Calcium carbonate / calcium phosphate composite hollow nanosphere as well as preparation method and application thereof

Abstract

The invention discloses a calcium carbonate / calcium phosphate composite hollow nanosphere as well as a preparation method and application thereof, the preparation method comprises the following steps: mixing an alcohol suspension of amorphous calcium carbonate nanospheres with an aqueous solution of phosphoric acid, pyrophosphoric acid, metaphosphoric acid, orthophosphate, pyrophosphate, metaphosphate, tripolyphosphate or phosphonic acid organic matters, reacting and centrifuging to obtain an amorphous calcium carbonate nanosphere solution; the calcium carbonate / calcium phosphate composite hollow nanospheres are obtained. The preparation method disclosed by the invention has the advantages of mild reaction conditions, simple preparation steps, high reaction speed and good large-scale production prospect, and the obtained calcium carbonate / calcium phosphate composite hollow nanospheres have the characteristics of uniform particle size, controllable size, good dispersity and high stability. The method has application prospects in the fields of rubber, plastics, papermaking, printing ink, coatings, daily chemical products, agricultural and biomedical materials and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of inorganic functional materials, and specifically relates to a calcium carbonate / calcium phosphate composite hollow nanosphere and a preparation method and application thereof. Background Art

[0002] Calcium carbonate and calcium phosphate are the most important mineral species in the biological world. They are widely present in nature and organisms. Calcium carbonate mainly exists in the form of limestone and calcite. Ultrafine calcium carbonate powder is currently the most widely used and largest type of ultrafine powder material. Due to its wide source, low price, non-toxic and tasteless characteristics, calcium carbonate has become one of the common fillers in plastics, rubber, coatings, inks and other materials; in addition, calcium carbonate is also often used in the field of biomedicine due to its biodegradability and good safety. At present, the main forms of ultrafine calcium carbonate powder include cubic, needle-shaped, spherical, and flake-shaped, but they are all solid materials. However, the density of solid calcium carbonate powder is relatively high. Adding it as a filler to materials such as rubber and ink will increase the overall density of the composite material, thereby increasing the economic cost of the material. In addition, compared with solid calcium carbonate, hollow structure calcium carbonate has significant advantages such as large specific surface area and internal cavity that can be loaded with drugs, and has good application prospects in the fields of adsorption separation and drug delivery. Therefore, the preparation of hollow structure nano calcium carbonate is one of the frontier research areas of materials science in recent years.

[0003] However, the preparation methods of hollow calcium carbonate nanospheres reported at home and abroad have disadvantages such as complex process flow, multiple additive components, harsh reaction conditions, poor particle size uniformity, and high economic cost.

[0004] Patent ZL202210820959.4 discloses a porous hollow calcium carbonate nanosphere, a preparation method and an application. It uses peroxide to regulate amorphous calcium carbonate to prepare porous hollow calcium carbonate nanospheres, but the hollow nanospheres prepared by this method are composed of a single calcium carbonate component, which is relatively unstable. Summary of the invention

[0005] In view of the technical problem that calcium carbonate hollow nanospheres in the prior art are unstable, the purpose of the present invention is to provide a calcium carbonate / calcium phosphate composite hollow nanosphere and a preparation method and application. The method is simple and fast, and the prepared calcium carbonate / calcium phosphate composite hollow nanospheres have a uniform hollow structure.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0007] A method for preparing calcium carbonate / calcium phosphate composite hollow nanospheres comprises the following steps:

[0008] The alcohol suspension of amorphous calcium carbonate nanospheres is mixed with an aqueous solution of phosphoric acid, pyrophosphate, metaphosphate, orthophosphate, pyrophosphate, metaphosphate, tripolyphosphate or phosphonic acid organic matter, and centrifuged after reaction to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0009] Furthermore, the alcohol is methanol, ethanol or propanol.

[0010] Furthermore, the orthophosphate, pyrophosphate, metaphosphate and tripolyphosphate are corresponding sodium salts, potassium salts or ammonium salts.

