CN113350510A

CN113350510A - Amorphous nano calcium carbonate capable of stably existing and preparation method and application thereof

Info

Publication number: CN113350510A
Application number: CN202110510315.0A
Authority: CN
Inventors: 洪海龙; 许丹; 竺宁; 韩利民
Original assignee: Inner Mongolia University of Technology
Current assignee: Inner Mongolia University of Technology
Priority date: 2021-05-11
Filing date: 2021-05-11
Publication date: 2021-09-07
Anticipated expiration: 2041-05-11
Also published as: CN113350510B

Abstract

The invention relates to a preparation method of amorphous nano calcium carbonate capable of stably existing, which comprises the following steps: s1: reacting Ca (OH)₂Polyvinylpyrrolidone and CO₂Carrying out carbonization reaction in liquid alcohol to prepare alcohol suspension containing amorphous calcium carbonate; s2: centrifuging the alcohol suspension, and taking supernatant to obtain a colloidal solution containing amorphous calcium carbonate; s3: drying the colloidal solution to obtain amorphous nano calcium carbonate ACC-doped agent with stable polyvinylpyrrolidonePVP. The invention adopts a carbonization method, and a proper amount of PVP (polyvinyl pyrrolidone) can prepare and obtain stable amorphous nano calcium carbonate under the condition of liquid alcohol, the product can continuously and stably exist in an amorphous shape, and has small particle size (only about 10 nm) and large specific surface area (as high as 334 m)².g^‑1) And the solubility is high, and the like, and the drug delivery carrier is good.

Description

Amorphous nano calcium carbonate capable of stably existing and preparation method and application thereof

Technical Field

The invention relates to the technical field of preparation of nano calcium carbonate for a drug carrier, in particular to amorphous nano calcium carbonate capable of stably existing and a preparation method and application thereof.

Background

Calcium carbonate is used as an important inorganic chemical product, is widely applied to the fields of papermaking, coatings, plastics, printing ink, medicines and the like, plays the role of a filler and a modifier, can increase the volume of the product, reduce the cost, improve the surface glossiness of the product and improve the comprehensive performance of the product. In recent years, research on nano calcium carbonate has been advanced, the preparation of nano calcium carbonate is continuously refined, the yield is continuously improved, but the problems of large calcium carbonate particle size, poor dispersibility, unstable morphology and properties and the like still exist, and the nano calcium carbonate can not meet the increasing market demand. Therefore, the preparation of the nano calcium carbonate product with small particle size, stable performance and high grade, the application performance and the added value of the nano calcium carbonate product are improved, and the preparation method is still a hot point of research in the industry.

Calcium carbonate has three anhydrous crystal forms, three hydrated metastable states and an Amorphous Calcium Carbonate (ACC) phase. Compared with other calcium carbonates, the ACC has the advantages of small particles, large specific surface area, high solubility, good biocompatibility and the like, so that the ACC has excellent performances in the aspects of improving the bioavailability of the medicine and overcoming the biological barrier in vivo. However, ACC is highly unstable and is easily converted to crystalline calcium carbonate such as vaterite, aragonite or calcite under different conditions. Therefore, it is very important to control the synthesis of stable ACC.

In the prior art disclosed at present, some methods for preparing micro-nano calcium carbonate are also mentioned, and mainly relate to a double decomposition method, namely a water-soluble calcium salt and carbonate are reacted under proper process conditions (usually in an aqueous solution) to prepare a calcium carbonate product, so that micro-nano crystalline calcium carbonate can be easily obtained. If the method is adopted to prepare the ACC product, on one hand, the problem of great control difficulty exists, and a great amount of chloride ions are adsorbed on the surface of the ACC product in the process of forming calcium carbonate, so that a great amount of time is needed for washing, and the purity of the ACC product cannot be guaranteed. In addition, most of the studies related to the preparation of stabilized ACC at present have introduced additives to retard the crystallization of ACC, and commonly used additives are magnesium ions, phosphate ions, polymers, highly carboxylated substances, silica, and the like. The presence of these additives, while serving to stabilize ACC, also limits their use in certain applications, such as the pharmaceutical industry.

In view of the above, it is desirable to provide a novel method for the preparation of stable ACC suitable for use in the pharmaceutical industry.

Disclosure of Invention

Technical problem to be solved

In view of the above disadvantages and shortcomings of the prior art, the present invention provides a method for preparing amorphous nano calcium carbonate that can exist stably, which solves the technical problem that it is difficult to prepare stable ACC products or stable ACC products cannot be used for pharmaceutical carriers in the prior art.

