WO2021189435A1 - 具有核壳结构的新型复合磷酸钙活性材料及其制备方法 - Google Patents

具有核壳结构的新型复合磷酸钙活性材料及其制备方法 Download PDF

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WO2021189435A1
WO2021189435A1 PCT/CN2020/081730 CN2020081730W WO2021189435A1 WO 2021189435 A1 WO2021189435 A1 WO 2021189435A1 CN 2020081730 W CN2020081730 W CN 2020081730W WO 2021189435 A1 WO2021189435 A1 WO 2021189435A1
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tcp
core
calcium
calcium phosphate
shell structure
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PCT/CN2020/081730
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English (en)
French (fr)
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董良润
刘思羽
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苏州信和隆医疗器械有限公司
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Priority to PCT/CN2020/081730 priority Critical patent/WO2021189435A1/zh
Publication of WO2021189435A1 publication Critical patent/WO2021189435A1/zh

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    • 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
    • A61L27/10—Ceramics or glasses
    • 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • 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
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/01—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics
    • C04B35/447—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on phosphates, e.g. hydroxyapatite

Definitions

  • the invention relates to the field of composite calcium phosphate materials, in particular to a novel composite calcium phosphate active material with a core-shell structure and a preparation method thereof.
  • ⁇ -tricalcium phosphate ⁇ -TCP
  • ⁇ -TCP ⁇ -tricalcium phosphate
  • calcium phosphate composite materials composed of two or more calcium phosphates may have both biological activity, degradation rate or mechanical properties. Therefore, composite calcium phosphate materials in recent years It has been successfully used in biomedicine.
  • the most common example is the biphasic calcium phosphate HA/ ⁇ -TCP composed of hydroxyapatite (HA) and ⁇ -tricalcium phosphate ( ⁇ -TCP). This material is often used clinically for filling and repairing various bone defects.
  • ⁇ -TCP has a faster degradation rate, and the slower degradation of HA maintains the higher compressive strength of the bone filler material during the formation of new bone.
  • similar two-phase calcium phosphate composite materials are also combined.
  • two-phase ⁇ -TCP/ ⁇ -TCP composite tricalcium phosphate is sintered from ACP or other calcium phosphate materials.
  • ACP calcium phosphate
  • the three-phase calcium phosphate composite material composed of HA/ ⁇ -TCP/ ⁇ -TCP was successfully obtained by parameters such as ratio and sintering temperature.
  • the present invention provides a novel composite calcium phosphate active material with a core-shell structure and a preparation method thereof, which solves the lack of calcium phosphate composite materials with other crystal phase composition and composite HA/ ⁇ -TCP in the prior art. Or ⁇ -TCP/ ⁇ -TCP biphasic materials, HA and ⁇ -TCP or ⁇ -TCP and ⁇ -TCP two-phase uniform distribution problem.
  • a new type of composite calcium phosphate active material with a core-shell structure which is composed of calcium ions, phosphate ions and other non-calcium and non-phosphorus heteroelements (ions), of which calcium and phosphorus
  • the (Ca/P) molar ratio is 0.1-10, and the mass fraction of hetero element ions is 0.1%-50%.
  • the calcium phosphate composite material includes calcium dihydrogen phosphate (MCP), calcium hydrogen phosphate (DCPA), ⁇ -tricalcium phosphate ( ⁇ -TCP), ⁇ -tricalcium phosphate ( ⁇ -TCP), amorphous phosphoric acid Tricalcium (ACP), Calcium Tetraphosphate (TTCP), Calcium Oxide (CaO), Hydroxyapatite (HA), Calcium Deficiency Apatite (CDHA), Fluorapatite (FA), Calcium Fluoride (CaF2) , Calcium octaphosphate (OCP), calcium silicate (CaSiO3) and other compounds of at least two, one or more of them constitute the outer shell of the composite material, and the other or more constitute the core of the composite material.
  • MCP calcium dihydrogen phosphate
  • DCPA calcium hydrogen phosphate
  • ⁇ -TCP calcium hydrogen phosphate
  • ⁇ -TCP ⁇ -tricalcium phosphate
  • ACP Calcium
  • the selected calcium ion source is one or more of CaCO 3 , Ca(NO 3 ) 2 , Ca(OH) 2 , CaO, CaSi O 3 , and CaF 2 , or MCP, DCPA, ⁇ -TCP , ⁇ -TCP, ACP, TTCP, CaO, HA, CDHA, FA, OCP and other calcium phosphate one or more.
  • the selected phosphate ion source is one or more of P 2 O 5 , (NH 4 ) 3 PO 4 , (NH 4 ) 2 HPO 4 , NH 4 H 2 PO 4 , or MCP, DCPA , ⁇ -TCP, ⁇ -TCP, ACP, TTCP, CaO, HA, CDHA, FA, OCP and other calcium phosphate one or more, or Sr, K, Na, Mg, Zn, Fe phosphate, including Its normal salt, acid salt, basic salt.
  • the non-calcium and non-phosphorus hetero elements (ions) are one or more of Sr, Si, K, Na, Mg, Zn, and Fe.
  • the ion source used when the non-calcium and non-phosphorus hetero elements (ions) are added to the composite calcium phosphate can be hydroxides, oxides, fluorides, carbonates, nitrates, phosphates or their acidic forms. Salt, basic salt or combination.