[0011] Further, the phosphonic acid organic compound is phytic acid, methylene diphosphonic acid, glycerophosphate, hydroxyethylidene diphosphonic acid, phosphorylcholine, alendronic acid, zoledronic acid, pamidronic acid, minodronic acid, etidronic acid, clodronic acid, risedronic acid, ibandronic acid, incadronic acid, neridronic acid, adenosine monophosphate, adenosine diphosphate, adenosine triphosphate, phytic acid sodium salt, methylene diphosphonic acid sodium salt, glycerophosphate sodium salt, hydroxyethylidene diphosphonic acid sodium salt, choline phosphate sodium salt, alendronate sodium salt, zoledronic acid sodium salt, pamidronate sodium salt, minodronic acid sodium salt, etidronic acid sodium salt, clodronate sodium salt, risedronate sodium salt, ibandronic acid sodium salt, incadronate sodium salt, neridronic acid sodium salt, adenosine monophosphate sodium salt, adenosine diphosphate sodium salt, adenosine triphosphate sodium salt, phosphoethanolamine, octylphosphonic acid, butylphosphonic acid, hexylphosphonic acid, aminomethylphosphonic acid or 2-aminoethylphosphonic acid.

[0012] Furthermore, the mass concentration of the amorphous calcium carbonate nanosphere alcohol suspension is 0.1% to 50%.

[0013] Furthermore, the mass concentration of the aqueous solution of phosphoric acid, pyrophosphate, metaphosphate, orthophosphate, pyrophosphate, metaphosphate, tripolyphosphate or phosphonic acid organic matter is 0.02% to 10%.

[0014] Furthermore, the volume ratio of the alcohol suspension to the aqueous solution is 1:40 to 10:1.

[0015] Furthermore, amorphous calcium carbonate nanospheres are prepared by the following process: placing an alcohol solution of calcium ions in a container with a plurality of pores, then placing the container in a dryer filled with ammonium carbonate and / or ammonium bicarbonate, allowing the reaction to stand at 20 degrees Celsius to 50 degrees Celsius for 6 hours to 5 days, and centrifuging to obtain amorphous calcium carbonate nanospheres.

[0016] Furthermore, the alcohol solution of calcium ions is a methanol, ethanol or propanol solution of calcium chloride, calcium chloride dihydrate, calcium nitrate or calcium nitrate tetrahydrate.

[0017] Furthermore, the concentration of the calcium ion in the alcohol solution is 0.2 mmol / L to 4 mol / L, and the mass of the ammonium carbonate, ammonium bicarbonate or the mixture of ammonium carbonate and ammonium bicarbonate is 1 g to 30 g.

[0018] Furthermore, the calcium carbonate nanospheres are amorphous and have a diameter of 10 nanometers to 1000 nanometers.

[0019] Furthermore, the centrifugal speed is 4000 rpm to 15000 rpm, and the centrifugal time is 5 minutes to 30 minutes.

[0020] A calcium carbonate / calcium phosphate composite hollow nanosphere has a hollow spherical structure, a particle size that can be adjusted within a range of 10 nanometers to 1000 nanometers, and a cavity of 2 nanometers to 900 nanometers.

[0021] The invention discloses a calcium carbonate / calcium phosphate composite hollow nanosphere for use in the fields of rubber, plastic, papermaking, ink, coating, daily chemical products, agriculture, biomedical materials and preparation of anti-tumor drugs.

[0022] Furthermore, the application of calcium carbonate / calcium phosphate composite hollow nanospheres in the field of biomedical materials, using disulfiram (DSF) as a model drug, evaluates the effect of calcium carbonate / calcium phosphate composite hollow nanospheres in delivering anticancer drugs to cancer cells. First, 2 ml of 30 mg / ml DSF dimethyl sulfoxide solution was mixed with 1 ml of 30 mg / ml calcium carbonate / calcium phosphate composite hollow nanosphere ethanol suspension, stirred for 3 hours, and centrifuged to obtain porous hollow calcium carbonate nanospheres loaded with disulfiram.