In addition, the invention also provides the amorphous nano calcium carbonate prepared by the preparation method and the drug composite particles containing the amorphous nano calcium carbonate.

(II) technical scheme

In order to achieve the purpose, the invention adopts the main technical scheme that:

in a first aspect, the present invention provides a method for preparing amorphous nano calcium carbonate capable of stably existing, which comprises the following steps:

s1: reacting Ca (OH)₂Polyvinylpyrrolidone and CO₂Carrying out carbonization reaction in liquid alcohol to prepare alcohol suspension containing amorphous calcium carbonate;

s2: centrifuging the alcohol suspension of S1, and taking supernatant to obtain a colloidal solution containing amorphous calcium carbonate;

s3: and drying the colloidal solution to obtain amorphous nano calcium carbonate ACC-PVP with stable polyvinylpyrrolidone.

Preferably, in S1, the liquid alcohol is methanol. When the reaction solvent is replaced by dichloromethane, petroleum ether, ethyl acetate or water, amorphous nano calcium carbonate ACC cannot be synthesized in the solvent, and only extremely low content of ACC can be obtained in ethanol and propanol, so methanol is preferred as the reaction solvent.

Preferably, in S1, the carbonization reaction temperature is 20-60 ℃. Above 60 c, the methanol is rapidly vaporized, causing precipitation of crystalline calcium carbonate, which significantly reduces the yield of ACC. The temperature lower than 20 ℃ slows down the reaction rate and the yield of ACC is significantly reduced.

Preferably, in S1, the carbonization reaction is performed under the stirring condition of a stirrer, and the stirring speed of the stirrer is 200-600 r/min. When the rotation speed is too low, stirring is not uniform, and the yield of ACC decreases significantly. When the rotating speed is too high, the energy consumption is large, and the method is not economical.

Preferably, in S1, Ca (OH) is firstly₂Uniformly dispersing polyvinylpyrrolidone in liquid alcohol to obtain a reaction solution, and introducing CO under the stirring condition₂And carrying out carbonization reaction.

Preferably, in S1, Ca (OH)₂：CO₂: the molar ratio of PVP is 1: (1-3): (3.8*10^-5～7.6*10^-4)。

The PVP used in the preferred embodiment of the invention is PVP-K30 (relative molecular weight approximately 40000). PVP to Ca (OH)₂When the amount is too low, the effect of stabilizing ACC cannot be achieved, and when the addition amount of PVP is too high, the specific surface area of the ACC product is obviously reduced.

Preferably, in S1, the carbonization reaction time is 1-4 h. Preferably, in S2, the centrifugal rotation speed is 6000 to 8000r/min, and the centrifugal time is 8 to 15min, preferably 10 min.

Preferably, in S3, the drying temperature is 140-155 ℃, and the drying time is 2-6 h.

In a second aspect, the present invention provides a polyvinylpyrrolidone-stabilized amorphous nano calcium carbonate (ACC-PVP) prepared by the method of any one of the above embodiments.

The amorphous nano calcium carbonate stabilized by the polyvinylpyrrolidone has special purposes in the aspects of improving the pH responsiveness of the drug, improving the release of the insoluble drug in the gastric juice environment and the like, and can be used as a promising drug carrier of the pH responsiveness and the insoluble drug. pH responsiveness refers to the sensitivity of drug release to changes in environmental pH.

In a third aspect, the present invention also provides a method for preparing a carrier drug containing ACC-PVP, comprising the steps of:

step 1: reacting Ca (OH)₂Polyvinylpyrrolidone and CO₂Carrying out carbonization reaction in liquid alcohol to prepare alcohol suspension containing amorphous calcium carbonate;

step 2: centrifuging the alcohol suspension obtained in the step 1, and taking supernatant to obtain a colloidal solution containing amorphous calcium carbonate;

and step 3: and (3) adding the pharmacodynamic ingredients to be dispersed into the colloidal solution obtained in the step (2), dissolving the pharmacodynamic ingredients, and drying to obtain the ACC-PVP loaded drug composite particles.

Preferably, the pharmacodynamic ingredient is fluorouracil (5-FU) or Curcumin (CUR), and the prepared drug composite particles are 5-FU @ AC-PVP particles or CUR @ AC-PVP particles correspondingly.

