CN115957237A - A tooth mineralization antibacterial bifunctional gel, preparation method and application - Google Patents

Abstract

The invention discloses a tooth mineralization and antibacterial dual-function gel, a preparation method and application thereof, wherein the preparation method comprises the following steps: dissolving a stabilizer, a calcium salt and a metal ion salt additive in a solvent to obtain a mixed solution, then adding a gelling agent, and swelling uniformly to prepare gel i; dissolving phosphate and fluoride in a solvent to obtain a mixed solution, adjusting the pH value of the solution to 8-12, adding a gelling agent, and swelling uniformly to prepare gel ii. And stirring and mixing the gel i and the gel ii according to the proportion to prepare the hybrid amorphous calcium phosphate gel. The tooth mineralization gel prepared by the invention contains the mineralization component of the hybrid amorphous calcium phosphate, can provide a stable calcium and phosphorus source, induces the mineralization of teeth, and can be doped with metal ion salts and fluoride additives to adjust the hybrid degree of the mineralization component of the amorphous calcium phosphate, thereby endowing the tooth mineralization gel with dual functions of mineralization and antibiosis, and can be used for preventing and treating oral diseases such as tooth leukoplakia, early caries, dentin sensitivity and the like.

Description

A tooth mineralization antibacterial bifunctional gel, preparation method and application

technical field

The invention belongs to the technical field of preparation of biomedical materials, and relates to a tooth mineralization and antibacterial dual-function gel, a preparation method and an application.

Background technique

Caries is a common and frequently-occurring disease that endangers human health, and usually begins with the demineralization of the enamel surface and its underlying surface. Leukoplakia is the most common early demineralization of tooth enamel in clinic. It is manifested as white plaque on the surface of tooth enamel, which not only affects the appearance, but also hinders the health of the tooth. If it is not prevented in time, it will easily cause further demineralization of tooth tissue and lead to severe caries. sick. At present, the clinical prevention and treatment materials for enamel leukoplakia mainly include fluoride-containing products, such as: fluoride-containing toothpaste, mouthwash, gel, varnish, etc.; Repair materials, such as: infiltration resin, all-ceramic restorations, etc. However, the clinical effects of the above materials are still controversial, mainly related to biological safety, remineralization effect, resin durability, tooth tissue damage and other issues. At present, there is no oral material that can effectively reverse leukoplakia in clinical practice, which has become a problem. Problems that need to be solved urgently.

With the concept of modern minimally invasive dentistry, biomineralization technology has become the trend of caries prevention and treatment. In particular, there is an urgent need for amorphous calcium phosphate (ACP) capable of releasing large amounts of bioactive Ca ²⁺ and PO ₄ ^3- ions for hard tissue remineralization. ACP is widely recognized as an important precursor in the formation of hydroxyapatite (HAP) and plays an important role in the biomineralization of teeth. For a long time, the biomimetic mineralization system based on ACP has been widely developed, and oral caries-preventing materials such as mouthwash, toothpaste, tooth mousse and adhesives have been derived. However, the thermodynamic instability of ACP limits its application and preservation as a liquid mineralization source; as a solid mineralization source, the loss of hydration layer structure and the limited diffusion in solid carriers will affect its good mineralization activity. . Furthermore, the currently developed ACP-based remineralization systems lack the ability to inhibit bacterial adhesion and biofilm formation under long-term colonization of oral microorganisms.

The main inorganic component of dental hard tissue is non-stoichiometric hydroxyapatite, cations such as Na ⁺ , Mg ²⁺ , Zn ²⁺ , Sr ²⁺ can replace the binding site of Ca ²⁺ , and F ^- can replace OH ^- or the binding site for CO ₃ ^2- . By incorporating functional metal elements into hydroxyapatite, the functional transformation of hydroxyapatite can be realized, thereby enhancing the antibacterial or anti-acid properties of teeth. Therefore, with the help of the mineralization activity of ACP, the ACP material mixed with various elements, such as Ag, Mg, Zn, F, etc., has become an ideal dental mineralization material due to its characteristics of antibacterial, mineralization, and enhanced tooth acid resistance. application prospects.