[0023] Furthermore, the anti-tumor drug is an anti-breast cancer drug

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The present invention can prepare calcium carbonate / calcium phosphate composite hollow nanospheres by simply mixing an alcohol suspension of amorphous calcium carbonate nanospheres and phosphoric acid, pyrophosphoric acid, metaphosphoric acid or its inorganic salt or phosphonic acid organic aqueous solution. The volume of the nanosphere cavity can be effectively controlled by regulating the volume ratio of ethanol and water. The invention has the advantages of mild reaction conditions, simple preparation steps, fast reaction speed and good prospects for large-scale production. The obtained calcium carbonate / calcium phosphate composite hollow nanospheres have the characteristics of uniform particle size, controllable size, good dispersibility and amorphous crystal structure. At room temperature, the solubility of calcium carbonate is 0.0065 grams, while the solubility of calcium phosphate is 0.0025 grams. Compared with single calcium carbonate, the calcium carbonate / calcium phosphate composite hollow nanospheres have lower solubility and better stability and biocompatibility. The composite microspheres will greatly broaden the application scope of calcium carbonate, making it have broad application prospects in many fields such as rubber, plastics, papermaking, ink, coatings, daily chemicals, agriculture and biomedical materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1is a transmission electron microscope photograph of the amorphous calcium carbonate nanospheres synthesized in Example 1; wherein A is a low-magnification transmission electron microscope photograph, and B is a high-magnification transmission electron microscope photograph;

[0027] Figure 2 1 is a transmission electron microscope photograph of the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 1; wherein A is a low-magnification transmission electron microscope photograph, and B is a high-magnification transmission electron microscope photograph;

[0028] Figure 3 1 is an element distribution diagram of the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 1; wherein (a) is a high-angle annular dark field image of a scanning transmission electron microscope, (b) represents the distribution of calcium (Ca) elements, (c) represents the distribution of oxygen (O) elements, and (d) represents the distribution of phosphorus (P) elements;

[0029] Figure 4 is a scanning electron microscope image of the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 1;

[0030] Figure 5 is an infrared spectra of amorphous calcium carbonate and calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 1; wherein a represents amorphous calcium carbonate, and b represents calcium carbonate / calcium phosphate composite hollow nanospheres;

[0031] Figure 6 : is the thermogravimetric curve of amorphous calcium carbonate and calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 1; wherein a represents amorphous calcium carbonate, and b represents calcium carbonate / calcium phosphate composite hollow nanospheres;

[0032] Figure 7 is the X-ray diffraction spectrum of the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 1;

[0033] Figure 8 This is a fluorescent picture of live-dead staining of 4T1 cells after the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 1 were loaded with disulfiram and co-cultured with mouse breast cancer 4T1 cells for 24 hours;

[0034] Fig. 9 is a transmission electron microscope photograph of the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 2;

[0035] Fig.10 is a transmission electron microscope photograph of the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 3;

[0036] Fig.11 is a transmission electron microscope photograph of the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 4;

[0037] Fig.12 is a transmission electron microscope photograph of the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 5;

[0038] Fig.13 is a transmission electron microscope photograph of the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 6;

[0039] Fig.14 is a transmission electron microscope photograph of the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 7;

[0040] Fig.15 This is a transmission electron microscope photograph of the calcium carbonate / calcium phosphate composite hollow nanospheres synthesized in Example 8. DETAILED DESCRIPTION

[0041] In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. The preferred embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thoroughly and comprehensively understood.

[0042] Calcium phosphate is the main inorganic component of vertebrate bones and teeth. Its good biocompatibility and bioactivity make it widely used in bone replacement, tooth filling, drug delivery and medical imaging. Calcium phosphate is also an important industrial raw material and is widely used in various fields such as fertilizers, glass, ceramics, and food additives. Using calcium phosphate to dope calcium carbonate will greatly improve the stability of calcium carbonate, give calcium carbonate better biocompatibility and multiple functions such as bone induction, thereby greatly broadening the application range of calcium carbonate.

[0043] A method for preparing calcium carbonate / calcium phosphate composite hollow nanospheres of the present invention comprises the following steps:

[0044] (1) placing an alcohol solution of calcium ions in a container with a plurality of pores, then placing the container in a dryer filled with ammonium carbonate and / or ammonium bicarbonate, allowing the reaction to stand at 20°C to 50°C for 6 hours to 5 days, and centrifuging the reaction solution to obtain amorphous calcium carbonate nanospheres.

[0045] (2) mixing an alcohol suspension of amorphous calcium carbonate nanospheres with an aqueous solution of phosphoric acid, pyrophosphoric acid, metaphosphoric acid or its inorganic salt or phosphonic acid organic matter, reacting for 5 minutes to 12 hours, and then centrifuging to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0046] The alcohol solution of calcium ions in step (1) is a methanol, ethanol or propanol solution of calcium chloride, calcium chloride dihydrate, calcium nitrate or calcium nitrate tetrahydrate, the concentration of the calcium ions in the alcohol solution is 0.2 mmol / L to 4 mol / L, and the mass of the ammonium carbonate, ammonium bicarbonate or the mixture of ammonium carbonate and ammonium bicarbonate is 1 g to 30 g.