  • the new composite calcium phosphate active material is most typically ⁇ -TCP@ ⁇ -TCP core-shell structure material with ⁇ -TCP core and ⁇ -TCP shell and ⁇ with ⁇ -TCP core and ⁇ -TCP shell.
  • -TCP@ ⁇ -TCP core-shell structure material the possible applications of the new composite calcium phosphate active material include tooth remineralization materials, artificial bone materials and the like.
  • the tooth remineralization material includes mouthwash, toothpaste, tooth protector, fluorine protective paint, light-curable resin, adhesive, desensitizer, etc.
  • the artificial bone includes powder, granular, Block and other solid artificial bones, or paste-like, injection-like artificial bones.
  • Preparation method of novel composite calcium phosphate active material with core-shell structure including preparation method of ⁇ -TCP@ ⁇ -TCP core-shell calcium phosphate composite material and preparation method of ⁇ -TCP@ ⁇ -TCP core-shell calcium phosphate composite material method,
  • the invention provides a novel composite calcium phosphate active material with a core-shell structure and a preparation method thereof. Has the following beneficial effects:
  • this invention provides a calcium phosphate composite material composed of more crystal phases, so that the material can be used in more fields, such as tooth remineralization materials, artificial bone materials and other fields, and can take into account Material stability, physical and chemical properties, biocompatibility.
  • the two phases of calcium phosphate in this invention are not evenly distributed like HA/ ⁇ -TCP. Instead, one of the two phases forms the core of the particle but the other phase forms the core-shell structure of the shell.
  • Composite materials such as ⁇ -TCP@ ⁇ -TCP core-shell structure, ⁇ -TCP@ ⁇ -TCP core-shell structure, etc.).
  • the advantage of this material is that the inner and outer parts of the core-shell structure have different biocompatibility and physical and chemical properties , One of which has lower solubility or higher stability, and the other has higher solubility or biological activity.
  • the material has different performance in clinical use. Nature, more to meet the clinical requirements.
  • ⁇ -TCP and ⁇ -TCP have different biocompatibility, solubility, degradability and mechanical properties, dual-phase ⁇ -TCP@ ⁇ -TCP or ⁇ -TCP@ ⁇ -TCP core-shell structured calcium phosphate
  • the material has different properties, and the material can be used to control the amount and rate of calcium and phosphate ion release, so it has different uses in materials engineering or in medicine and clinics.
  • ⁇ -TCP@ ⁇ -TCP with ⁇ -TCP core and ⁇ -TCP shell has a highly reactive core and a relatively inert shell.
  • This material can be used as a source of calcium and phosphorus ions for tooth remineralization.
  • This material has high stability in water-based toothpaste and does not react with fluoride.
  • the abrasive in the toothpaste can easily remove the outer shell of ⁇ -TCP, exposing the highly reactive ⁇ -TCP core to provide abundant calcium and phosphate ions, and promote tooth remineralization.
  • the surface produces hydroxyapatite HA similar to the enamel structure or combines with fluoride ions to form a more acid-resistant fluoroapatite, which protects the enamel structure and prevents dental caries.
  • the outstanding advantage of using ⁇ -TCP@ ⁇ -TCP core-shell structure material remineralization toothpaste is that it can combine the anti-caries effect of fluoride with the remineralization effect of calcium phosphate to protect teeth to a greater extent. An ideal material for dental caries prevention.
  • This ⁇ -TCP@ ⁇ -TCP core-shell structure material can also be used to prepare pre-mixed calcium phosphate cement (self-curing artificial bone), and the inert ⁇ -TCP shell can prevent the material from overwhelming even in the presence of water. Early reaction, thus improving the stability of the pre-mixed artificial bone. In clinical use, mechanical breaking or introduction of weak acid components will remove the inert ⁇ -TCP shell and make the highly reactive ⁇ -TCP core rapidly react and harden.
  • the ⁇ -TCP@ ⁇ -TCP core-shell structure material with ⁇ -TCP core and ⁇ -TCP shell will have a reactive ⁇ -TCP outer layer and a relatively inert ⁇ -TCP core, which can be formulated using this material
  • a new type of self-curing artificial bone When this artificial bone powder is mixed with the hardening solution, the outer layer of ⁇ -TCP is quickly converted into HA to harden the bone material, so that the operation can be sutured, and the inner layer of ⁇ -TCP is in It is not converted into HA during the hardening process, so it has a faster degradation rate than HA materials, and is more suitable for clinical requirements for bone filling materials.
  • the material can be applied to the research and development of tooth remineralization materials and self-curing artificial bones. Because the material has a relatively inert ⁇ -TCP shell, it has high stability in water-based toothpaste and does not react with fluoride. When brushing teeth, the abrasive in the toothpaste removes the ⁇ -TCP shell, exposing the highly reactive ⁇ -TCP core, releasing calcium and phosphorus ions to form hydroxyapatite similar to the enamel structure on the tooth surface, so that the enamel structure is protected and prevented Caries.
  • the material can be applied to the research and development of tooth remineralization materials and self-curing artificial bones. Because the material has a highly reactive ⁇ -TCP shell and a relatively inert ⁇ -TCP core, when using this material to prepare self-curing artificial bone powder, the outer layer of ⁇ -TCP is reactive when the bone powder is mixed with the hardening liquid. The higher and rapid conversion into HA hardens the bone material and saves operation time, while the inner ⁇ -TCP does not convert into hard-to-degrade HA during the hardening process, so it has a faster degradation rate than HA material and is more suitable for clinical use. Requirements for bone filling materials.
