui-isostearate (CHOs), Sorbi added to any one of said three components used to form the tan Sesquioleate (CHOs), Sorbitan Sesquistearate cement, and can be added in an amount that is larger that 1 (CHOs), Sorbitan tri-isostearate (CHOs), Sorbitan weight percent (w/w) of the third component. trioleate (CHOs), Sorbitan tristearate (CHOs). The Viscosity of the mixing liquidis (as seen above) impor glyceryl monooleate (CHO), isopropyl myristate tant to prevent filter-pressing. The Viscosity of the cement (C.H.O.), isopropyl palmitate (CHO), lanolin CAS paste is also a very important factor. The cement viscosity registry number 8006-54-0, lanolin alcohols ICAS registry should be high enough to prevent a too fast mix with body number 8027-33-6, hydrous lanolin CAS registry number fluids, such as blood. A mix with body fluids could prevent 8020-84-6), lecithin CAS registry number 8002-43-5), cement setting and hence lead to complications. The paste 25 medium chain triglycerides (no registry number), monoetha Viscosity is also very important to prevent cement extravasa nolamine (CH7NO), oleic acid (C7HCOOH), polyethyl tion during bone augmentation (injection of cement into ene glycol monocetyl ether CAS registry number 9004-95 bone): the larger the viscosity, the lower the risk of extrava 9, polyethylene glycol monostearyl ether CAS registry sation. Therefore, the cement viscosity should be larger than number 9005-00-9, polyethylene glycol monolauryl ether 1 Pa's at a shear rate of 400s, one minute after the start of 30 CAS registry number 9002-92-0, polyethylene glycol cement mixing, and preferably above 10 or even 100 Pa's at a monooleyl ether CAS registry number 9004-98-2, poly shear rate of 400s', one minute after the start of cement ethoxylated castor oil CAS registry number 61791-12-6, mixing. polyoxyl 40 stearate (CHO), polyoxyl 50 stearate The viscosity of the cement paste depends obviously on the (C18H2O52), triethanolamine (CHNOs), anionic emul powder-to-liquid (P/L) ratio. An increase of the P/L ratio 35 sifying wax ICAS registry number 8014-38-8), nonionic leads to a increase of the cement viscosity. If the P/L ratio is emulsifying wax CAS registry number 977069-99-0, and too high, the amount of mixing liquid is too low to fill up all Sodium dodecyl Sulphate (NaCHSO). the pores between the different solid particles, and hence to Quite often, bone defects are not due to a traumatic event, form a cement paste. The Volume of mixing liquid (VL) but to a disease, e.g. bone tumor, infection, etc . . . In these should be in the range of: 0.5VT-VL<10VT where VT is the 40 cases, it would be interesting to incorporate drugs, in particu powder volume of the cement paste. More typical values are lar pharmaceutically or physiologically active Substances, in the range of 1.0 VT-VL-2.5VT. By volume is meant the preferably antibiotics, anti-inflammatory drugs, anti-cancer real Volume (and not the apparent Volume), i.e. the weight drugs, peptides, and proteins such as growth factors. divided by the density of the material. The present invention provides a method for producing a CPC particles have the disadvantage that they do not have 45 matrix of apatite as temporary bone replacement material, macropores, i.e. pores larger than 50-100 um in diameter, in which method comprises the steps of: which blood vessels and bone cells can grow in. As a result, mixing (A) a first component comprising C-tricalcium the bioresorption occurs layer-by-layer and not everywhere in phosphate powder particles, (B) a second component the cement bulk. To prevent this, bioresorbable or biodegrad comprising calcium Sulphate dihydrate (CSD), and (C) a able granules made of calcium phosphate, CSD, polymer or 50 third component comprising water, wherein (D) said bioglass whose diameter are at least two times larger than the hydraulic cement does not contain more calcium Sulfate average diameter of the powder particles of the first compo hemihydrate (CSH) than 10% of a total amount of said nent can be added to the first or second component of the calcium Suphate dihydrate (CSD) and whereby (E) said cement paste according