[0047] The calcium carbonate nanospheres described in step (1) are amorphous in shape and have a diameter of 10 to 1000 nanometers.

[0048] The alcohol in step (2) is methanol, ethanol or propanol.

[0049] The orthophosphate, pyrophosphate, metaphosphate and tripolyphosphate described in step (2) are corresponding sodium salts, potassium salts or ammonium salts, and the phosphonic acid organic compound is phytic acid, methylene diphosphonic acid, glycerophosphoric acid, hydroxyethylidene diphosphonic acid, phosphoric acid choline, alendronic acid, zoledronic acid, pamidronic acid, minodronic acid, etidronic acid, clodronic acid, risedronic acid, ibandronic acid, incadronic acid, neridronic acid, adenosine monophosphate, adenosine diphosphate, adenosine triphosphate and their sodium salts, as well as phosphoethanolamine, octylphosphonic acid, butylphosphonic acid, hexylphosphonic acid, aminomethylphosphonic acid or 2-aminoethylphosphonic acid.

[0050] The mass concentration of the amorphous calcium carbonate nanosphere alcohol suspension in step (2) is 0.1% to 50%, the mass concentration of the aqueous solution of phosphoric acid, pyrophosphate, metaphosphate, orthophosphate, pyrophosphate, metaphosphate, tripolyphosphate or phosphonic acid organic matter is 0.02% to 10%, and the volume ratio of the alcohol suspension to the aqueous solution is 1:40 to 10:1.

[0051] The centrifugal speed in steps (1) and (2) is 4000 rpm to 15000 rpm, and the centrifugal time is 5 minutes to 30 minutes.

[0052] The calcium carbonate / calcium phosphate composite hollow nanospheres obtained by the above method have a hollow spherical structure, a particle size that can be adjusted within the range of 10 nanometers to 1000 nanometers, a cavity size of 2 nanometers to 900 nanometers, good dispersibility, and can be used in rubber, plastics, papermaking, ink, coatings, daily chemical products, agriculture or biomedical materials and other fields.

[0053] The following are specific embodiments.

[0054] Example 1

[0055] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 10 g of ammonium bicarbonate, and allowed to react at 40 degrees Celsius for 48 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0056] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.5% and 80 ml of an aqueous sodium phosphate solution with a mass concentration of 0.1% were mixed, reacted for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0057] from Figure 1 As can be seen from A and B in the figure, the prepared amorphous calcium carbonate is spherical, has good dispersibility, and has a particle size of about 105 nanometers.

[0058] from Figure 2 As can be seen from A and B in the figure, the prepared calcium carbonate / calcium phosphate composite hollow nanospheres have a spherical hollow structure, good dispersibility, a particle size of about 108 nanometers, and a cavity diameter of about 90 nanometers.

[0059] from Figure 3 As can be seen from (a), (b), (c), (d) and (e), the elements calcium, oxygen and phosphorus are evenly distributed in the nanospheres, indicating that calcium carbonate / calcium phosphate composite hollow nanospheres were successfully prepared.

[0060] from Figure 4 It can be seen that the prepared calcium carbonate / calcium phosphate composite hollow nanospheres have good dispersibility and small pores are distributed on the surface.

[0061] from Figure 5 It can be seen that the characteristic peak of PO vibration (1046cm -1 and 574cm -1 ) and the characteristic peak of CO vibration (1494cm -1 , 1405cm -1 and 876cm -1 ), proving the existence of calcium phosphate and calcium carbonate.

[0062] according to Figure 6 It can be calculated that the mass contents of calcium phosphate and calcium carbonate in the calcium carbonate / calcium phosphate composite hollow nanospheres are 24% and 76%, respectively.

[0063] from Figure 7 It can be seen that the prepared calcium carbonate / calcium phosphate composite hollow nanospheres are amorphous in crystal form.