  • the material can be applied to the research and development of tooth remineralization materials and self-curing artificial bones.
  • the material can be applied to the research and development of tooth remineralization materials and self-curing artificial bones.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • the material has both the high solubility of DCP and the biocompatibility of ⁇ -TCP. It can be applied to the research and development of tooth remineralization materials, solid artificial bones and self-solidified artificial bones. The artificial bones using this material have faster performance than expected. Degradation rate.
  • the material has high reactivity and biocompatibility, and is an ideal material for tooth remineralization and self-curing artificial bone.
  • the self-curing artificial bone using the material has a shorter hardening time.
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • strontium can be doped into the calcium phosphate crystal phase.
  • Strontium ions can promote bone fusion and promote calcium phosphate degradation.
  • the material can be used for the development of solid artificial bone and self-solidifying artificial bone.
  • the material can be applied to the research and development of tooth remineralization materials and self-curing artificial bones. Because the material has a relatively inert F/ ⁇ -TCP shell, it has high stability in water-based toothpaste and does not react with fluoride. When brushing teeth, the abrasive in the toothpaste removes the F/ ⁇ -TCP shell, exposing the more reactive F/ ⁇ -TCP core, releasing calcium phosphate ions, and generating hydroxyapatite similar to the enamel structure on the tooth surface, part of which is released The F ions combine to form a more acid-resistant fluoroapatite FA, which makes tooth enamel more resistant to acid corrosion and has a stronger effect on preventing dental caries.
  • calcium silicate can be doped into calcium phosphate to form calcium phosphosilicate similar to biological glass
  • the doping of silicon changes the bonding of calcium phosphate ions, which is similar to that in biological glass to promote the dissolution of calcium phosphate and calcium phosphate ions. Release rate.
  • the material used in oral remineralization materials helps the release of calcium and phosphorus ions.
  • the more soluble ⁇ -TCP/CaSiO 3 in the outer layer helps to release calcium and phosphorus ions to promote remineralization.
  • the stable ⁇ -TCP/CaSiO 3 particles help to stably fill and block dentin tubules and relieve tooth hypersensitivity to cold and heat.
  • the material is an ideal material that combines tooth remineralization and tooth desensitization.
  • the material also combines the advantages of calcium phosphate biocompatibility and bio-glass bone fusion performance, and is an ideal material for solid artificial bone and self-solidifying artificial bone.
  • Embodiment 11 is a diagrammatic representation of Embodiment 11:
  • the material can be applied to the research and development of tooth remineralization materials and artificial bones. Because the material has a relatively inert ⁇ -(K 2 O) 2 (CaO) 3 (SiO 2 )(P 2 O 5 ) shell, it has high stability in water-based toothpaste and does not react with fluoride.
  • the abrasive in the toothpaste removes the ⁇ -(K 2 O) 2 (CaO) 3 (SiO 2 )(P 2 O 5 )) shell, exposing the highly reactive ⁇ -(K 2 O) 2 (CaO) 3 (SiO 2 )(P 2 O 5 ) core releases calcium and phosphorus ions, and generates hydroxyapatite similar to the enamel structure on the tooth surface to protect the enamel structure and prevent dental caries.
  • Embodiment 12 is a diagrammatic representation of Embodiment 12
  • the material can be applied to the research and development of tooth remineralization materials and self-curing artificial bones. Since ⁇ -TCP has lower reactivity and lower alkalinity than TTCP, artificial bone using TTCP/ ⁇ -TCP composite calcium phosphate material has a more controllable and slower hardening rate, and the surface of the bone material after hardening It is closer to neutral, has better biocompatibility, and is less toxic to cells and tissues.
  • Embodiment 13 is a diagrammatic representation of Embodiment 13:
  • the material can be applied to the research and development of tooth remineralization materials, solid artificial bone and self-solidifying artificial bone
  • the material can be used in the research and development of tooth remineralization materials and artificial bones.
  • the potassium ions released can help alleviate the hot and cold tooth hypersensitivity.