Contents of the invention

Based on this, the present invention provides a tooth mineralization antibacterial bifunctional gel, preparation method and application, the main active ingredient of the tooth mineralization antibacterial bifunctional gel obtained from mineralization is hybrid amorphous calcium phosphate, hybrid amorphous calcium phosphate The particle size of calcium phosphate is 30-40nm, the shape is regular spherical particles, and it is doped with different metal ions and fluoride ions, which has the properties of antibacterial and mineralization promotion. The preparation method is simple and easy, the preparation cost is low, and it is convenient for large-scale production and clinical popularization and use.

Technical scheme of the present invention is as follows:

The present invention at first provides a kind of preparation method of tooth mineralization antibacterial bifunctional gel, and it comprises the following steps:

1) Dissolving the stabilizer, calcium salt and at least one metal ion salt additive in a solvent to obtain a mixed solution, and then adding a gelling agent to swell evenly to obtain a gel i;

2) dissolving phosphate and fluoride in a solvent to obtain a mixed solution, adjusting the pH of the solution to 8-12, and then adding a gelling agent to swell evenly to obtain gel ii;

3) Mix the gel i obtained in step 1) with the gel ii obtained in step 2) in proportion to obtain a tooth mineralization and antibacterial dual-function gel.

Further, in the step 1), each component is calculated in parts by weight: 10-100 parts of stabilizer, 50-500 parts of calcium salt, 50-250 parts of metal ion salt additive, 50-200 parts of gelling agent, 50-2000 parts of solvent.

Further, in the step 2), each component is calculated in parts by weight: 50-500 parts of phosphate, 10-50 parts of fluoride, 50-200 parts of gelling agent, and 50-2000 parts of solvent.

Further, the proportional mixing described in step 3) is, through the selection of the ratio of gel agent i and gel ii, the metal ions in the calcium and metal ion salt additives in the tooth mineralization antibacterial bifunctional gel The molar ratio of calcium and metal ions in the salt additive is 1 to 10:1; the molar ratio of the sum of calcium and metal ions to phosphorus is 1.3 to 2.1:1.

The present invention also provides the tooth mineralization antibacterial dual-function gel prepared by the method, the active ingredient of the tooth mineralization antibacterial dual-function gel is hybrid amorphous calcium phosphate, and the particle size of the hybrid amorphous calcium phosphate is The diameter is 30-40nm, the shape is spherical particles, doped with metal ions and fluorine ions in metal ion salt additives.

In the invention, the gel is used as a carrier and polyaspartic acid and other stabilizers are used to chelate free calcium ions, dope metal ions, phosphate ions and fluoride ions, thereby obtaining hybrid amorphous calcium phosphate gel. This mineralization method is simple and easy to implement. The two-component gel can be stored separately before use. When in use, hybrid ACP can be synthesized immediately. The degree of heterozygosity of different metal ions is controllable. The stability of combined ACP is controllable, and the size and shape of the product are controllable.

The present invention also provides an application of the hybrid amorphous calcium phosphate gel set in the preparation of medicaments for biomimetic mineralization of teeth. Preferably, the drug for tooth biomimetic mineralization is a drug for preventing and treating white spots of teeth, a drug for treating early caries or a drug for treating tooth desensitization.

Compared with the prior art, the present invention has the following advantages:

(1) The main active ingredient of the preparation of the present invention is heterozygous amorphous calcium phosphate. Since calcium and phosphorus are used to separate the two-component mode, it can be mixed and freshly prepared in use to avoid amorphous phosphate The problem of premature conversion of calcium to crystalline apatite in aqueous media ensures that the product has good mineralizing activity.

(2) The phase stability and degree of heterozygosity of the amorphous calcium phosphate material contained in the preparation of the present invention are controllable, endowing it with good mineralization and antibacterial properties.

(3) The preparation method of tooth mineralization antibacterial bifunctional gel provided by the present invention is simple and easy, does not need large-scale equipment, has high production efficiency and low cost, is suitable for large-scale production, and can be used for dental leukoplakia, early caries, The prevention and treatment of oral diseases such as dentin sensitivity has a huge market prospect.