[0064] Disulfiram (DSF) was used as a model drug to evaluate the effect of calcium carbonate / calcium phosphate composite hollow nanospheres in delivering anticancer drugs to cancer cells. First, 2 ml of 30 mg / ml DSF dimethyl sulfoxide solution was mixed with 1 ml of 30 mg / ml calcium carbonate / calcium phosphate composite hollow nanosphere ethanol suspension. After stirring for 3 hours, the porous hollow calcium carbonate nanospheres loaded with DSF were obtained by centrifugation. Subsequently, the live-dead cell staining method was used to evaluate the killing ability of mouse breast cancer 4T1 cells. 4T1 cells were cultured at 1×10 5 The cells were inoculated at a density of 10 cells / dish on a laser confocal culture dish. After conventional culture for 24 hours, nanospheres were added to the dish and cultured for another 24 hours. The cells were then stained with a live-dead cell staining kit and observed under a fluorescence microscope. The cells without drug addition were used as the control group.

[0065] from Figure 8 It can be seen that compared with the control group, the breast cancer 4T1 cells in the experimental group of mice shrank and the number of dead cells increased, proving that it has application potential in the field of tumor treatment. Specifically, it can be used in the preparation of anti-tumor drugs, and the anti-tumor drugs are anti-breast cancer drugs.

[0066] Example 2

[0067] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 10 g of ammonium bicarbonate, and allowed to react at 40 degrees Celsius for 48 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0068] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.5% and 80 ml of a sodium phosphate aqueous solution with a mass concentration of 0.5% were mixed, reacted for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0069] from Fig. 9 It can be seen that the prepared calcium carbonate / calcium phosphate composite hollow nanospheres have a spherical hollow structure and good dispersibility.

[0070] Example 3

[0071] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 10 g of ammonium bicarbonate, and allowed to react at 40 degrees Celsius for 48 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0072] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.5% and 40 ml of an aqueous sodium phosphate solution with a mass concentration of 0.1% were mixed, reacted for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0073] from Fig.10 It can be seen that the prepared calcium carbonate / calcium phosphate composite hollow nanospheres have a spherical hollow structure and good dispersibility.

[0074] Example 4

[0075] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 10 g of ammonium bicarbonate, and allowed to react at 40 degrees Celsius for 48 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0076] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.5% and 400 ml of a sodium phosphate aqueous solution with a mass concentration of 0.1% were mixed, reacted for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0077] from Fig.11 It can be seen that the prepared calcium carbonate / calcium phosphate composite hollow nanospheres have a spherical hollow structure and good dispersibility.

[0078] Example 5

[0079] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 10 g of ammonium bicarbonate, and allowed to react at 40 degrees Celsius for 48 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0080] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.5% and 80 ml of a sodium dihydrogen phosphate aqueous solution with a mass concentration of 0.1% were mixed, reacted for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0081] from Fig.12 It can be seen that the prepared calcium carbonate / calcium phosphate composite hollow nanospheres have a spherical hollow structure and good dispersibility.

[0082] Example 6

[0083] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 10 g of ammonium bicarbonate, and allowed to react at 40 degrees Celsius for 48 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0084] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.5% and 80 ml of an aqueous solution of sodium tripolyphosphate with a mass concentration of 0.1% were mixed, reacted for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0085] from Fig.13 It can be seen that the prepared calcium carbonate / calcium phosphate composite hollow nanospheres have a spherical hollow structure and good dispersibility.

[0086] Example 7

[0087] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 10 g of ammonium bicarbonate, and allowed to react at 40 degrees Celsius for 48 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0088] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.5% and 80 ml of an aqueous phosphoric acid solution with a mass concentration of 0.03% were mixed, reacted for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0089] from Fig.14 It can be seen that the prepared calcium carbonate / calcium phosphate composite hollow nanospheres have a spherical hollow structure and good dispersibility.

[0090] Example 8

[0091] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 10 g of ammonium bicarbonate, and allowed to react at 40 degrees Celsius for 48 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0092] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.5% and 100 ml of an aqueous solution of alendronic acid with a mass concentration of 0.1% were mixed, reacted for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0093] from Fig.15It can be seen that the prepared calcium carbonate / calcium phosphate composite hollow nanospheres have a spherical hollow structure and good dispersibility.

[0094] Example 9

[0095] (1) A 0.02 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 10 g of ammonium bicarbonate, and allowed to react at 40 degrees Celsius for 48 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0096] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.5% and 100 ml of an aqueous sodium phosphate solution with a mass concentration of 0.1% were mixed, reacted for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0097] Example 10

[0098] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 15 g of ammonium bicarbonate, and allowed to react at 40 degrees Celsius for 24 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0099] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.5% and 100 ml of an aqueous sodium phosphate solution with a mass concentration of 0.1% were mixed, reacted for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0100] Embodiment 11

[0101] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 15 g of ammonium bicarbonate, and allowed to react at 40 degrees Celsius for 24 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0102] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.5% and 100 ml of a 0.1% pamidronate aqueous solution were mixed, reacted for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0103] Example 12

[0104] (1) A 0.01 mol / L calcium chloride ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator containing 1 gram of ammonium carbonate, and allowed to react at 20 degrees Celsius for 6 hours, and then centrifuged at 4000 rpm for 30 minutes to obtain amorphous calcium carbonate nanospheres.

