TW201231045A - A composite of amorphous calcium phosphate/calcium sulfate hemihydrate (CSH/ACP) for bone implantation and process for producing the same - Google Patents

Abstract

The invention provides a composite of α -calcium sulfate (CS) hemihydrate/amorphous calcium phosphate(α -CSH/ACP), comprising α -CSH and ACP at a weight ratio of about 10: 90 to about 90: 10. Particularly, the composite of the invention has a resorption period of 3-6 months. The invention also provides a one-pot process for producing α -CSH/ACP composite of the invention. The one-pot process of the invention can produce α -CSH and ACP in a single process and easily obtain α -CSH/ACP composite.

Description

201231045 VI. Description of the Invention: [Technical Field] The present invention provides an α_calcium sulfate hemihydrate/amorphous calcium silicate (α-CSH/ACP) composite and a preparation method thereof. The complex of the invention comprises cx-CSH and ACP and the weight ratio of the two is from about 〇:9〇 to about 90:10. [Prior Art] Synthetic bone graft subsutilus (SBGSs) have been widely used in the repair of bone defects because of their good biocompatibility, osteoconductivity and low risk of disease transmission. Typical pottery bone graft materials such as hydroxyapatite (ha, β_tricalcium phosphate (P-Ca3(P04)2, β-TCP) and calcium sulfate (cs, CaS〇4), etc. Different forms such as granules, flakes, pastes or lumps are used in various bone defects. A variety of bone graft preparation methods have been developed and are summarized in Table 1. Table 1 Product Name (manufacturer, factory) Collagrafit (Zimmer Inc, USA) MBCP (Biomatlante) Triosite (Zimmer Europe Ltd, UK) BCP (Bioland) Ostilit (Stryker Howmedica Osteonics, UK) Composition (Content) HA Replaniform (porous ceramic) coated with 70% Type I bovine collagen Coral macroporous HA 200: Porites 60% HA, 40% TCP 60% HA, > 40% TCP 20% HA, '80% TCP, no macroporous component (phase) Absorbent R-type particles and strips, Need to amplify particles, rectangular strips, cylinders or wedges at the rate of bone marrow perforation, also known as MBCP (macroporous biphasic calcium phosphate or BCP)

Granules and lumps for non-structural colonization 150466.doc 201231045

BoneSave (Stryker HowmedicaOsteonics, UK

Cerasorb ORTHO (curasan)

VitossTM Scaffold (curasan)

ConduitTM TCP Particles (DePuy Spine) CellplexTM TCP Synthetic Sea Cotton (Wright)

Ceros 82

Synthes (USA) chronOSTM (Synthes)

Calciresorb (Ceraver Osteal, France)

Synthograf (Milter, USA) Augmen (Milter, USA) SkeliteTM (Millenium Biologix)

Norian Skeletal Repair System (SRS)__ 20%HA, 80% TCP, void size 400-600 μιη pure phase β-TCP, microporosity: <80 μιη β-TCP, microporosity: <1-1000 μπι > 99% (β-TCP) Ca3(P〇4)2,

Porosity: 1-600 μηι Porous calcium phosphate prepared by TCP, pore size: 100-400 μηι β-TCP β-TCP, pore size: 100-500 μηι

Porous TCP

Small and dense TCP Large and dense TCP multiphase, porous phosphate fishing solidified phosphate cement particles, stronger than Ostilit, as void filler and transfer particle size 500-1, 〇〇〇μιη Or 1,000-2,000 μηι flakes (1-4 mm size) and massive (9 x 23 mm cylinders) irregularly shaped particles with an average diameter of 1.5 to 3 mm

Lower compressive strength particles, block, wedge or rounded periodontal application compared to Ceros 80. Application of periodontal application of granules and massive injectable cement, fracture increases in the dental field, and the absorption rate of SBGSs remains Room for improvement. SBGSs used in bone defects need to be quickly absorbed and replaced by new bones, allowing them to perform dental implant placement as early as possible. However, the ideal absorption period for SBGSs used in dentistry is still unknown. According to clinical studies, bone tissue is 3 to 6 months during stress-free therapy. For example, Kawai et al., in the study of X-ray examination of jaw defects and fracture healing, proposed time for bone healing. In 3 to 6 months (Kawai T, Murakami S, Hiranuma H, Sakuda Μ. Healing after removal of benign cysts and tumors of the jaws. A radiologic appraisal. Oral 150466.doc 201231045