Preferably, the drug loading of the 5-FU @ ACC-PVP particles is 26-30%; the drug loading of the CUR @ ACC-PVP particles is 4-6%.

Preferably, in the step 3, the drying temperature is 145-155 ℃ (preferably 150 ℃), and the drying time is 2-6 h.

Preferably, the method further comprises the step 4: further preparing the drug composite particles loaded by ACC-PVP obtained in the step 3 into oral preparations, including but not limited to tablets, capsules or granules. For example, the 5-FU @ ACC-PVP granules and the CUR @ ACC-PVP granules are further tableted into tablets, or added with auxiliary materials to be filled into capsules or granules.

(III) advantageous effects

The invention has the technical effects that:

(1) the invention adopts a carbonization method to convert CO gas into CO gas₂The method for preparing ACC by diffusing the ACC into calcium salt or calcium hydroxide solution has the advantages of simple operation, rich raw materials, easy industrial production and the like. In the preparation of ACC, polyvinylpyrrolidone (PVP) is used to disperse Ca (OH) in liquid alcohol, in particular methanol₂Then introducing CO₂And carrying out carbonization reaction to prepare nanometer calcium carbonate (ACC-PVP) with stable polyvinylpyrrolidone. Generally, amorphous calcium carbonate is unstable and can be easily converted into vaterite, calcite and aragonite crystal forms and the like, and the method can obtain stable amorphous nano calcium carbonate which can continuously and stably exist in amorphous shapes.

(2) The amorphous nano calcium carbonate prepared by the invention has small particle size (only about 10 nm) and large specific surface area (as high as 334 m)².g^-1) And the drug delivery carrier has the advantages of high solubility (sensitive pH responsiveness or release property after drug loading), and the like, and is a good drug delivery carrier. The PVP contained in the compound is also a synthetic water-soluble high molecular compound, has excellent physiological inertia of the PVP, does not participate in human metabolism, has excellent biocompatibility, does not form any stimulation to skin, mucous membrane, eyes and the like, and is one of three main medicinal auxiliary materials advocated internationally, so that the PVP is remained in the product and does not influence the application of the amorphous nano calcium carbonate as a medicament carrier.

(3) The 5-FU @ ACC-PVP particle prepared by the invention shows good pH responsiveness, and the CUR @ ACC-PVP particle shows good drug release in a simulated gastric juice environment.

The preparation process of the ACC-PVP is simple in process and low in cost, the preparation process is green and environment-friendly, the method has the characteristics of short production period, simple process, resource saving, environmental friendliness and low cost, the experimental operation process is simple and controllable, industrial production is easy to realize, and the method has a good application prospect.

Drawings

Fig. 1 is FE-SEM and TEM images (electron diffraction (ED) images taken from the circle of the C image) of the polyvinylpyrrolidone-assisted synthesized stable amorphous nano calcium carbonate prepared in example 1.

FIG. 2 is FT-IR, XRD patterns of the stabilized amorphous nano calcium carbonate synthesized with the assistance of polyvinylpyrrolidone prepared in examples 1-4.

FIG. 3 shows the N of the stable amorphous nano calcium carbonate synthesized by polyvinylpyrrolidone in the assisted manner in examples 1-4₂Adsorption/desorption isotherms and pore size profiles.

FIG. 4 is a graph of the cumulative release of 5-FU @ ACC-PVP particles 5-FU @ ACC-PVP prepared in example 5 in 0.02M phosphate buffer (pH7.4, 6.6, 5.5) and the cumulative release of CUR @ ACC-PVP prepared in example 6 in simulated gastric fluid (pH1.2 with 0.05% SDS).

Fig. 5 is an SEM image of the crystalline calcium carbonate prepared in comparative example 1.

Fig. 6 is an XRD pattern of the crystalline calcium carbonate prepared in comparative example 1.

Detailed Description

For the purpose of better explaining the present invention and to facilitate understanding, the present invention will be described in detail by way of specific embodiments with reference to the accompanying drawings.