[0105] (2) 1 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 0.1% and 40 ml of an aqueous sodium phosphate solution with a mass concentration of 0.02% were mixed, reacted for 5 minutes, and then centrifuged at 4000 rpm for 20 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0106] Embodiment 13

[0107] (1) A methanol solution of calcium nitrate with a concentration of 0.01 mol / L is placed in a container with a plurality of pores, and then the container is placed in a desiccator containing 5 g of ammonium bicarbonate, and allowed to react at 30 degrees Celsius for 48 hours, and then centrifuged at 15,000 rpm for 5 minutes to obtain amorphous calcium carbonate nanospheres.

[0108] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 1% and 1 ml of a sodium phosphate aqueous solution with a mass concentration of 0.1% were mixed, reacted for 12 hours, and then centrifuged at 10,000 rpm for 20 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0109] Embodiment 14

[0110] (1) A propanol solution of calcium nitrate tetrahydrate with a concentration of 0.01 mol / L is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 15 g of ammonium bicarbonate and 15 g of ammonium carbonate, and allowed to react at 40 degrees Celsius for 120 hours, and then centrifuged at 6000 rpm for 15 minutes to obtain amorphous calcium carbonate nanospheres.

[0111] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 10% and 200 ml of an aqueous sodium phosphate solution with a mass concentration of 1% were mixed, reacted for 1 hour, and then centrifuged at 8000 rpm for 20 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0112] Embodiment 15

[0113] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 20 g of ammonium bicarbonate, and allowed to react at 50 degrees Celsius for 80 hours, and then centrifuged at 8000 rpm for 15 minutes to obtain amorphous calcium carbonate nanospheres.

[0114] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 50% and 10 ml of a sodium phosphate aqueous solution with a mass concentration of 5% were mixed, reacted for 5 hours, and then centrifuged at 12,000 rpm for 5 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0115] Example 16

[0116] (1) A 0.01 mol / L calcium chloride dihydrate ethanol solution is placed in a container with a plurality of pores, and then the container is placed in a desiccator filled with 10 g of ammonium bicarbonate, and allowed to react at 35 degrees Celsius for 50 hours, and then centrifuged at 10,000 rpm for 10 minutes to obtain amorphous calcium carbonate nanospheres.

[0117] (2) 10 ml of an ethanol suspension of amorphous calcium carbonate nanospheres with a mass concentration of 30% and 2 ml of a sodium phosphate aqueous solution with a mass concentration of 10% were mixed, reacted for 8 hours, and then centrifuged at 8000 rpm for 10 minutes to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

[0118] The phosphonic acid organic compound in the present invention is phytic acid, methylene diphosphonic acid, glycerophosphate, hydroxyethylidene diphosphonic acid, choline phosphate, alendronic acid, zoledronic acid, pamidronic acid, minodronic acid, etidronic acid, clodronic acid, risedronic acid, ibandronic acid, incadronic acid, neridronic acid, adenosine monophosphate, adenosine diphosphate, adenosine triphosphate, phytic acid sodium salt, methylene diphosphonic acid sodium salt, glycerophosphate sodium salt, hydroxyethylidene diphosphonic acid sodium salt, choline phosphate sodium salt ... Phosphonic acid sodium salt, zoledronic acid sodium salt, pamidronate sodium salt, minodronic acid sodium salt, etidronic acid sodium salt, clodronate sodium salt, risedronate sodium salt, ibandronic acid sodium salt, incadronate sodium salt, neridronic acid sodium salt, adenosine monophosphate sodium salt, adenosine diphosphate sodium salt, adenosine triphosphate sodium salt, phosphoethanolamine, octylphosphonic acid, butylphosphonic acid, hexylphosphonic acid, aminomethylphosphonic acid or 2-aminoethylphosphonic acid can all be used to prepare calcium carbonate / calcium phosphate composite hollow nanospheres.