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Abstract

具有核壳结构的新型复合磷酸钙活性材料及其制备方法，涉及复合磷酸钙材料领域。该具有核壳结构的新型复合磷酸钙活性材料，其材料组成为钙离子、磷酸根离子和其他非钙磷杂元素(离子)，其中钙磷(Ca/P)摩尔比为0.1-10，杂元素的质量分数在0.1％-50％；通过该制备方法可以制备多种新型复合磷酸钙活性材料，可以应用于多个领域，该材料由核壳两部分组成，核壳结构的内外部分具有不同的生物相容性和物理化学性能，其中一种具有较低的溶解性或较高的稳定性，另一种具有较高的溶解性或生物活性。通过设计核壳结构的内外组成，使该材料更易满足不同临床要求。

Description

具有核壳结构的新型复合磷酸钙活性材料及其制备方法 技术领域
本发明涉及复合磷酸钙材料领域，具体为具有核壳结构的新型复合磷酸钙活性材料及其制备方法。
背景技术
由于其优异的生物相容性、降解性能、机械性能等，磷酸钙生物材料广泛用于骨缺损的填充修复、牙齿再矿化等领域。虽然HA是骨骼和牙釉质的主要成分，但由于其极低的溶解性，临床使用时显示有限的生物活性和降解性能。由于钙磷比和晶体结构的不同，磷酸钙材料有多种不同类型，并在生物相容性和物理化学性能各有优势和不足。例如，β-磷酸三钙(β-TCP)具有很好的生物相容性，但过快的降解速率和较低的压缩强度限制了单一磷酸钙材料的广泛应用。
基于不同的溶解性、生物活性和机械性能，由两种或两种以上的磷酸钙组成的磷酸钙复合材料可能具有二者兼顾的生物活性、降解速率或机械性能，因此，近年复合磷酸钙材料已成功用于生物医学。其中最常见的例子是羟基磷灰石(HA)和β-磷酸三钙(β-TCP)组成的双相磷酸钙HA/β-TCP，该材料临床上常用于各类骨缺损的填充修复，使用时β-TCP具有较快的降解速度，而降解较慢的HA则在新骨形成过程中维持了骨填充材料较高的压缩强度。此外，类似的双相磷酸钙复合材料也有和成，例如，双相α-TCP/β-TCP复合磷酸三钙由ACP或其他磷酸钙材料等烧结而成，另外还有文献报道通过改变钙磷比和烧结温度等参数成功得到HA/α-TCP/β-TCP组成的三相磷酸钙复合材料。
虽然有文献报道了上述HA/β-TCP、α-TCP/β-TCP或HA/α-TCP/β-TCP的制备，但是尚无其他晶相组成的磷酸钙复合材料，比如DCP/TCP、TTCP/TCP、HA/TTCP等。并且，文献报道的复合HA/β-TCP或α-TCP/β-TCP双相材料中， HA和β-TCP或α-TCP和β-TCP两相均匀分布，所以需要发明具有核壳结构的新型复合磷酸钙活性材料及其制备方法。
发明内容
(一)解决的技术问题
针对现有技术的不足，本发明提供了具有核壳结构的新型复合磷酸钙活性材料及其制备方法，解决了现有技术中缺少其他晶相组成的磷酸钙复合材料以及复合HA/β-TCP或α-TCP/β-TCP双相材料中，HA和β-TCP或α-TCP和β-TCP两相均匀分布的问题。
(二)技术方案
为实现以上目的，本发明通过以下技术方案予以实现：具有核壳结构的新型复合磷酸钙活性材料，其组成为钙离子、磷酸根离子和其他非钙非磷杂元素(离子)，其中钙磷(Ca/P)摩尔比为0.1-10，杂元素离子的质量分数在0.1％-50％。
优选的，所述磷酸钙复合材料包括磷酸二氢钙(MCP)、磷酸氢钙(DCPA)、α-磷酸三钙(α-TCP)、β-磷酸三钙(β-TCP)、无定形磷酸三钙(ACP)、四磷酸钙(TTCP)、氧化钙(CaO)、羟基磷灰石(HA)、缺钙磷灰石(CDHA)、氟磷灰石(FA)、氟化钙(CaF2)、八磷酸钙(OCP)、硅酸钙(CaSiO3)等化合物中的至少两种，其中一种或几种组成复合材料的外壳，另一种或几种组成复合材料的内核。
优选的，所选择的钙离子源为CaCO 3、Ca(NO 3) 2、Ca(OH) 2、CaO、CaSi O 3、CaF 2中的一种或几种，或者MCP、DCPA、α-TCP、β-TCP、ACP、TTCP、CaO、HA、CDHA、FA、OCP等磷酸钙中的一种或几种。
优选的，所选择的磷酸根离子源为P 2O 5、(NH 4) 3PO 4、(NH 4) 2HPO 4、NH 4H 2PO 4中的一种或几种，或者MCP、DCPA、α-TCP、β-TCP、ACP、TTCP、CaO、HA、CDHA、FA、OCP等磷酸钙中的一种或几种，或者Sr、K、Na、Mg、Zn、Fe的磷 酸盐，包括其正盐、酸式盐、碱式盐。
优选的，所述非钙非磷杂元素(离子)为Sr、Si、K、Na、Mg、Zn、Fe中的一种或几种。
优选的，所述非钙非磷杂元素(离子)加入复合磷酸钙中时所用的离子源可以是氢氧化物、氧化物、氟化物、碳酸盐、硝酸盐、磷酸盐或者它们的酸式盐、碱式盐或者组合。
优选的，所述新型复合磷酸钙活性材料最典型的为具有α-TCP内核和β-TCP外壳的α-TCP@β-TCP核壳结构材料以及具有β-TCP内核和α-TCP外壳的β-TCP@α-TCP核壳结构材料，所述新型复合磷酸钙活性材料可能的应用包括牙齿再矿化材料、人工骨材料等。