Example 1

Measuring 40mL of methanol by using a measuring cylinder, adding the methanol into a 50mL reaction kettle, then placing the reaction kettle into a magnetic stirrer, adjusting the temperature and the rotating speed of the magnetic stirrer to be 50 ℃ and 600r/min respectively, and adding 500mgCa (OH) accurately weighed under full stirring₂And 10mg of PVP, the reaction kettle is sealed, and 0.4MPa of CO is charged₂(Ca(OH)₂：CO₂: PVP molar ratio 0.9: 1: 3.3*10^-5) Carbonizing for 1h, releasing the pressure of the reaction kettle, and finishing the reaction. The obtained reaction solution was put in 8000rmin^-1Centrifuging for 10min, taking the supernatant after centrifuging, placing the supernatant into a 100ml round-bottom flask, removing a large amount of methanol solvent by rotary evaporation with a rotary evaporator, and finally placing the obtained precipitate into a vacuum drying oven, and drying for 4h at 150 ℃ to obtain ACC-PVP.

Example 2

Measuring 40mL of methanol by using a measuring cylinder, adding the methanol into a 50mL reaction kettle, then placing the reaction kettle into a magnetic stirrer, adjusting the temperature and the rotating speed of the magnetic stirrer to be 50 ℃ and 600r/min respectively, and adding 500mgCa (OH) accurately weighed under full stirring₂And 50mg of PVP, sealing the reaction kettle, and recharging 0.4MPa of CO₂(Ca(OH)₂：CO₂: PVP molar ratio 0.9: 1: 1.65*10^-4) Carbonizing for 1h, releasing the pressure of the reaction kettle, and finishing the reaction. The obtained reaction solution was put in 8000rmin^-1Centrifuging for 10min, collecting supernatant in 100ml round-bottom flask, removing a large amount of methanol solvent by rotary evaporation with rotary evaporator, placing the obtained precipitate in vacuum drying oven,drying for 4h at 150 ℃ to obtain ACC-PVP.

Example 3

Measuring 40mL of methanol by using a measuring cylinder, adding the methanol into a 50mL reaction kettle, then placing the reaction kettle into a magnetic stirrer, adjusting the temperature and the rotating speed of the magnetic stirrer to be 50 ℃ and 600r/min respectively, and adding 500mgCa (OH) accurately weighed under full stirring₂And 100mg of PVP, sealing the reaction kettle, and recharging 0.4MPa of CO₂(Ca(OH)₂：CO₂: PVP molar ratio 0.9: 1: 3.3*10^-4) Carbonizing for 1h, releasing the pressure of the reaction kettle, and finishing the reaction. The obtained reaction solution was put in 8000rmin^-1Centrifuging for 10min, taking the supernatant after centrifuging, placing the supernatant into a 100ml round-bottom flask, removing a large amount of methanol solvent by rotary evaporation with a rotary evaporator, and finally placing the obtained precipitate into a vacuum drying oven, and drying for 4h at 150 ℃ to obtain ACC-PVP.

Example 4

Measuring 40mL of methanol by using a measuring cylinder, adding the methanol into a 50mL reaction kettle, then placing the reaction kettle into a magnetic stirrer, adjusting the temperature and the rotating speed of the magnetic stirrer to be 50 ℃ and 600r/min respectively, and adding 500mgCa (OH) accurately weighed under full stirring₂And 200mg of PVP, sealing the reaction kettle, and recharging 0.4MPa of CO₂(Ca(OH)₂：CO₂: PVP molar ratio 0.9: 1: 6.67*10^-4) Carbonizing for 1h, releasing the pressure of the reaction kettle, and finishing the reaction. The obtained reaction solution was put in 8000rmin^-1Centrifuging for 10min, taking the supernatant after centrifuging, placing the supernatant into a 100ml round-bottom flask, removing a large amount of methanol solvent by rotary evaporation with a rotary evaporator, and finally placing the obtained precipitate into a vacuum drying oven, and drying for 4h at 150 ℃ to obtain ACC-PVP.

Example 5

Measuring 40mL of methanol by using a measuring cylinder, adding the methanol into a 50mL reaction kettle, then placing the reaction kettle into a magnetic stirrer, adjusting the temperature and the rotating speed of the magnetic stirrer to be 50 ℃ and 600r/min respectively, and adding 500mgCa (OH) accurately weighed under full stirring₂And 50mg of PVP, sealing the reaction kettle, and recharging 0.4MPa of CO₂(Ca(OH)₂：CO₂: PVP molar ratio 0.9: 1: 1.65*10^-4) Carbonizing for 1h, releasing the pressure of the reaction kettle, and finishing the reaction.The obtained reaction solution was put in 8000rmin^-1Centrifuging for 10min, taking supernatant after centrifuging, adding 150mg of 5-FU (fluorouracil) into a 100ml round-bottom flask, performing ultrasonic treatment to completely dissolve the supernatant, removing a large amount of methanol solvent by using a rotary evaporator, and finally putting the obtained precipitate into a vacuum drying oven, and drying for 4h at 150 ℃ to obtain the 5-FU @ ACC-PVP.