Surg Oral Med Oral Pathol Oral Radiol Endod 1995; 79(4): 517-25; Kawai T, Murakami S, Hiranuma H, Sakuda M. Radiographic changes during bone healing after mandibular fractures. Br J Oral Maxillofac Surg 1997; 35(5 ): 312-8)° Therefore, in the state of natural healing, the average time for healing of the jaw defect should be 3 to 6 months, and the absorption time of SBGSs should also meet the above-mentioned bone healing time. Troubled. Calcium sulfate (CS) is a bone substitute that is rapidly absorbed and biocompatible and has bone-directing properties. Calcium sulfate can be classified into calcium sulfate dihydrate (CaS04.2H20, i.e., stone paste), calcium sulfate hemihydrate (CaSO4.0.5 H20, i.e., calcined gypsum) or anhydrous calcium sulfate (CaS04), depending on the amount of crystal water contained. The following is the chemical reaction equation for the above reaction: Dehydration reaction: CaSCVlHaCKsHheat-CaSCVZHbCKsHieHzO CaS〇41/2H20(s)+heat-^CaS〇4+2 H20 Hydration reaction: CaSCV% H20(s)+3/2 H20-CaS04 .2H20 (s) Calcium sulphate hemihydrate is longer in the body than calcium sulphate dihydrate. However, calcium sulphate hemihydrate is converted into calcium sulphate dihydrate by hydration reaction. Therefore, commercial production of ingot calcium sulphate When the bone substitute material is used, the semi-aqueous sulfuric acid is firstly adjusted to form a swirling dihydrate sulfuric acid mother', and then the ingot-shaped dihydrate sulfuric acid word is dehydrated and converted into calcium sulfate hemihydrate. CS is associated with many biological materials. It has been reported that osteoblasts are attached to cs and CS for in vitro studies by osteoclasts. However, the absorption time in vivo for 1 to 2 months seems to be too rapid, so the rate of absorption is There is still room for improvement. . The literature suggests combining CS with a slower-absorbing calcium phosphate compound using 150466.doc 201231045 to reduce the absorption rate of CS composites such as hydroxyapatite (HAp), beta-tricalcium phosphate (β-TCP) and Combination of α-tricalcium phosphate (α-TCP) (Urban RM, Turner TM, Hall DJ, Inoue N, Gitelis S. Increased bone formation using calcium sulfate-calcium phosphate composite graft. Clin Orthop Relat Res 2007; 459:110- 7; Nilsson M, Wang JS, Wielanek L, Tanner KE, Lidgren L. Biodegradation and biocompatibility of a calcium sulfate-hydroxyapatite bone substitute. J Bone Joint Surg 2004; 86(1): 120-125) ° US Patent Publication No. 20050119746 Providing an artificial bone mineral substitute comprising at least one ceramic and at least one water soluble non-ionic X-ray contrast agent, and providing an embodiment comprising 1 to 30% calcium sulfate hemihydrate and 50 to 99% alpha-TCP 'However, the absorbance of this alternative is too slow. Amorphous calcium phosphate (ACP, a chemical formula with approximately Ca3(PO4)2-0.8H2O), is a non-crystalline form and the most soluble form of tricalcium phosphate. In vivo, it is usually used as a bone-forming organism. Before the bone, the ACP is the first phase precipitated by a supersaturated solution obtained by rapidly mixing a solution containing calcium and phosphate ions. Previous studies have confirmed that ACP is more biologically active than HAp because it has better adhesion, proliferation and differentiation ability to ACP matrix than crystalline HAp matrix. However, after contacting the water, the ACP will change to a HAp with a longer absorption rate via phase transition. U.S. Patent No. 7,351,280 is directed to a composition and a bone cement (MICPCs) having interconnected macroporous, absorbable and injectable calcium phosphate-based bone cements which are self-curing carbonates ( CPC), the 150466.doc •6-201231045 patent invention adds carbonate, magnesium, zinc, fluorine and pyrophosphate ions to stabilize ACP. U.S. Patent No. 7,67,419 discloses an aqueous bone cement for surgery which is based on calcium phosphate and which comprises A) a first component comprising calcium phosphate of powder particles; and B) a second component It contains water. The patented invention preheated the ACP to 5 〇〇. (:, then grinding to shorten the time of cpc hydration and hardening. US Patent Publication No. 2, 183, 417 to a method for citrate per bone graft, a method for preparing the calcium phosphate bone graft, and the calcium phosphate Bone implant made of bone graft material. This patent applies ACP to the surface of HAp to form a new bone implant in the form of plasma odor. This patent is not used as a bone substitute. U.S. Patent Publication No. 20080014242 discloses a synthetic bone substitute material suitable for use as a sponge bone substitute in a bone graft composition comprising a bioceramic stent having interconnected pore configurations and a solid non-porous The composition comprising a calcium sulphate in a composition which fills the interstitial pore volume and is in intimate contact with the reticular skeleton. However, the bone substitutes provided by the prior art described above have no satisfactory absorption rate. In the technical field, there is still a need for an improved bone substitute material having an absorption rate similar to that of a human bone. The present invention provides an alpha. a calcium sulphate hemihydrate/amorphous calcium phosphate CSH/ACP) complex comprising a_CSH & ACp and having a weight ratio of from about 10:90 to about 90:10. The invention also provides a method for preparing a-calcium sulfate hemihydrate/amorphous calcium phosphate CSH/ACP) composite, comprising the following steps: 150466.doc 201231045 (a) respectively containing a calcium ion solution and a sulfate-containing ion The solution is dissolved in the calcium carbonate solution; (b) the solution of the step (a) is heated to about 80 ° C to 10 ° C, and the two solutions are mixed to produce α-hemihydrate sulfuric acid (α-CSH) (c) filtering the solution obtained in the step (b) to separate the α-CSH solid in the solution; (d) adding the phosphoric acid compound to the solution of the step (c) to react with the vaporized calcium of the step (a) Amorphous calcium phosphate (ACP); and (e) mixing the α-CSH of step (c) and the ACP of step (d), followed by adding water to prepare α-calcium sulfate hemihydrate and amorphous calcium phosphate (α-CSH) /ACP) Complex. The invention develops an absorbable a-calcium sulfate hemihydrate/apatic calcium phosphate (a-CSH/ACP) complex which can be used as a substitute for bone transplantation, and an a-calcium sulfate hemihydrate/amorphous calcium phosphate (a-CSH/ACP) Single-tank preparation method for absorbable bone graft substitutes. Surprisingly, the a-CSH/ACP complex of the present invention has an absorption period of 3 to 6 