to the invention. Upon implantation, hydraulic cement does not contain a very basic compo the granules will dissolve, hence leaving empty pores. Typi 55 nent; and cally, these granules, e.g. CSD granules, should have an aver allowing said mixture to harden. age size in the range of 100 to 500 um, or more preferably, in In one embodiment, the first and second components are the range of 200 um to 350 Lum. pre-mixed and the third component is added Subsequently. A different way to create macropores in the cement struc The invention also provides a temporary bone replacement ture is to incorporate gas bubbles in the cement paste. This 60 material obtained by the method, wherein said temporary incorporation can be promoted by adding a tensioactive bone replacement material comprises an apatite. In one agent. Tensioactive agents can also be used to incorporate a embodiment, the temporary bone replacement material fur poorly water-soluble contrasting agent into the cement paste, ther comprises CSD embedded in the apatite matrix. And, the for example organic iodine compounds (see above). The ten invention also provides granules or blocks obtained by hard Sio-active agent may be incorporated in one of said three 65 ening the cement for in vivo implants. components of the cement, preferably in the third component, The various features of novelty which characterise the and is preferably taken from the group of invention are pointed out with particularity in the claims US 7,393,405 B2 7 8 annexed to and forming part of this disclosure. For the better powder (SSA: 0.3 m/g), 2.4 ml of a solution containing 0.2M understanding of the invention, its operating advantages and NaHPO and 1.0% w/whyaluronate (Mw =1000 kDa), and specific objects attained by its use, reference should be made 0.5 ml iopamidol solution were mixed for 60 seconds in a to the examples and descriptive matter in which are illustrated beaker using a spatula. Afterwards, the cement paste was and described preferred embodiments of the invention. 5 placed into a pre-heated mould and left to harden at 37° C. The setting time of the cement was 6.5+0.9 min. The cement EXAMPLE1 was placed in a phosphate buffer solution for 24 hours and tested mechanically. The compressive strength of the cement All the cement components were pre-heated at 37° C. for was 215 MPa. one hour. 5g O-TCP powder (specific surface area: 0.6 m/g), 10 0.8 g. CSD powder (SSA: 0.3 m/g), 0.2 g hydroxyapatite EXAMPLE 6 powder (SSA: 48 m/g), and 2 ml 1.0% w/w hyaluronate solution (Mw = 1000 kDa) were mixed for 60 seconds in a All the cement components were pre-heated at 37° C. for beaker using a spatula. Afterwards, the cement paste was one hour. 5 g O-TCP powder (SSA: 0.6 m/g), 0.8 g. CSD placed into a pre-heated mould and left to harden at 37° C. 15 powder (SSA: 0.3 m/g), 0.2g hydroxyapatite powder (SSA: The setting time of the cement was 9.3+1.1 min. The cement 48 m/g), and 2 ml of a solution containing 2.0% w/whyalu was placed in a phosphate buffer solution for 24 hours and ronate (Mw = 1000 kDa) and 5% w/w gentamicin sulphate tested mechanically. The compressive strength of the cement were mixed for 60 seconds in a beaker using a spatula. After was 22-5 MPa. wards, the cement paste was placed into a pre-heated mould and left to harden at 37°C. The setting time of the cement was EXAMPLE 2 13.3+1.6 min. The cement was placed in a phosphate buffer Solution for 24 hours and tested mechanically. The compres All the cement components were pre-heated at 37° C. for sive strength of the cement was 19+4MPa. one hour. 5 g O-TCP powder (SSA: 0.6 m/g), 3.0 g CSD EXAMPLE 7 powder (SSA: 0.3 m/g), 0.2 g calcium-deficient hydroxya 25 patite powder (SSA: 27 m/g), and 2.8 ml 1.0% w/whyalur All the cement components were pre-heated at 37° C. for onate solution (Mw = 1000kDa) were mixed for 60 seconds in one hour. 5 g O-TCP powder (SSA: 0.6 m/g), 0.8 g. CSD a beaker using a spatula. Afterwards, the cement paste was powder (SSA: 0.3 m/g), 0.2 g calcium-deficient hydroxya placed into a pre-heated mould and left to harden at 37° C. patite powder (SSA: 27 m/g), 0.2g KHPO, powder, and 2.8 