Example 6

Measuring 40mL of methanol by using a measuring cylinder, adding the methanol into a 50mL reaction kettle, then placing the reaction kettle into a magnetic stirrer, adjusting the temperature and the rotating speed of the magnetic stirrer to be 50 ℃ and 600r/min respectively, and adding 500mgCa (OH) accurately weighed under full stirring₂And 100mg of PVP, sealing the reaction kettle, and recharging 0.4MPa of CO₂(Ca(OH)₂：CO₂: PVP molar ratio 0.9: 1: 3.3*10^-4) Carbonizing for 1h, releasing the pressure of the reaction kettle, and finishing the reaction. The obtained reaction solution was put in 8000rmin^-1Centrifuging for 10min, taking supernatant after centrifuging, adding 50mg of CUR (curcumin) into a 100ml round-bottom flask, performing ultrasonic treatment to completely dissolve the CUR, removing a large amount of methanol solvent by using a rotary evaporator, and finally putting the obtained precipitate into a vacuum drying oven to dry for 4h at 150 ℃ to obtain the CUR @ ACC-PVP.

Example 7

Respectively mixing 5-FU @ ACC-PVP and CUR @ ACC-PVP composite particles with compressible starch, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, simultaneously mixing with aerosil, microcrystalline cellulose, sodium dodecyl sulfate, magnesium stearate and the like, and tabletting by a direct compression method to obtain the 5-FU dispersible tablet and the CUR dispersible tablet.

Example 8

And (3) mixing the 5-FU @ ACC-PVP and CUR @ ACC-PVP composite particles with mannitol powder respectively, adding hydroxypropyl methyl cellulose to prepare soft materials, sieving and granulating, drying, adding talcum powder, mixing uniformly, and tabletting to obtain the 5-FU chewable tablets and the CUR chewable tablets.

Example 9

And (3) respectively mixing the 5-FU @ ACC-PVP and CUR @ ACC-PVP composite particles with a proper amount of auxiliary materials, and encapsulating to obtain 5-FU capsules and CUR capsules.

Example 10

And (2) uniformly mixing the 5-FU @ ACC-PVP and CUR @ ACC-PVP composite particles with sugar powder and dextrin according to a certain proportion, adding a proper wetting agent or adhesive to adjust the humidity and viscosity, sieving, drying and packaging to obtain 5-FU granules and CUR granules.

Comparative example 1

Measuring 40mL of methanol by using a measuring cylinder, adding the methanol into a 50mL reaction kettle, then putting the reaction kettle into a magnetic stirrer, adjusting the temperature and the rotating speed of the magnetic stirrer to be 50 ℃ and 600r/min respectively, and adding 500mg of Ca (OH) accurately weighed under full stirring₂Sealing the reaction kettle, and recharging 0.4MPa CO₂(Ca(OH)₂：CO₂Molar ratio 0.9: 1) carbonizing for 1h, releasing the pressure of the reaction kettle, and finishing the reaction. The obtained reaction solution was put in 8000rmin^-1Centrifuging for 10min, collecting supernatant in 100ml round-bottom flask, removing a large amount of methanol solvent by rotary evaporation with rotary evaporator, and drying the obtained precipitate at 150 deg.C for 4 hr to obtain calcium carbonate.

Test results and conclusions

(1): referring to fig. 1, FE-SEM and TEM images (electron diffraction (ED) images taken from the circle of the C diagram) of the polyvinylpyrrolidone-assisted synthesized stable amorphous nano calcium carbonate ACC-PVP prepared in example 1 are shown. In FIG. 1, A-B are FE-SEM images of porous ACC, C-D are TEM images, and ED image in upper right corner of C image is taken from circle in lower left of C image.

It can be seen from the figure that the ACC-PVP particle size prepared in example 1 is about 10nm, and only diffuse diffraction rings are observed in ED (electron diffraction), indicating the lack of crystallinity in the sample, the product being identified as amorphous nanocalcium carbonate.