months, which is suitable for dental implant surgery. In addition, the single-tank process of the present invention can produce a-CSH and ACP in a single process and easily produce a-CSH/ACP composites. In one aspect, the invention provides an a-calcium sulfate hemihydrate/amorphous calcium phosphate (a-CSH/ACP) complex comprising a-CSH and ACP and having a weight ratio of from about 10:90 to about 90: 10. In one embodiment, a-CSH is a-CaS04.0.5H2O. In another embodiment, the weight ratio of the a-CSH to the ACP is about 10:90, about 20:80, about 30:70, about 40:60, about 50:50, about 60:40, about 70: 30. About 80:20 or to about 90:10. In another embodiment of the present invention, the α-CSH/ACP complex of the present invention is in the form of a granule, a powder form 150466.doc 201231045 or a paste form. According to the present invention, the ideal absorption rate of the implanted bone graft material (SBGS) should be similar to the natural healing rate of the human bone, and the present invention surprisingly finds that α-CSH and ACP can be added at a specific ratio. Hydration, and α-CSH and ACP are not converted into HAp with longer absorption time and calcium sulfate dihydrate (CSD) with shorter absorption time. The invention combines α-CSH and ACP to prepare an SBGS with an in vivo absorption period of 3 to 6 months, because the absorption period of the a-CSH/ACP complex conforms to the regeneration rate of the mandibular tissue, so the invention is particularly suitable. For use in the dental field. According to the present invention, the addition of ACP to the CS improves the bone regeneration promoting bone regeneration efficiency by reducing the absorption rate and simulating the natural bone structure and mineral composition. The a-CSH/ACP of the present invention is a biocompatible, osteoconductive and absorbable bone substitute having an absorption period of 3 to 6 months. The a-CSH/ACP complex of the present invention shortens graft healing and treatment periods. The rate of absorption is comparable to that of the mandibular defect, and therefore, the composite of the present invention is an ideal SBGS that is well suited for use in dental bone defects. In another aspect, the present invention provides a method of preparing a-calcium sulfate hemihydrate/amorphous calcium phosphate (a-CSH/ACP) complex comprising the steps of: (a) separately containing a calcium ion solution and The sulfate ion solution is dissolved in the vaporized calcium solution; (b) the solution of the step (a) is heated to about 80 ° C to 10 ° C, and the two solutions are mixed to produce α-hemihydrate calcium sulfate ( (c) filtering the solution obtained in the step (b) to separate the a-CSH solid in the solution; (d) adding the acid compound in the solution of the step (c) to the step (a) 150466 .doc 201231045 Calcium carbide reaction produces amorphous calcium phosphate (ACP); and (e) mixing a_cSH of step (c) and ACP of step (d), followed by adding water to prepare α-calcium sulfate hemihydrate and amorphous Calcium Phosphate (a_cSH/ACP) Complex 0 The present invention provides a single-tank preparation method for preparing the a_CSH/ACP complex of the present invention. The method simultaneously prepares a_CSH and ACP, and by mixing the obtained a-CSH and ACP. The a_CSH/ACP complex was obtained. Briefly, the above reaction can be carried out in a single-tank preparation process, and a_CSH, ACP and a-CSH/ACP can be easily produced by the single-tank preparation method. According to the present invention, at the step of the method ( In a), a calcium ion-containing solution and a sulfate ion-containing solution are dissolved in the vaporized calcium solution, respectively. In the present invention - the tactile solution is a shale acid feed, but is not limited to a solution containing gasification, hydrogen peroxide, nitric acid or cerium oxide. Preferably, the about ionic solution is a solution. In another embodiment of the invention, the sulfate ion solution is sulfuric acid-, but is not limited to, a sulfate-containing solution containing sodium sulfate or sulfuric acid. According to the present invention, the method (4) is used as a crystallization catalyst to ensure that the calcium sulphate hemihydrate phase produced in the step (b) is not converted into calcium sulfate dihydrate. According to the present invention, in the step (8) of the method, the solution of the step (4) is heated to a temperature of 8 G ° C, and mixed to make it inverse ροττ, ^ , and a-aqua-calcium sulfate (α·CSH). Preferably, the solution is heated to % embodiment. The reaction time is at least 2 hours. "One of the clarifications according to the present invention, in the step (4) of the method, the liquid system is separated from the dissolved solids by squeaking, and the solution is obtained by separately obtaining the I50466.doc 201231045 α-CSH and the solution portion. In the present invention, in the step of the method (in the sentence, a phosphoric acid compound is added to the solution of the step (c) to react with the calcium chloride of the step (a) to produce amorphous calcium phosphate (ACP). In the present invention In one embodiment, the phosphate compound is 'but is not limited to, sodium dihydrogen phosphate (Na2HP〇3), potassium dihydrogen phosphate (K: 2HP〇3) or phosphoric acid (h3P〇4). Preferably, the phosphoric acid The root compound is filled with sodium dihydrogenate. In another embodiment of the invention, the reaction is effected at an alkaline pH, preferably 'the pH is between 7.5 and 10. 〇. According to the invention, In the step (e) of the method, the α_CSH of the step (c) and the ACP of the step (d) are mixed to form a mixture, and then water is added to the mixture to prepare α-calcium sulfate hemihydrate and amorphous phosphoric acid. a complex of calcium (α_CSH/ACP). In one embodiment of the invention, the 〇1_(:811 and ACP are The amount ratio is about 10:90 to about 9:1 〇 mixed. According to the present invention, adding water to the mixture of α-CSH and ACP causes it to produce a hydration reaction, and prepares and hardens the α-CSH/ACP complex. In one embodiment of the present invention, the α-CSH and the ACP are mixed in a range of ratios to obtain a desired absorption period. Preferably, the α-CSH is a-CaSO4.0.5H2O. In another embodiment The α-CSH and ACP are mixed at a weight ratio of about 6 〇: 4 Torr. Preferably, the a-CSH/ACP complex of the present invention has a absorption period of 3 to 6 months. The following examples should not be regarded as excessive. The present invention is intended to be limited and modified by the embodiments of the present invention without departing from the spirit and scope of the invention. Way] 150466.doc 11 201231045