Description of drawings

FTIR+XRD+SEM figure of Fig. 1 gel preparation;

The FTIR figure of Fig. 2 gel formulation phase stability;

Figure 3 digital photography+Micro-CT image of inhibiting the formation of enamel leukoplakia; wherein, a) digital photography image shows that the preparation treatment group of the present invention has the least change in surface color of the enamel sample during the 4-week pH cycle. b) Micro-CT images show that after 4 weeks of pH cycling, the enamel mineral loss and demineralization depth of the preparation treatment group of the present invention are the smallest.

Figure 4 SEM images of treated early enamel caries.

Detailed ways

The present invention will be further described through examples of implementation below, which are preferred examples of the present invention. All modifications and changes made within the principles of the present invention are within the protection scope of the present invention.

The tooth mineralization and antibacterial dual-functional gel provided by the present invention can generally be prepared according to the following steps:

1) Dissolving the stabilizer, calcium salt and at least one metal ion salt additive in a solvent to obtain a mixed solution, and then adding a gel agent to swell evenly to obtain a gel i; in step 1), each component is calculated in parts by weight It is: 10-100 parts of stabilizer, 50-500 parts of calcium salt, 50-250 parts of metal ion salt additive, 50-200 parts of gelling agent, and 50-2000 parts of solvent.

2) Dissolving phosphate and fluoride in a solvent to obtain a mixed solution, adjusting the pH of the solution to 8-12, and then adding a gelling agent to swell evenly to obtain a gel ii; the components in step 2) are measured in parts by weight It is: 50-500 parts of phosphate, 10-50 parts of fluoride, 50-200 parts of gelling agent, and 50-2000 parts of solvent.

3) Mix the gel i obtained in step 1) with the gel ii obtained in step 2) in proportion to obtain a tooth mineralization antibacterial dual-function gel; The selection of the ratio of agent i and gel ii makes the molar ratio of calcium and metal ion in the metal ion salt additive in the tooth mineralization antibacterial bifunctional gel be 1 to 10:1; The molar ratio of the sum of metal ions to phosphorus is 1.3-2.1:1.

Wherein, as a preferred embodiment of the present invention, the stabilizer is polygluconic acid, polyaspartic acid, polyacrylic acid, polymaleic acid, polyglutamic acid, polyvinylphosphonic acid, carboxymethyl chitosan , ethylenediaminetetraacetic acid, sodium tripolyphosphate, sodium hexametaphosphate, sodium pyrophosphate, any one or a combination of more;

As a preferred embodiment of the present invention, the calcium salt is a soluble calcium salt selected from calcium chloride and/or its hydrate, calcium acetate and/or its hydrate, calcium lactate and/or its hydrate, calcium citrate And/or its hydrate, calcium bicarbonate, calcium dihydrogen phosphate any one or combination of more.

As a preferred embodiment of the present invention, the metal ion salt additive is selected from any one of soluble silver, zinc, strontium, magnesium, copper, gallium, manganese, cerium, zirconium, titanium nitrate, sulfate or chloride or a combination of several.

As a preferred embodiment of the present invention, in the step 1) and step 2), the gelling agent is methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, acrylamide polymer, Any of acrylic polymers, vinyl alcohol polymers, polyvinylpyrrolidone, polyethylene glycol, carboxymethyl chitosan, lignin, sodium alginate, agar, starch, collagen, hyaluronic acid and polypeptide compounds one or more combinations;

As a preferred embodiment of the present invention, the solvent is deionized water, glycerin deionized water in any ratio, and ethanol deionized water in any ratio.

As a preferred embodiment of the present invention, the phosphate is a soluble phosphate, selected from sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, diammonium hydrogen phosphate, phosphoric acid Any one or combination of sodium, potassium phosphate, ammonium phosphate; the fluoride is stannous fluoride, sodium fluoride, potassium fluoride, silver fluoride, potassium monofluorophosphate, sodium fluorosilicate any one or a combination of more.

The tooth mineralization antibacterial bifunctional gel provided by the present invention can be directly prepared by the above method, and the prepared tooth mineralization antibacterial bifunctional gel can exist stably for 4 hours without phase change, as an optional embodiment , the tooth mineralization antibacterial dual-function gel is prepared prior to preparation of gel i and gel ii; gel i and gel ii are stored separately, and when it is necessary to prepare tooth mineralization antibacterial or mixed. That is, when using, the obtained gel i and the obtained gel ii are mixed uniformly in proportion to obtain a hybrid amorphous calcium phosphate gel; the mixing ratio is controlled to make the moles of calcium and metal cations in the hybrid amorphous calcium phosphate gel The ratio is 1-10:1; the molar ratio of the sum of calcium and metal cations to phosphorus is 1.3-2.1:1.