(2): referring to FIG. 2, the FT-IR and XRD test results of the stable amorphous nano calcium carbonate ACC-PVP synthesized with the assistance of polyvinylpyrrolidone prepared in examples 1-4 are shown. In each figure curve a corresponds to the product of example 1, curve B corresponds to the product of example 2, curve C corresponds to the product of example 3 and curve D corresponds to the product of example 4. The XRD pattern of the product immediately after the preparation is completed is shown on the left row in FIG. 2, and the XRD pattern of the product when the product is placed in a semi-closed condition for 5 months is shown on the right row in FIG. 2. The bottom row in FIG. 2 is FT-IR immediately after the product has been prepared.

Experiments prove that the prepared ACC can stably exist for 5 months without crystallization under the semi-closed condition. It is demonstrated that the products of examples 1-4 are stable and stable.

In contrast, referring to fig. 5-6, SEM and XRD patterns of ACC particles prepared in comparative example 1 were set in a semi-closed condition for 3 weeks. As a result of the experiment, it was found that comparative example 1, in which polyvinylpyrrolidone was not added during the preparation of ACC by the carbonation method, was found that the product was remarkably crystallized after three weeks (FIG. 6), and a large amount of vaterite-type crystalline calcium carbonate was present and the particle size was increased to 1 μm (FIG. 5). The experimental results show that the stability of the synthesized ACC of comparative example 1 is very poor.

(3): referring to FIG. 3, N is shown for the polyvinylpyrrolidone-assisted synthesis of stable amorphous nano calcium carbonate prepared in examples 1-4₂Adsorption/desorption isotherms. Panel A of FIG. 3 corresponds to the product of example 1, panel B corresponds to the product of example 2, panel C corresponds to the product of example 3, and panel D corresponds to the product of example 4.

According to calculation, the specific surface area of ACC-PVP prepared by the method is as high as 334m².g^-1And N of the products of examples 1 to 4₂The adsorption/desorption isotherms showed consistency, indicating that the process of the invention has good reproducibility and stability.

(4): referring to FIG. 4, for the cumulative release of 5-FU @ ACC-PVP particles prepared in example 5 (left panel) and CUR @ ACC-PVP particles prepared in example 6 (right panel) in simulated gastric fluid (pH1.2 containing 0.05% SDS), the physical mixture is physical mixture and the CUR is curcumin without ACC-PVP vector, in 0.02M phosphate buffer (pH7.4, 6.6, 5.5).

The release result of 5-FU @ ACC-PVP particle drug shows that after 40min, the release amount of the pH 7.45-FU is 58%, the release amount of the pH 6.65-FU reaches 77%, and the release amount of the pH 5.55-FU is close to 90%.

The release result of the CUR @ ACC-PVP particle drug shows that after 60min, over 70% of the CUR @ ACC-PVP is released in the CUR @ ACC-PVP, and the release is 3.5 times of that of the CUR bulk drug. Thus, ACC-PVP prepared according to the method of the present invention can be a promising drug carrier for poorly pH responsive (pH sensitive) and poorly soluble drugs.

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing amorphous nano calcium carbonate capable of stably existing is characterized by comprising the following steps:

s3: drying the colloidal solution to obtain the amorphous nano calcium carbonate with stable polyvinylpyrrolidone.

2. The method according to claim 1, wherein in S1, the liquid alcohol is methanol.

3. The method according to claim 1, wherein the carbonization temperature in S1 is 20 to 60 ℃.

4. The method according to claim 1, wherein in S1, Ca (OH) is first added₂Uniformly dispersing polyvinylpyrrolidone in liquid alcohol, and introducing CO under stirring₂And carrying out carbonization reaction.

5. The method according to claim 1, wherein in S1, Ca (OH)₂：CO₂: the molar ratio of PVP is 1: (1-3): (3.8*10^-5～7.6*10^-4)。

6. The method according to claim 1, wherein in S1, the carbonization reaction time is 1 to 4 hours; in S2, the centrifugal speed is 6000-8000 r/min, and the centrifugal time is 8-15 min; in S3, the drying temperature is 140-155 ℃, and the drying time is 2-6 h.

7. Amorphous nano calcium carbonate capable of being stably present, which is prepared by the preparation method of any one of claims 1 to 6.

8. A method for preparing a carrier drug containing ACC-PVP is characterized by comprising the following steps:

9. The method according to claim 8, wherein the pharmaceutically effective ingredient is fluorouracil or curcumin.

10. The method of claim 8, further comprising step 4: and (3) further preparing the ACC-PVP loaded drug composite particles obtained in the step (3) into tablets, capsules or granules.