Example 1 Preparation of α-CSH/ACP Complex of the Invention Preparation of a-CSH Calcium carbonate (CaCl 2 ) was used as a crystal form catalyst and pure a-CSH° 0.1 Μ calcium nitrate (Ca(N03) was prepared by wet precipitation method. ) 24H20) and 0.1 Μ potassium sulphate (K2S04) were dissolved in 3.5 Ca of 50 ml of CaCl 2 solution, respectively. Both solutions were preheated to 95 ° C, mixed and reacted at atmospheric pressure for two hours. The detailed procedure is described in U.S. Patent No. 7,700,066. The crystalline state of 〇1-€811 was analyzed by X-ray diffraction (XRD), scanning thermal differential (DCS), and scanning electron microscopy (SEM). The SEM of α-CSH is shown in Fig. 1(a), which has a slender, needle-like, and interlaced crystal form; in addition, its XRD analysis is shown in Fig. 1(c), for the crystal faces (110), (310). ), (220) and (-114) have peaks at 14.75, 25.71, 29.76 and 31.91 of 2Θ, which can be confirmed as (X-CSH, and its DCM spectrum is shown in Fig. 1(d)), about 210 °C There is an endothermic peak and a slight exothermic peak at 230 ° C, showing the characteristics of α-CSH.