In parts by mass, the gel i includes: 10-100 parts of a stabilizer, 50-500 parts of a calcium salt, 50-250 parts of a metal ion salt additive, 50-200 parts of a gelling agent, and 50-2000 parts of a solvent; The preparation method of gel i is as follows: dissolving stabilizer, calcium salt and metal ion salt additives in a solvent to obtain a mixed solution, and then adding a gel agent to swell evenly to obtain gel i; the gel ii includes: phosphate 50-500 parts, 10-50 parts of fluoride, 50-200 parts of gel, 50-2000 parts of solvent, the preparation method of gel ii is: dissolve phosphate and fluoride in the solvent to obtain a mixed solution, and adjust the concentration of the solution pH to 8-12, then add a gelling agent to swell evenly to obtain gel ii.

Implementation Case 1

The gel preparation process of the present embodiment is as follows:

(1) Using deionized water as a solvent, prepare a mixed solution containing 0.8mol/L calcium chloride, 0.2mol/L zinc chloride, and 36g/L polyaspartic acid, and add 0.1g hydroxypropane per 1mL of the mixed solution Base methyl cellulose, form gel i after fully swelling;

(2) Using deionized water as a solvent, prepare a mixed solution containing 0.48mol/L disodium hydrogen phosphate and 4g/L sodium fluoride, and adjust the pH of the solution to 8-12 with sodium hydroxide, and add 0.1 g hydroxypropyl methylcellulose, fully swollen to form a gel ii;

(3) Stir and mix gel i and gel ii in equal volumes to obtain a tooth mineralization and antibacterial dual-function gel containing hybrid amorphous calcium phosphate.

The gel i and gel ii implemented in this case can be stored separately and mixed before use to ensure the phase stability and mineralization activity of the hybrid amorphous calcium phosphate.

Implementation Case 2

The gel preparation process of the present embodiment is as follows:

(1) Using deionized water as a solvent, prepare a mixed solution containing 1.2mol/L calcium chloride, 0.3mol/L strontium chloride, and 42g/L polyacrylic acid, and add 0.1g carboxymethyl chitosan to every 1mL mixed solution Sugar, fully swollen to form a gel i;

(2) Using deionized water as a solvent, prepare a mixed solution containing 1mol/L dipotassium hydrogen phosphate and 5g/L sodium fluoride, and adjust the pH of the solution to 8-12 with potassium hydroxide, and add 0.1g per 1mL of the mixed solution Carboxymethyl chitosan, fully swollen to form a gel ii;

(3) Stir and mix gel i and gel ii in equal volumes to obtain a tooth mineralization and antibacterial dual-function gel containing hybrid amorphous calcium phosphate.

The gel i and gel ii implemented in this case can be stored separately and mixed before use to ensure the phase stability and mineralization activity of the hybrid amorphous calcium phosphate.

Implementation Case 3

The gel preparation process of the present embodiment is as follows:

(1) Using deionized water as a solvent, prepare a mixed solution containing 2mol/L calcium chloride, 0.1mol/L cerium chloride, and 58g/L polyacrylic acid, and add 0.1g hydroxypropyl methylcellulose to every 1mL mixed solution Element, form gel i after fully swelling;

(2) Using deionized water as a solvent, prepare a mixed solution containing 1.2mol/L disodium hydrogen phosphate and 5g/L sodium fluoride, and adjust the pH of the solution to 8-12 with sodium hydroxide, and add 0.1 g carboxymethyl chitosan, fully swollen to form gel ii;

(3) Stir and mix gel i and gel ii in equal volumes to obtain a tooth mineralization and antibacterial dual-function gel containing hybrid amorphous calcium phosphate.

The gel i and gel ii implemented in this case can be stored separately and mixed before use to ensure the phase stability and mineralization activity of the hybrid amorphous calcium phosphate.