[0119] The above description is only for the best embodiment of the present invention, but it should not be understood as limiting the claims. The present invention is not limited to the above embodiments, and its specific structure is allowed to be changed. However, all changes made within the protection scope of the independent claims of the present invention are within the protection scope of the present invention.

[0120] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

Claims

1. A method for preparing calcium carbonate / calcium phosphate composite hollow nanospheres, characterized in that: The following steps are involved: The alcohol suspension of amorphous calcium carbonate nanospheres is mixed with an aqueous solution of phosphoric acid, pyrophosphate, metaphosphate, orthophosphate, pyrophosphate, metaphosphate, tripolyphosphate or phosphonic acid organic matter, and centrifuged after reaction to obtain calcium carbonate / calcium phosphate composite hollow nanospheres.

2. The method for preparing calcium carbonate / calcium phosphate composite hollow nanospheres according to claim 1, characterized in that: The alcohol is methanol, ethanol or propanol.

3. The method for preparing calcium carbonate / calcium phosphate composite hollow nanospheres according to claim 1, characterized in that: The orthophosphate, pyrophosphate, metaphosphate and tripolyphosphate are corresponding sodium salts, potassium salts or ammonium salts.

4. The method for preparing calcium carbonate / calcium phosphate composite hollow nanospheres according to claim 1, characterized in that: Phosphonic acid organic substances are phytic acid, methylene diphosphonic acid, glycerophosphate, hydroxyethylidene diphosphonic acid, phosphoric acid choline, alendronic acid, zoledronic acid, pamidronic acid, minodronic acid, etidronic acid, clodronic acid, risedronic acid, ibandronic acid, incadronic acid, neridronic acid, adenosine monophosphate, adenosine diphosphate, adenosine triphosphate, phytic acid sodium salt, methylene diphosphonic acid sodium salt, glycerophosphate sodium salt, hydroxyethylidene diphosphonic acid sodium salt, Phosphocholine sodium salt, alendronate sodium salt, zoledronic acid sodium salt, pamidronate sodium salt, minodronic acid sodium salt, etidronic acid sodium salt, clodronate sodium salt, risedronate sodium salt, ibandronic acid sodium salt, incadronate sodium salt, neridronic acid sodium salt, adenosine monophosphate sodium salt, adenosine diphosphate sodium salt, adenosine triphosphate sodium salt, phosphoethanolamine, octylphosphonic acid, butylphosphonic acid, hexylphosphonic acid, aminomethylphosphonic acid or 2-aminoethylphosphonic acid.

5. The method for preparing calcium carbonate / calcium phosphate composite hollow nanospheres according to claim 1, characterized in that: The mass concentration of the amorphous calcium carbonate nanosphere alcohol suspension is 0.1% to 50%.

6. The method for preparing calcium carbonate / calcium phosphate composite hollow nanospheres according to claim 1, characterized in that: The mass concentration of the aqueous solution of phosphoric acid, pyrophosphate, metaphosphate, orthophosphate, pyrophosphate, metaphosphate, tripolyphosphate or phosphonic acid organic matter is 0.02% to 10%.

7. The method for preparing calcium carbonate / calcium phosphate composite hollow nanospheres according to claim 1, characterized in that: The volume ratio of the alcohol suspension to the aqueous solution is 1:40 to 10:

1.

8. The method for preparing calcium carbonate / calcium phosphate composite hollow nanospheres according to claim 1, characterized in that: Amorphous calcium carbonate nanospheres are prepared by the following process: placing an alcohol solution of calcium ions in a container with a plurality of pores, then placing the container in a dryer filled with ammonium carbonate and / or ammonium bicarbonate, allowing the reaction to stand at 20 degrees Celsius to 50 degrees Celsius for 6 hours to 5 days, and centrifuging to obtain amorphous calcium carbonate nanospheres.

9. A calcium carbonate / calcium phosphate composite hollow nanosphere prepared according to the method according to any one of claims 1 to 8, characterized in that: The nanosphere has a hollow spherical structure, the particle size can be adjusted within the range of 10 nanometers to 1000 nanometers, and the cavity is 2 nanometers to 900 nanometers.

10. Use of calcium carbonate / calcium phosphate composite hollow nanospheres prepared by the method according to any one of claims 1 to 8 in the fields of rubber, plastics, papermaking, ink, coatings, daily chemicals, agriculture, biomedical materials, and preparation of anti-tumor drugs.

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