Preparation of ACP 100 ml of distilled water was added to sodium hydroxide (NaOH) to prepare an alkaline aqueous solution having a pH of 9. ACP was prepared by rapidly adding 100 ml of an aqueous solution of disodium hydrogen phosphate (J.T. Baker, ST, USA) (2.33 M) and 100 ml of a calcium carbonate solution (3.5 M) to an aqueous alkaline solution. The resulting amorphous calcium phosphate was subjected to high power (Sibata, Circulating Aspirator WJ-20, Tokyo, Japan) and stored in a freezer. After two days of freeze drying, the crystalline form was confirmed by XRD analysis. The XRD pattern of the calcium phosphate prepared by the wet precipitation method exhibited a broad spectrum (Fig. 1 (c)), showing that it was in an amorphous state, and Fig. 1 (b) showed that the ACP exhibited a sheet shape under SEM. 150466.doc 201231045 Preparation of a-CSH/ACP (60/40) particles After mixing a-CSH and ACP in a weight ratio of 60:40, the resulting mixture is mixed with distilled water in a ratio of 10:6, and the temperature of the mixture reaches room temperature. Then dry in an oven at 80 °C. This material was pulverized in a mortar and sieved to obtain 420-840 μηη particles. When a-CSH was mixed with water at a ratio of 10:6 for 24 hours, XRD analysis showed that a-CSH completely converted into calcium sulfate dihydrate (CSD) via hydration reaction because it was in the crystal plane of CSD (020) , (021), (040), and (041) at 11.64. 20.75. 23.41. And there are new peaks at 29.14°. Conversely, when 〇1-€811/八0?(60/40) was mixed with water overnight, the XRD of the hydrated composite showed its crystal faces (110), (310), (220) with CSH and (-114) Related 14.75. 25.66. , 29.76° and 31.91. The position has a peak, and there is no measurable peak in the 2Θ showing phase transition to CSD (see Figure 2). Figure 3 shows an SEM image of a-CSH/ACP (60/40). Example 2 a-CSH/ACP in vitro dissolution test The in vitro dissolution test is indispensable to demonstrate the solubility characteristics of clinically usable bioabsorbable materials. Prepare various test materials, a_ CSH/ACP (60/40) and CS lg. The samples were placed in tea bags and placed in polyethylene tubes and weighed with an accuracy of 0·01 mg. Then, 50 ml of a buffered acid buffer (PBS) was added to each tube and incubated at 37 ° C in a shaker at 30 rpm (B603D, FIRSTREK, ST, USA). Three days later, the polyethylene tube was centrifuged (Hermle, Z 323 K, United Corps, Germany) and the PBS was carefully removed. The sample was washed with 30 ml of deionized water, dried and cooled, and the new weight was recorded. An additional 50 ml of fresh PB S was added and placed in the condenser for another three days. The percent retention weight of the sample is calculated to measure the dissolution ratio of the sample. After 3 months, the test was stopped when the small loss ratio was difficult to measure. Figure 4(a) shows the retention weight chart for a-CSH/ACP (60/40) and CS immersed in PBS for up to 90 days, both showing rapid dissolution in the first 20 days, followed by a decrease in degradation rate and reaching During the stationary period, after 90 days of degradation, the percentage of residual samples was 13.5 ± 0.7% and 40.5 ± 1.4%, respectively. Figure 4(b) shows the residue of the in vitro dissolution test by XRD analysis. Both of them were found to have low crystalline hydroxyl-filled limestone (HAp), but none of the CS was found. Therefore, after dissolving in PBS, Both CS and a-CSH/ ACP (60/40) are converted to low crystalline HAp. Example 3 Animal Test Eight Miguel dogs (about one year old) were used for the test. The dogs are raised in the Department of Science and Technology at National Pingtung University. Animal selection, management, and surgical procedures are approved by the Animal Care and Use Committee of the Taipei Medical University. Intramuscular injection of 0.1 mg/kg of atopine (Tai-Yu Co., Hsinchu, Taiwan) and 6 to 12 mg/kg of Zoletil/Virbac 50 (Virbac Laboratories, France) For general or local anesthesia. Injection of lidocaine/epinephrine (Ora Inj. cartridge, 2% lidocaine hydrochloride and epinephrine 1:73,000, Showa 11<;111^11_1^31<;0,^{)&11) for local anesthesia〇 The first molar, the second, third and fourth premolars (Ml and P2 to P4) of the bilateral chin of the dog were removed, and the wound was given a healing period of three months. The dog was given ampicillin after surgery to resist inflammation. The lower jaw is drilled to a depth of 5 and 8 mm, and is 〇1-CSH/ACP(60/40) ' Osteoset® (CS, Wright Medical Technology, 150466.doc 14 201231045