The setting time of the cement was 12.0+2.2 min. The cement 30 ml of a solution containing 1.3% w/w chondroitin sulphate was placed in a phosphate buffer solution for 24 hours and (Mw =1300 kDa) were mixed for 60 seconds in a beaker using tested mechanically. The compressive strength of the cement a spatula. Afterwards, the cement paste was placed into a was 133 MPa. pre-heated mould and left to harden at 37°C. The setting time of the cement was 5.9-0.7 min. The cement was placed in a EXAMPLE 3 35 phosphate buffer solution for 24 hours and tested mechani All the cement components were pre-heated at 37° C. for cally. The compressive strength of the cement was 25+5 MPa. one hour. 5 g O-TCP powder (SSA: 0.6 m/g), 1.0 g CSD powder (SSA: 0.3 m/g), 2.0 g CSD granules (diameter 150 EXAMPLE 8 250 um, 85% apparent density), 0.2 g calcium-deficient 40 All the cement components were pre-heated at 37° C. for hydroxyapatite powder (SSA: 27 m/g), and 2.5 ml 1.0% w/w one hour. 5 g O-TCP powder (SSA: 2.5 m/g), 0.8 g. CSD hyaluronate solution (Mw =1000 kDa) were mixed for 60 powder (SSA: 0.3 m/g), 0.2 g calcium-deficient hydroxya seconds in a beaker using a spatula. Afterwards, the cement patite powder (SSA: 27 m/g), 0.2 g KHPO powder, and 2.8 paste was placed into a pre-heated mould and left to harden at ml of a solution containing 1.3% w/w chondroitin sulphate 37°C. The setting time of the cement was 10.0+2.4 min. The 45 (Mw =1300 kDa) were mixed for 60 seconds in a beaker using cement was placed in a phosphate buffer solution for 24 hours a spatula. Afterwards, the cement paste was placed into a and tested mechanically. The compressive strength of the pre-heated mould and left to harden at 37°C. The setting time cement was 18-4 MPa. of the cement was 5.9-0.7 min. The cement was placed in a phosphate buffer solution for 24 hours and tested mechani EXAMPLE 4 50 cally. The compressive strength of the cement was 25+5 MPa. All the cement components were pre-heated at 37° C. for EXAMPLE 9 one hour. 5 g O-TCP powder (SSA: 0.6 m/g), 0.8 g. CSD powder (SSA: 0.3 m/g), 0.2 g calcium-deficient hydroxya x ga-TCP(SSA=2.4 m2/g) were mixed with 0.37 g CSD patite powder (SSA: 27 m/g), and 2.5 ml of a solution con 55 (0.8 m2/g) and (4-0.37-X)g of calcium carbonate (CaCO3; 1.5 taining 0.2 M NaHPO and 1.0% w/w hyaluronate m2/g) where x varied between 3.20 and 3.63 g. The powder (Mw =1000kDa) were mixed for 60 seconds in a beaker using was then mixed with 1.5-1.7 mL of a potassium phosphate a spatula. Afterwards, the cement paste was placed into a solution (0.2 M KH2PO4) and the resulting paste was pre-heated mould and left to harden at 37°C. The setting time kneaded for 60 seconds. Afterwards, the paste was placed into of the cement was 4.3-0.7 min. The cement was placed in a 60 a Syringe whose tip had been previously cut off and its setting phosphate buffer solution for 24 hours and tested mechani time was determined. The cement setting time increased cally. The compressive strength of the cement was 28+4MPa. gradually with an increase in CaCO3 content. The X-ray dif fraction analysis (XRD) of the cement after two days of EXAMPLE 5 incubation at 37 C showed that the setting reaction was 65 strongly slowed by the addition of CaCO3. However, the All the cement components were pre-heated at 37° C. for specific Surface area of the cement was strongly increased one hour. 5 g O-TCP powder (SSA: 0.6 m/g), 0.8 g. CSD (+50% with 5% CaCO3). US 7,393,405 B2 9 10 EXAMPLE 10 2. The cement according to claim 1, wherein the cement does not contain more calcium sulfate hemihydrate (CSH) The following pre-sterilized components, i.e. 7.26 ga-TCP than 2% of the total amount of the calcium sulfate dihydrate (SSA=2.4 m2/g), 0.74g CSD (0.8 m2/g), 0.10 g NaH2PO4. (CSD). 