Implementation Case 4

The tooth mineralization antibacterial dual-performance gel obtained in Example 1 was subjected to Fourier transform infrared spectroscopy (FTIR) testing, X-ray diffraction analysis (XRD), scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX) analysis. Result as shown in Figure 2, as can be seen from Figure 2, the gel formulation characterization result of the present invention A) FTIR diagram is in the characteristic infrared absorption peak of 1061 and 572cm-1, shows that this formulation contains the mineralization component of amorphous calcium phosphate; B) XRD shows diffuse peaks at 2θ=20° and 2θ=30°, indicating that the calcium phosphate component contained is an amorphous phase; C) SEM figure amorphous calcium phosphate in the gel is spherical particles, particle size About 30-40nm. That is, the calcium phosphate salt composition contained in the gel of the present invention is an amorphous mineral phase; scanning electron microscopy shows that the amorphous calcium phosphate is spherical particles, which are evenly distributed in the gel matrix, and the particle size is 30-40nm; elemental analysis shows that it contains Chemical composition of Ca, P, Zn, F, C, O, H.

Implementation Case 5

The phase stability of the tooth mineralization and antibacterial dual performance gel obtained in Example 1 was tested. The immediately mixed gel preparation was incubated in artificial saliva at 37°C, and samples were taken at different time points for FTIR testing. It can be seen from the test results in Figure 2 that the active ingredient of amorphous calcium phosphate in the gel can maintain a metastable state in artificial saliva for up to 4 hours, which is conducive to its good mineralization potential.

Implementation Case 6

The preventive effect of the tooth mineralization and antibacterial dual performance gel obtained in Example 1 was evaluated.

Preparation of normal enamel slices: Select a freshly extracted human premolar without caries, defects, cracks and spots for the experiment. Under water cooling, 36 enamel blocks of 4mm×4mm×1.5mm were cut out on the buccal and lingual side with an Isomet precision cutting machine. Use silicon carbide abrasive paper to grind and polish the outer surface of the enamel, and then coat it with double-layer acid-resistant nail polish, leaving a 3mm×3mm window surface.

The above-mentioned gel preparation was coated on the enamel surface, put into 5mL of artificial saliva and incubated for 8 hours, then taken out and rinsed, and then put into the demineralization solution and incubated for 16 hours. Fresh gel preparations and treatment solutions were replaced every day, and a blank control group (demineralized enamel) and a positive control group (GC Tooth Mousse Plus, a commonly used clinical remineralization preparation) were set up. Samples were placed in a 37°C incubator for 2 weeks and 4 weeks. Digital photography, Micro-CT, and SEM were used to observe the effect of the gel preparation of the present invention on inhibiting the formation of enamel leukoplakia.

Effect observation

Enamel color appearance in enamel samples at baseline, 2-week demineralization-remineralization cycle, and 4-week demineralization-remineralization cycle was assessed using digital photography under standard conditions:

As shown in Figure 3, during the 4-week demineralization and remineralization cycle process, the enamel surface color of each treatment group turned white with time, and the gel preparation of the present invention treated the group with the smallest degree of whitening, indicating that it has the ability to inhibit tooth decay. The effect of enamel demineralization has the effect of inhibiting the formation of enamel white spots, and can be used for the prevention and treatment of tooth white spots.

Micro-CT observation of enamel lesion depth and mineral loss:

Using a desktop Micro-CT scanner, the same sample was scanned twice, at baseline and 4 weeks after the demineralization-remineralization cycle. As shown in Figure 3, compared with baseline, the gel formulation treatment group had the least lesion depth and mineral loss after the 4-week demineralization-remineralization cycle process.

Scanning electron microscopy to observe the demineralization of tooth enamel:

After the enamel was removed, it was rinsed with deionized water, and the samples were dehydrated with an ethanol gradient, then dried in air and sprayed with gold, and the demineralization was observed by SEM. The roughness and porosity of the enamel surface in the blank control group increased, the enamel column and interstitial demineralization was obvious, and no new mineral deposition was detected; the enamel surface of the gel preparation group was relatively smooth, and obvious mineral deposition was visible. The interstitial structure of the columns and enamel columns was complete, and the new minerals were densely deposited in the gaps of the enamel crystals; the remineralization degree of the positive control group was not as good as that of the gel preparation group.