Arlington, TN, USA) was filled, and another substance was not filled as a blank control group. The sample (η is 4) was collected after 3 weeks and 6 weeks. At each collection time point, a bone drill (diameter 6 mm) was used. Collect specimens and quickly place them in 1% of Formalin. The sliced samples were stained with hematoxylin and eosin. The biocompatibility and bone regenerability of the sections were examined using an optical microscope. The area percentage of new bone formation was calculated by ImageJ l.37c (Nati〇nal insthutes 〇f (>^1), 6 by 1^3 (^, river 0, 118 8) software. Defects of the test group and control group defects The difference in the percentage of area of new bone formation was tested using the unpaired Student's t-test, and the p-value was less than 〇〇5. Figure 5 shows that the wound in the blank control group was full of connectives at 3 weeks. Tissue, while the commercial items Osteoset® and a-CSH/ACP (60/40) showed significant bone formation' but there were still some connective tissue in the two. No observation was observed after six weeks. There were any fibrous tissue or inflammatory cells, and a few bones were observed in the blank control group, but there were also many unhealed cavities. In the a-CSH/ACP (60/40) group and the Osteoset® group, Significant bone production was observed, whereas the Osteoset® group had more unhealed cavities than the a-CSH/ACP (60/40) group. The exact bone formation area was determined by the following tissue morphology method. Example 4. Tissue Type Test (Quantitative Measurement) New bone formation with image software Quantification, the results are summarized in Table 1. At the third week, the new bone formation rate of the a-CSH/ACP (60/40) group was 21.1 ± 15.0 ° /, which was significantly higher than that of the blank control group. 9.5% (p value < 〇.〇5), but there is no significant difference between the new bone formation rate of 28.0±16.0% in the Osteoset® group. Since 150466.doc 15 201231045 Therefore, within 3 weeks, a -CSH/ACP (60/40) or Osteoset® filling defects can increase the rate of new bone regeneration. Six weeks after surgery, the new bone formation rate of the defect treated with a-CSH/ACP (60/40) was 62.2± 6.8%, the new bone regeneration rate was higher than the 53.3±4.6% (ρ value <0.01) of the Osteoset® group and the blank control (40.1 soil 7.2%) (ρ value <0.0002). It is shown that the a-CSH/ ACP (60/40) group has a good performance. Therefore, adding ACP to CS can improve the performance of bone regeneration. Finally, using the linear least squares fitting technique In the canine model experiment, the time to complete the bone defect was predicted after the α-CSH/ACP (60/40) bone substitute was implanted. The extrapolation circle (Fig. 6) was estimated to use a-CSH/ACP (60/). 40) The complete healing time of the bone substitute is 10 Within 12 weeks (10.3 weeks), the bone regeneration rate of dogs is usually 1.5 to 2 times faster than that of humans. Therefore, the healing time of 10 to 12 weeks in this test is about the same as that of human body 15 to 18 weeks (3.75). Up to 4.5 months). Table 1 Group new bone formation (%) 3 weeks (SD) 6 weeks (SD) a-CSH /ACP 21.1 (15.0)* 62.2 (6.8) *** Osteoset® 29.0(16.0)* 53.3 (4.6) * Blank Control group 13.6 (9.5) 40.1 (7.2) [Simplified illustration] Figure 1 (a) shows the SEM image of a-CSH; Figure 1 (b) shows the SEM image of ACP; Figure 1 (c) shows a-CSH and XRD pattern of ACP; and Figure 1 (d) shows DSC spectrum of a-CSH; 150466.doc -16- 201231045 Figure 2 shows XRD patterns of transformed ACP, α-CSH/ACP, CSH and CSD; SEM image of α-CSH/ACP; Figure 4(a) shows the dissolution test of calcium sulfate (CS) alone and a-CSH/ACP (60/40) in PBS, and Figure 4(b) shows CS and α- XRD pattern of CSH/ACP residue after PBS dissolution test; Figure 5 shows micrograph of tissue section with a-CSH/ACP (60/40), Osteoset® filling bone defect and blank control (each image is 20 times magnification for the original; CT: connective tissue; NT: new osteogenesis; and Figure 6 shows the a-CSH/ACP (60/40) bone substitute drawn by extrapolation during complete healing of the dog's alveolar bone defect Trend. I50466.doc