2.0 mL of iopamidol (organic iodine solution) and 1.2 mL of 5 3. The cement according to claim 2, wherein essentially no a 4% sodium hyaluronate solution, were mixed together in a calcium sulfate hemihydrate (CSH) is detectable in the sterile and closed mixer. After 30 seconds of thorough mix Cement. ing, the paste was injected from the mixer into two 2 mL 4. The cement according to claim 1, wherein the powder Syringes. The paste present in the Syringes was then injected particles of said first component have an average diameter into the osteoporotic vertebrae (BMD=-3.5) of a corpse. The 10 less than 20 Jum. X-ray analysis of the vertebra showed a very good radio 5. The cement according to claim 1, wherein at least one of graphical contrast, as well as a perfect cement distribution the three cement components comprises a setting regulator. (spherical distribution). 6. The cement according to claim 1, wherein the first or second component comprises a setting accelerator. EXAMPLE 11 15 7. The cement according to claim 1, wherein the setting accelerator is one of a calcium-deficient hydroxyapatite and a 9 ga-TCP (SSA=2.4 m2/g) were mixed with 0.9 g CSD hydroxyapatite powder. (0.8 m2/g), 2.1 g of calcium carbonate powder (CaCO3: 1.5 8. The cement according to claim 1, wherein the setting m2/g; average diameter in number: 1.9 m), and 4.5 mL of a accelerator is a water-soluble phosphate salt selected from the 0.1M MgSO4. 0.1M Na2HPO4, and 0.05 M. Na2H2P2O7 group consisting of NaHPO, NaH2PO, KHPO, KHPO Solution. After 2 minutes of mixing, the paste placed into a and NHHPO. cylindrical form, and vibrated with a vibrator to eliminate air 9. The cement according to claim 1, wherein the third bubbles. The top of the form was then covered with a wet component comprises a setting accelerator. piece of cloth. Thirty minutes after setting (Setting time=47 10. The cement according to claim 9, wherein the setting min--/-5 min), the block was unmoulded and placed in 10 mL 25 accelerator is a dissolved phosphate salt selected from the of phosphate buffer solution (pH 7.4, 0.15M) at 37 C for 5 group consisting of NaHPO, NaH2PO, KHPO, KHPO days. After that time, the block was dried at 60 C for 3 days and NHHPO. and then ground (with a mortar and a pestle) and sieved. The 11. The cement according to claim 5, wherein the setting granules in the range of 0.125 mm to 2.8 mm were collected regulator is a setting retarder. for further use in an in vivo application. All operations were 30 12. The cement according to claim 1, wherein the first or performed in aseptic conditions with sterile components. second component comprises a setting retarder. 13. The cement according to claim 12, wherein the setting EXAMPLE 12 retarder is selected from the group consisting of citrate, pyro phosphate, carbonate and magnesium ions. 9 ga-TCP (SSA=2.4 m2/g) were mixed with 0.9 g CSD 35 14. The cement according to claim 1, wherein a setting time (0.8 m2/g), 2.1 g of calcium carbonate powder (CaCO3: 1.5 of a cement paste obtained by mixing said three components m2/g; average diameter in number: 1.9 m), 4 g of maltose at 37°C. is between 1 and 20 minutes. crystals (0.2 mm in diameter), and 4.5 mL of a 0.1MMgSO4, 15. The cement according to claim 14, wherein the setting 0.1M Na2HPO4, and 0.05 M. Na2H2P2O7 solution. After 2 time of the cement paste at 37° C. is between 2 and 15 minutes of mixing, the paste placed into a cylindrical form, 40 minutes. and vibrated rapidly with a vibrator to eliminate air bubbles. 16. The cement according to claim 15, wherein the setting The top of the form was then covered with a wet piece of time of the cement paste at 37° C. is between 5 and 12 cloth. Thirty minutes after setting (Setting time=47 min--/-5 minutes. min), the block was unmoulded and placed in 50 mL of 17. The cement according to claim 1, whereina Ca/P molar phosphate buffer solution (pH 7.4,0.15M) at 37 C for 5 days. 45 ratio of a cement paste obtained by mixing said three com After that time, the block was dried at 60° C. for 3 days for ponents is greater than 1.5. further use in an in vivo application. All operations were 18. The cement according to claim 17, wherein the Ca/P performed in aseptic conditions with sterile components. molar ratio of the cement is equal to 1.667. 