优选的，所述的牙齿再矿化材料包括漱口水、牙膏、护牙素、氟保护漆、光固化树脂、粘接剂、脱敏剂等，所述的人工骨包括粉末状、颗粒状、块状等固体人工骨、或浆状、注射状人工骨。
具有核壳结构的新型复合磷酸钙活性材料的制备方法，包括β-TCP@α-TCP核壳结构磷酸钙复合材料的制备方法和α-TCP@β-TCP核壳结构磷酸钙复合材料的制备方法，
α-TCP@β-TCP核壳结构磷酸钙复合材料的制备方法：
(1).将含有钙磷离子源及杂元素化合物的混合物放入高温炉中加热升温至约1120-1900℃，恒温1-96小时后，然后降温至400-1100℃并保温1-300分钟，然后将高温炉冷至室温。
(2).或者将含有钙磷离子源及杂元素化合物的混合物放入高温炉中加热升温至约1120-1900℃，恒温1-96小时后，然后将高温炉降温至室温，将烧结材料粉碎至指定粒径范围(0.1-1000μm)后，再升温至400-1100℃并保温1-300分钟，然后再将高温炉冷至室温。
β-TCP@α-TCP核壳结构磷酸钙复合材料的制备方法：
(1).将含有钙磷离子源及杂元素化合物的混合物放入高温炉中加热升温至约400-1100℃，恒温1-96小时后，然后升温至1120-1900℃并保温1-300分钟，然后将高温炉冷至室温。
(2).或者将含有钙磷离子源及杂元素化合物的混合物放入高温炉中加热升温至约400-1100℃，恒温1-96小时后，然后将高温炉降温至室温，将烧结材料粉碎至指定粒径范围(0.1-1000μm)后，然后升温至1120-1900℃并保温1-300分钟，然后将高温炉冷至室温。
(三)有益效果
本发明提供了具有核壳结构的新型复合磷酸钙活性材料及其制备方法。具备以下有益效果：
1、相比于现有技术，该发明提供了更多晶相组成的磷酸钙复合材料，使得该材料可以在更多领域使用，如牙齿再矿化材料、人工骨材料等领域，且能够兼顾材料稳定性、物理化学性能、生物相容性。
2、相较于现有技术，该发明构成两相的磷酸钙并不像HA/β-TCP那样均匀分布，而是两相之一形成颗粒的核但另一相形成壳的核-壳结构复合材料(如α-TCP@β-TCP核壳结构、β-TCP@α-TCP核壳结构等)，该材料的优点是核壳结构的内外部分具有不同的生物相容性和物理化学性能，其中一种具有较低的溶解性或较高的稳定性，另一种具有较高的溶解性或生物活性，通过设计核壳结构的内外部分组成，使得该材料在临床使用时表现不同的性质，更以满足临床要求。
3、由于α-TCP和β-TCP具有不同的生物相容性、溶解性、降解性和机械性能，双相α-TCP@β-TCP或β-TCP@α-TCP核壳结构复合磷酸钙材料具有不同的性能，该材料可用于控制钙和磷酸根离子释放的量和速率，因而在材料工程上或医学临床上有不同的用途。
4、例如具有α-TCP内核和β-TCP外壳的α-TCP@β-TCP具有较高反应性 的内核和相对惰性的外壳，该材料可以用作牙齿再矿化的钙和磷离子源。该材料在水基牙膏中具有较高的稳定性，并且不与氟化物反应。当在口腔中使用时，牙膏中的磨料可以轻易地去除β-TCP的外壳，暴露出反应活性较高的α-TCP内核以提供丰富的钙和磷酸根离子，促使牙齿再矿化，在牙齿表面生成类似于牙釉质结构的羟基磷灰石HA或与氟离子结合形成更加耐酸的氟磷灰石，使牙釉质结构得到保护，预防龋齿。使用α-TCP@β-TCP这种核壳结构材料的再矿化牙膏的突出优势就是能够将氟化物的防龋齿作用与磷酸钙的再矿化作用结合起来，更大程度地保护牙齿，是龋齿预防的一种理想材料。
5、这种α-TCP@β-TCP核壳结构材料还可用于配制预混合的磷酸钙骨水泥(自固化人工骨)，惰性β-TCP外壳即使在有水的情况下也可以防止材料过早反应，因而提高预混合人工骨的稳定性，在临床使用时，机械打碎或引入弱酸性成分会除去惰性的β-TCP外壳，使反应活性较高的α-TCP内核迅速反应硬化。
6、另外，具有β-TCP内核和α-TCP外壳的β-TCP@α-TCP核壳结构材料将具有反应性α-TCP外层和相对惰性的β-TCP内核，使用这种材料可以配制新型自固化人工骨，这种人工骨粉料在和硬化液混合时由于外层α-TCP反应性较高而快速转化为HA使骨材料硬化，使手术可以缝合，而内层的β-TCP在硬化过程中并不转化为HA，因而具有比HA材料更快的降解速度，更适合临床上对骨填充材料的要求。
具体实施方式
下面将结合本发明，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：
制备α-TCP@β-TCP核壳结构复合磷酸钙材料：
将CaO和P 2O 5按照摩尔比3/1混合，将混合物放入高温炉中加热缓慢升温至约1500℃，恒温24小时后，快速降温至1000℃并保温30分钟，以使α-TCP粒子的表面覆盖β-TCP外层，将高温炉骤冷至室温，得到具有α-TCP内核和β-TCP外壳的α-TCP@β-TCP核壳结构复合磷酸钙材料。
该材料可以应用于牙齿再矿材料和自固化人工骨的研发。由于该材料具有相对惰性的β-TCP外壳，在水基牙膏中具有较高的稳定性，并且不与氟化物反应。刷牙时牙膏中的磨料去除β-TCP外壳，暴露出反应活性较高的α-TCP内核释放钙磷离子在牙齿表面生成类似于牙釉质结构的羟基磷灰石，使牙釉质结构得到保护，预防龋齿。
实施例二：
制备β-TCP@α-TCP核壳结构复合磷酸钙材料：