Claims (1)

201231045 VII 1. 2. 3. 4. 5. 6. 7. 8. Patent scope: α, calcium sulfate hemihydrate/amorphous calcium phosphate (a_CSil/ACP) complex, 匕 containing cucSH and ACP And the weight ratio is about 10:90 to about 9 〇··ι〇. For example, the complex of the month 1 of the compound, wherein the a-CSH is a-CaSO4.0.5H2O. Wherein the weight ratio of the α-CSH to the ACP is about 20.80, about 30:70, about 40:60, about 50:50, about 60:40, about 70:30 or about 8:2. The composite, which is in the form of a particle. The composite of claim 1 is in the form of a powder. The composite of claim 1 is a paste type. The article 'has a 3 to 6 month absorption period in the human body. A method for preparing a-calcium sulfate hemihydrate/amorphous calcium phosphate (a_CSH/ACp) complex, comprising the following steps: (a) separately The calcium ion solution and the sulfate ion-containing solution are dissolved in the calcium chloride solution; (b) the solution of the step (4) is heated to about 8 Torr. 〇 to 1 〇〇. 〇, and the two kinds of lyoside are mixed to cause α_ Hemihydrate sulfuric acid I bow (a_CSH); (c) Filtering the solution obtained in the step (b) to separate the a_CSH solid in the solution; (d) adding the phosphoric acid compound to the solution of the step (c) to react with the calcined calcium of the step (&) to produce amorphous calcium phosphate ( ACp); and (e) mixing the a-CSH of step (c) and the ACP of step (d), followed by adding water to prepare a-calcium sulfate hemihydrate and amorphous calcium carbonate (a_CSH/Acp) complex 150466.doc 201231045. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. According to the knowledge of item 8, the calcium hydroxide, calcium nitrate D, the 3 calcium ion solution is calcium carbonate containing , Month & Calcium or Calcium Oxide Solution. If the request item g is large, liquid, etc., wherein the calcium ion solution is calcium nitrate per square of claim 8, earth potassium or sulphur. >, wherein the sulfate ion-containing solution is sulfuric acid-containing, such as the request of the formula, +. Λ method, wherein in the step (d), the phosphoric acid compound is a coded dihydrogen (Na^PO3), potassium dihydrogen carbonate (K2Hp (η3Ρ04). The method of the term 8 of the month, wherein in the step (d), the phosphate compound is sodium dihydrogenate. The method of β, wherein the step (d) is Reaction at alkaline pH, such as the method of β, wherein the value of 卩11 is between 7 5 and 1 〇〇. As in the method of claim 8, wherein the step (the illusion, the a_CSH & ACp is by weight Mixing from about 10:9 〇 to about 90:10. The method of claim 8 wherein the weight ratio of the a-CSH to the ACP is about 20:80, about 3:7, about 40:60, about 50:50, about 60:40, about 70:30 or Until about 80:20. The method of claim 8, wherein in the step (e), the a-CSH is a_CaS04.〇.5H20. The method of claim 8, wherein in the step (e), the generated a-CSH/ACP complex has a absorption period of 3 to 6 months in the human body. 150466.doc