19. The cement according to claim 17, wherein the Ca/P 50 molar ratio of the cement is greater than 1.667. The invention claimed is: 20. The cement according to claim 17, wherein the Ca/P 1. A hydraulic cement based on calcium phosphate for molar ratio of the cement is greater than or equal to 2.0. Surgical use comprising: 21. The cement according to claim 1, wherein one of the A) a first component comprising O-tricalcium phosphate components contain a radiological contrasting agent. powder particles (TCP); 55 22. The cement according to claim 21, wherein the radio B) a second component comprising calcium Sulfate dihy logical contrasting agent is a liquid compound. drate (CSD); and 23. The cement according to claim 22, wherein the radio C) a third component comprising water, logical contrasting agent is an organic iodine compound wherein selected from the group consisting of iopamidol 60 (C7H22INOs), iohexol (CoHINOo), and iotrolan D) the cement does not contain more calcium sulfate hemi (C7Haslo NaOs). hydrate (CSH) than 10% of a total amount of said cal 24. The cement according to claim 1, wherein one of said cium sulfate dihydrate (CSD); three components comprises an additive to control the cement E) the cement does not contain tetracalcium phosphate rheology. (TTCP); and 65 25. The cement according claim 24, wherein the third F) at least one of the components comprises an apatite component comprises an additive to control the cement rhe powder as a setting accelerator. ology. US 7,393,405 B2 11 12 26. The cement according to claim 24, wherein the additive palmitate (CHO), lanolin CAS registry number 8006 used to control the cement rheology is selected from the group 54-0, lanolin alcohols CAS registry number 8027-33-6. consisting of polysaccharide derivatives comprising hyalu hydrous lanolin CAS registry number 8020-84-6, lecithin ronic acid or salt, chondroitin Sulfate, dermantan Sulfate, CAS registry number 8002-43-5, medium chain triglycer heparan Sulfate, heparin, dextran, alginate, keratan Sulfate, ides (no registry number), monoethanolamine (CHNO), hydroxypropylmethyl cellulose, chitosan, Xanthan gum, guar oleic acid (CHCOOH), polyethylene glycol monocetyl gum, and carrageenan. ether CAS registry number 9004-95-9, polyethylene glycol 27. The cement according to claim 24, wherein the additive monostearyl ether CAS registry number 9005-00-9, poly used to control the cement rheology is hyaluronic acid and/or ethylene glycol monolauryl ether CAS registry number hyaluronic salt. 10 9002-92-0, polyethylene glycol monooleyl ether CAS reg 28. The cement according to claim 24, wherein a concen istry number 9004-98-2, polyethoxylated castor oil CAS tration of the additive used to control the cement rheology is registry number 61791-12-6, polyoxyl 40 stearate larger than 1 weight percent of the third component. (CoshocCa2), polyoxyl 50 Stearate (Cs2O52), trietha 29. The cement according to claim 1, wherein a volume VL nolamine (CHNO), anionic emulsifying wax CAS reg of the third component is in the range of 0.5 VTsVLs 10.0 15 istry number 8014-38-8), nonionic emulsifying wax CAS VT where VT is total powder volume of the first and second registry number 977069-99-0), and sodium dodecyl sulfate component. (NaCHSO4). 30. The cement according to claim 29, wherein the volume 38. The cement according to claim 1, wherein the specific VL of the third component is in the range of 1.0VTsVLs2.5 surface area (SSA) of the powder particles of said first com VT where VT is the total powder volume of the first and ponent is in the range of 0.05 to 10.000 m/g. second component. 39. The cement according to claim 38, wherein the specific 31. The cement according to claim 1, wherein the first or surface area (SSA) of the first component is in the range of 1 second component of the cement may further comprise biore to 2 m/g. sorbable or biodegradable granules whose diameter are at 40. The cement according to claim 1, whereina Viscosity of least two times larger than the average diameter of said pow 25 the cement is larger than 1 Pa's at a shear rate of 400s', one der particles of said first component. minute after the start of cement mixing. 32. The cement according to claim 31, wherein the gran 41. The cement according to claim 40, wherein the cement ules have an average diameter in the range of 100 um to 500 viscosity of the cement is larger than 10 Pa's at a shear rate of lm. 400s', one minute after the start of cement mixing. 