将Ca(OH) 2和CaHPO 4按照摩尔比1/2混合，将混合物放入高温炉中加热缓慢升温至约1000℃，恒温24小时后，快速升温至1500℃并保温30分钟，以使β-TCP粒子的表面覆盖α-TCP外层，将高温炉骤冷至室温，得到具有β-TCP内核和α-TCP外壳的β-TCP@α-TCP核壳结构复合磷酸钙材料。
该材料可以应用于牙齿再矿材料和自固化人工骨的研发。由于该材料具有反应性较高的α-TCP外壳和相对惰性的β-TCP内核，使用这种材料配制自固化人工骨骨粉时，这种骨粉在和硬化液混合时外层α-TCP反应性较高而快速转化为HA使骨材料硬化，节省手术时间，而内层的β-TCP在硬化过程中并不转化为难以降解的HA，因而具有比HA材料更快的降解速度，更适合临床上对骨填充材料的要求。
实施例三：
制备β-TCP@α-TCP核壳结构复合磷酸钙材料：
将Ca(NO 3) 2和CaHPO 4按照摩尔比1/2混合，将混合物放入高温炉中加 热缓慢升温至约900℃，恒温36小时后，将高温炉冷却至室温，粉碎至所需粒径后(D50＝2μm)，再快速升温至1300℃并保温3分钟，以使β-TCP粒子的表面覆盖α-TCP外层，将高温炉骤冷至室温，得到具有β-TCP内核和α-TCP外壳的β-TCP@α-TCP核壳结构复合磷酸钙材料。该材料可以应用于牙齿再矿材料和自固化人工骨的研发。
实施例四：
制备α-TCP@β-TCP核壳结构复合磷酸钙材料：
将CaCO 3和(NH 4)2HPO 4按照摩尔比3/2混合，将混合物放入高温炉中加热缓慢升温至约1600℃，恒温12小时后，将高温炉快速降温至室温，粉碎至所需粒径(D50＝100μm)后，再快速升温至700℃并保温10分钟，以使α-TCP粒子的表面覆盖β-TCP外层，将高温炉骤冷至室温，得到具有α-TCP内核和β-TCP外壳的α-TCP@β-TCP核壳结构复合磷酸钙材料。
该材料可以应用于牙齿再矿材料和自固化人工骨的研发。
实施例五：
制备β-TCP@α-TCP核壳结构复合磷酸钙材料：
将CaHPO 4和Ca 10(PO 4) 6(OH) 2按照摩尔比2/1混合，将混合物放入高温炉中加热缓慢升温至约700℃，恒温72小时后，快速升温至1200℃并保温60分钟，以使β-TCP粒子的表面覆盖α-TCP外层，将高温炉骤冷至室温，得到具有β-TCP内核和α-TCP外壳的β-TCP@α-TCP核壳结构复合磷酸钙材料。
该材料可以应用于牙齿再矿材料和自固化人工骨的研发。
实施例六：
制备DCP/β-TCP复合磷酸钙材料：
将CaO和(NH 4) 2HPO 4按照摩尔比1.2混合，将混合物放入高温炉中加热缓慢升温至约900℃，恒温72小时后，将高温炉骤冷至室温，得到DCP和β-TCP组成的DCP/β-TCP双相复合磷酸钙材料。
该材料兼具DCP的高溶解性和β-TCP的生物相容性，可以应用于牙齿再矿材料、固体人工骨和自固化人工骨的研发，使用该材料的人工骨与预期具有较快的降解速率。
实施例七：
制备DCP/α-TCP核壳结构复合磷酸钙材料：
将CaCO 3和P 2O 5按照摩尔比2.2混合，将混合物放入高温炉中加热缓慢升温至约1600℃，恒温12小时后，将高温炉骤冷至室温，得到DCP和α-TCP组成的DCP/α-TCP双相复合磷酸钙材料。
该材料具有较高的反应性和生物相容性，是牙齿再矿化和自固化人工骨的理想材料，使用该材料的自固化人工骨与其具有较短的硬化时间。
实施例八：
制备Sr/β-TCP@Sr/α-TCP核壳结构复合磷酸钙锶材料：
将Ca(NO 3) 2、CaHPO 4和SrCO 3按照摩尔比10/20/1混合，将混合物放入高温炉中加热缓慢升温至约1000℃，恒温36小时后得到锶掺杂的β-磷酸三钙Sr/β-TCP，将高温炉冷却至室温，粉碎至所需粒径后(D50＝500μm)，再快速升温至1300℃并保温10分钟，以使Sr/β-TCP粒子的表面覆盖Sr/α-TCP外层，将高温炉骤冷至室温，得到具有Sr/β-TCP内核和Sr/α-TCP外壳的Sr/β-TCP@Sr/α-TCP核壳结构复合磷酸钙锶材料。
由于离子半径与钙离子接近，锶元素可以掺杂进入磷酸钙晶相，锶离子具有促进骨融合和促进磷酸钙降解的作用，该材料可用于固体人工骨和自固化人工骨的研发。
实施例九：
制备F/α-TCP@F/β-TCP核壳结构复合氟化磷酸钙材料：
将CaO、P 2O 5和CaF 2按照摩尔比30/10/1混合，将混合物放入高温炉中加热缓慢升温至约1400℃，恒温24小时后，将高温炉快速降温至室温得 到复合氟化磷酸钙F/α-TCP，粉碎至所需粒径(D50＝0.5μm)后，再快速升温至700℃并保温10分钟，以使F/α-TCP粒子的表面覆盖F/β-TCP外层，将高温炉骤冷至室温，得到具有F/α-TCP内核和F/β-TCP外壳的F/α-TCP@F/β-TCP核壳结构复合氟化磷酸钙材料。
该材料可以应用于牙齿再矿材料和自固化人工骨的研发。由于该材料具有相对惰性的F/β-TCP外壳，在水基牙膏中具有较高的稳定性，并且不与氟化物反应。刷牙时牙膏中的磨料去除F/β-TCP外壳，暴露出反应活性较高的F/α-TCP内核释放钙磷离子，在牙齿表面生成类似于牙釉质结构的羟基磷灰石，部分与释放的F离子结合形成更加耐酸的氟磷灰石FA，使牙釉质更加耐酸的腐蚀，预防龋齿作用更强。