33. The cement according to claim 32, wherein the gran 30 42. The cement according to claim 1, wherein the cement ules have an average diameter in the range of 200 um to 350 consists of a powder/liquid formulation to be mixed, whereby lm. a) a powder comprises said first and second component; 34. The cement according to claim 31, wherein the gran and ules are made of calcium phosphate, CSD, polymer or bio b) a liquid comprises the third component. glass. 35 43. The cement according to claim 1, wherein the cement 35. The cement according to claim 1, wherein said first and consists of the following parts: second component is in the form of particles having an aver c) a powder comprising said first and second component age diameter larger than 0.1 Lum. d) a first viscous Solution comprising said third component; 36. The cement according to claim 1, wherein one or more and of said three components comprises pharmaceutically or 40 physiologically active Substances selected from the group e) a second solution comprising a contrasting agent. consisting of antibiotics, anti-inflammatory drugs, drugs 44. The cement according to claim 42, wherein component against osteoporosis, anti-cancer drugs, peptides, and pro a) additionally comprises water-soluble phosphate salts and teins. component b) comprises a polymer. 37. The cement according to claim 1, wherein the one of 45 45. The cement according to claim 1, wherein a setting time said three components comprises a tensio-active agent of the mixture of said three components is between 2 to 15 selected from the group consisting of docusate sodium minutes. (CoH7NaOS), Sodium lauryl Sulfate (C2H5NaOS), 46. A method for producing a matrix of apatite as tempo stearic acid (C.HCOOH), alkyldimethyl(phenylmethyl)- rary bone replacement material, comprising the steps of mix ammonium chloride CAS registry number 8001-54-5, ben 50 ing said three components of claim 1 and allowing said mix Zethonium chloride (CHCINO), cetrimide ture to harden. (CHBrN), glycerin monooleate (CHO), polysorbate 47. Method according to claim 46, wherein the first and 20 (CssHaO2), poly Sorbate 21 (C26HsoCo), poly Sorbate second component are pre-mixed and the third component is 40 (CHO), poly Sorbate 60 (CH2O), poly Sorbate added Subsequently. 61 (Cs2H2Oo), polysorbate 65 (CooHoO2s), polysorbate 55 48. A temporary bone replacement material obtained by the 80 (CHO), polysorbate 81 (CHO), polysorbate method according to claim 46, wherein said temporary bone 85 (CooHissO2s), poly Sorbate 120 (CH2O2), polyvinyl replacement material comprises an apatite. alcohol ((CHO)), Sorbitan di-isostearate (CHsO4), Sor 49. The temporary bone replacement material according to bitan dioleate (CHO), Sorbitan monoisoStearate claim 48, wherein said temporary bone replacement material (CHO). Sorbitan monolaurate (C18HO), Sorbitan 60 comprises CSD embedded in said apatite matrix. monooleate (CHO), sorbitan monopalmitate 50. Granules or blocks obtained by hardening the cement (C22H2O). Sorbitan monostearate (CHO), Sorbitan according to claim 1 for in Vivo implants. sesqui-isostearate (CHOs), Sorbitan sesquioleate 51. A hydraulic cement based on calcium phosphate for (CHOs), Sorbitan sesquistearate (CHOs), Sorbitan Surgical use comprising: tri-isostearate (CHOs), Sorbitan trioleate (CHOs), 65 a first component comprising O-tricalcium phosphate pow Sorbitan tristearate (CHOs), glyceryl monooleate derparticles (TCP) having an average diameter less than (C2H4O4), isopropyl myristate (C7HaO2), isopropyl 20 um; US 7,393,405 B2 13 14 a second component comprising calcium sulfate dihydrate at least one of the first, second or third components com (CSD); and prises an additive to control the cement rheology; and a third component comprising water; the cement does not contain more calcium Sulfate hemihy wherein: drate (CSH) than 10% of a total amount of said calcium 5 sulfate dihydrate (CSD). at least one of the first, second or third components com prises an apatite powder as a setting accelerator; k . . . .