实施例十：
制备β-TCP/CaSiO 3@α-TCP/CaSiO 3核壳结构复合磷硅酸钙材料：
将CaO、P 2O 5和SiO 2按照摩尔比3/1/1混合，将混合物放入高温炉中加热缓慢升温至约1000℃，恒温36小时后得到硅酸钙和β-磷酸三钙组成的复合磷硅酸钙β-TCP/CaSiO 3，将高温炉冷却至室温，粉碎至所需粒径后(D50＝20μm)，再快速升温至1300℃并保温10分钟，以使β-TCP/CaSiO 3粒子的表面覆盖α-TCP/CaSiO 3外层，将高温炉骤冷至室温，得到具有β-TCP/CaSiO 3内核和α-TCP/CaSiO 3外壳的β-TCP/CaSiO 3@α-TCP/CaSiO 3核壳结构复合磷硅酸钙材料。
由于硅酸钙可以掺杂进入磷酸钙形成类似于生物玻璃的磷硅酸钙，硅元素的掺杂改变磷酸钙离子键的键合，具有类似于生物玻璃中促进磷酸钙溶解和钙磷离子的释放速率，该材料用于口腔再矿化材料有助于钙磷离子的释放，外层溶解性更高的α-TCP/CaSiO 3有助于释放钙磷离子促进再矿化，内层的较稳定的β-TCP/CaSiO 3颗粒有助于稳定填充封堵牙本质小管，缓解牙齿冷热过敏，是结合牙齿再矿化和牙齿脱敏的理想材料。该材料还结合了磷酸钙生物 相容性与生物玻璃骨融合性能的优势，是固体人工骨和自固化人工骨理想材料。
实施例十一：
制备α-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5)@β-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5)核壳结构复合磷硅酸钙钾材料(生物玻璃)：
将CaCO 3、K 2HPO 4和SiO 2按照摩尔比3/2/1混合，将混合物放入高温炉中加热缓慢升温至约1600℃，恒温24小时后，将高温炉快速降温至室温得到复合磷硅酸钙钾α-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5)，粉碎至所需粒径(D50＝0.5μm)后，再快速升温至700℃并保温10分钟，以使α-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5)粒子的表面覆盖β-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5)外层，将高温炉骤冷至室温，得到具有α-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5)内核和β-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5)外壳的α-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5)@β-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5)核壳结构复合磷硅酸钙钾材料。
该材料可以应用于牙齿再矿材料和人工骨的研发。由于该材料具有相对惰性的β-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5)外壳，在水基牙膏中具有较高的稳定性，并且不与氟化物反应。刷牙时牙膏中的磨料去除β-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5))外壳，暴露出反应活性较高的α-(K 2O) 2(CaO) 3(SiO 2)(P 2O 5)内核释放钙磷离子，在牙齿表面生成类似于牙釉质结构的羟基磷灰石，使牙釉质结构得到保护，预防龋齿。
实施例十二：
制备TTCP/α-TCP复合磷酸钙材料：
将CaCO 3和P 2O 5按照摩尔比3.6/1混合，将混合物放入高温炉中快速升温至1500℃并保温36小时，将高温炉骤冷至室温，得到TTCP/α-TCP双相复合磷酸钙材料。
该材料可以应用于牙齿再矿材料和自固化人工骨的研发。由于α-TCP比 TTCP有更低的反应性和更低的碱性，使用TTCP/α-TCP复合磷酸钙材料的人工骨具有更为可控的较慢的硬化速率，并且硬化后骨材料表面更接近中性，具有更好的生物相容性，对细胞和组织的毒性更低。
实施例十三：
制备β-TCP/HA@α-TCP/HA核壳结构复合磷酸钙材料：
将Ca(NO 3) 2和CaHPO 4按照摩尔比11/20混合，将混合物放入高温炉中加热缓慢升温至约900℃，恒温36小时后，将高温炉冷却至室温，粉碎至所需粒径后(D50＝10μm)，再快速升温至1300℃并保温3分钟，以使β-TCP/HA粒子的表面覆盖α-TCP/HA外层，将高温炉骤冷至室温，得到具有β-TCP/HA内核和α-TCP/HA外壳的β-TCP/HA@α-TCP/HA核壳结构复合磷酸钙材料。
该材料可以应用于牙齿再矿材料、固体人工骨和自固化人工骨的研发
实施例十四：
制备K/α-TCP@K/β-TCP核壳结构复合磷酸钙材料：
将CaCO 3、(NH 4) 2HPO 4和KHCO 3按照摩尔比2.9/2/0.2混合，将混合物放入高温炉中加热缓慢升温至约1600℃，恒温12小时后，将高温炉快速降温至室温，粉碎至所需粒径(D50＝15μm)后，再快速升温至700℃并保温10分钟，以使K/α-TCP粒子的表面覆盖K/β-TCP外层，将高温炉骤冷至室温，得到具有K/α-TCP内核和K/β-TCP外壳的K/α-TCP@K/β-TCP核壳结构复合磷酸钙材料。
该材料可以应用于牙齿再矿材料和人工骨的研发，用于牙齿再矿化材料时，释放的钾离子有助于缓解牙齿的冷热过敏。

Claims (9)

  1. 具有核壳结构的新型复合磷酸钙活性材料，其特征在于：其组成为钙离子、磷酸根离子和其他非钙非磷的杂元素(离子)，其中钙磷(Ca/P)摩尔比为0.1-10，杂元素(离子)的质量分数在0.1％-50％。
  2. 根据权利要求1所述的具有核壳结构的新型复合磷酸钙活性材料，其特征在于：所述磷酸钙复合材料组成为磷酸二氢钙(MCP)、磷酸氢钙(DCPA)、α-磷酸三钙(α-TCP)、β-磷酸三钙(β-TCP)、无定形磷酸三钙(ACP)、四磷酸钙(TTCP)、氧化钙(CaO)、羟基磷灰石(HA)、缺钙磷灰石(CDHA)、氟磷灰石(FA)、氟化钙(CaF2)、八磷酸钙(OCP)、硅酸钙(CaSiO 3)等化合物中的至少两种，其中一种或几种组成复合材料的外壳，另一种或几种组成复合材料的内核。
  3. 根据权利要求1所述的具有核壳结构的新型复合磷酸钙活性材料，其特征在于：所选择的钙离子源为CaCO 3、Ca(NO 3) 2、Ca(OH) 2、CaO、CaSiO 3、CaF 2中的一种或几种，或者MCP、DCPA、α-TCP、β-TCP、ACP、TTCP、CaO、HA、CDHA、FA、OCP等磷酸钙中的一种或几种。
  4. 根据权利要求1所述的具有核壳结构的新型复合磷酸钙活性材料，其特征在于：所选择的磷酸根离子源为P 2O 5、(NH 4) 3PO 4、(NH 4) 2HPO 4、NH 4H 2PO4中的一种或几种，或者MCP、DCPA、α-TCP、β-TCP、ACP、TTCP、CaO、HA、CDHA、FA、OCP等磷酸钙中的一种或几种，或者Sr、K、Na、Mg、Zn、Fe的磷酸盐，包括其正盐、酸式盐、碱式盐。
  5. 根据权利要求1所述的具有核壳结构的新型复合磷酸钙活性材料，其特征在于：所述杂元素(离子)为Sr、K、Na、Mg、Zn、Fe、Si中的一种或几种。
  6. 根据权利要求所述的具有核壳结构的新型复合磷酸钙活性材料，其特征在于：所述杂元素(离子)加入复合磷酸钙中时所用的离子源可以是氢氧化物、氧化物、氟化物、碳酸盐、硝酸盐、磷酸盐或者它们的酸式盐、碱式 盐或者组合。
  7. 根据权利要求1所述的具有核壳结构的新型复合磷酸钙活性材料，其特征在于：所述新型复合磷酸钙活性材料最典型的为具有α-TCP内核和β-TCP外壳的α-TCP@β-TCP核壳结构材料以及具有β-TCP内核和α-TCP外壳的β-TCP@α-TCP核壳结构材料，所述新型复合磷酸钙活性材料可能的应用包括牙齿再矿化材料、人工骨材料等。
  8. 根据权利要求7所述的具有核壳结构的新型复合磷酸钙活性材料，其特征在于：所述的牙齿再矿化材料包括漱口水、牙膏、护牙素、氟保护漆、光固化树脂、粘接剂、脱敏剂等，所述的人工骨包括粉末状、颗粒状、块状等固体人工骨、或浆状、注射状人工骨。
  9. 具有核壳结构的新型复合磷酸钙活性材料的制备方法，包括β-TCP@α-TCP核壳结构磷酸钙复合材料的制备方法和α-TCP@β-TCP核壳结构磷酸钙复合材料的制备方法，其特征在于：
    α-TCP@β-TCP核壳结构磷酸钙复合材料的制备方法：
    (1).将含有钙磷离子源及杂元素化合物的混合物放入高温炉中加热升温至约1120-1900℃，恒温1-96小时后，然后降温至400-1100℃并保温1-300分钟，然后将高温炉冷至室温。
    (2).或者，将含有钙磷离子源及杂元素化合物的混合物放入高温炉中加热升温至约1120-1900℃，恒温1-96小时后，然后将高温炉降温至室温，将烧结材料粉碎至指定粒径范围(0.1-1000μm)后，再升温至400-1100℃并保温1-300分钟，然后再将高温炉冷至室温。
    β-TCP@α-TCP核壳结构磷酸钙复合材料的制备方法：
    (1).将含有钙磷离子源及杂元素化合物的混合物放入高温炉中加热升温至约400-1100℃，恒温1-96小时后，然后升温至1120-1900℃并保温1-300分钟，然后将高温炉冷至室温。
    (2).或者，将含有钙磷离子源及杂元素化合物的混合物放入高温炉中加热升温至约400-1100℃，恒温1-96小时后，然后将高温炉降温至室温，将烧结材料粉碎至指定粒径范围(0.1-1000μm)后，然后升温至1120-1800℃并保温1-300分钟，然后将高温炉冷至室温。
PCT/CN2020/081730 2020-03-27 2020-03-27 具有核壳结构的新型复合磷酸钙活性材料及其制备方法 WO2021189435A1 (zh)

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