Implementation Case 7

To evaluate the therapeutic effect of tooth mineralization and antibacterial dual performance gel on early enamel caries obtained in Example 1.

Preparation of early enamel caries samples: A freshly extracted human premolar tooth without caries, defects, cracks and spots was selected for the experiment. Under water cooling, 36 enamel blocks of 4mm×4mm×1.5mm were cut out on the buccal and lingual side with an Isomet precision cutting machine. Use silicon carbide abrasive paper to grind and polish the outer surface of the enamel, and then coat it with double-layer acid-resistant nail polish, leaving a 3mm×3mm window surface. Each enamel slice was soaked in 5 mL of acetic acid buffer solution for 6 days. After the lesion was formed, the samples were taken out and rinsed with deionized water, blotted dry with filter paper and stored at 4°C for later use.

Gel preparation of the present invention is coated on the demineralized tooth enamel surface, put into the artificial saliva of 5mL, change fresh gel preparation and artificial saliva every day, set blank control group (demineralized tooth enamel) and positive control group (commonly used clinical remineralization preparation GC Tooth Mousse Plus). Placed in a 37°C incubator for 1 week and 2 weeks for sampling. Digital photography, Micro-CT, and SEM were used to observe the therapeutic effect of the gel preparation of the present invention on early tooth enamel caries.

Effect observation

Digital photography of color changes in demineralized enamel samples at baseline, after demineralization, and after 2 weeks of remineralization. All treatments had a chalky appearance after demineralization compared to the baseline. After 2 weeks of remineralization, the color appearance of the demineralized enamel surface in the blank control group did not improve; the chalky appearance of the gel preparation group disappeared, and the gloss of the enamel surface increased; the color appearance of the demineralized enamel in the positive control group remained basically unchanged .

Changes in lesion depth and mineral content of samples from each group were scanned by Micro-CT at baseline, after demineralization and after 2 weeks of remineralization. After demineralization, samples from all groups showed obvious subsurface lesions of the enamel with significantly lower CT gray value compared with baseline. After 2 weeks of remineralization, the depth of enamel lesions in the gel preparation group was reduced, and the gray value of CT was significantly enhanced, and the effect was significantly better than that of the blank control group and the positive control group.

Scanning electron microscopy was used to compare the microstructure of normal enamel, demineralized enamel, and remineralized enamel in each treatment group. As shown in Figure 4, the surface of normal tooth enamel is smooth and flat, the structure of the enamel column and the interstitial structure of the enamel column is complete, and the gap between enamel crystals is not obvious; The integrity of the enamel was obviously destroyed, part of the interstitium of the enamel column disappeared, and obvious gaps appeared between the enamel crystals. After 2 weeks of remineralization, no signs of remineralization were observed in the blank control group; the demineralized morphology of the enamel surface in the gel preparation group disappeared, and the gaps between the originally exposed enamel crystals were densely deposited by new minerals, and the microstructure of the enamel was improved. repair; the remineralization effect of the positive control group was not as good as that of the gel preparation group.

The above-mentioned embodiments only express several implementation modes of the present invention, and the description thereof is relatively specific and detailed, but should not be construed as limiting the patent scope of the present invention. For those skilled in the art, without departing from the concept of the present invention, several modifications and improvements can be made, and these all belong to the protection scope of the present invention.

Claims (10)

1. A preparation method of a tooth mineralization and antibacterial dual-function gel is characterized by comprising the following steps:

1) Dissolving a stabilizer, a calcium salt and at least one metal ion salt additive in a solvent to obtain a mixed solution, then adding a gelling agent, and uniformly swelling to obtain gel i;

2) Dissolving phosphate and fluoride in a solvent to obtain a mixed solution, adjusting the pH value of the solution to 8-12, adding a gelling agent, and uniformly swelling to obtain gel ii;

3) Uniformly mixing the gel i obtained in the step 1) and the gel ii obtained in the step 2) in proportion to obtain the dental mineralization antibacterial dual-function gel.

2. The method of claim 1, wherein: in the step 1), the components in parts by weight are as follows: 10 to 100 portions of stabilizer, 50 to 500 portions of calcium salt, 50 to 250 portions of metal ion salt additive, 50 to 200 portions of gel and 50 to 2000 portions of solvent.

3. The method of claim 1, wherein: in the step 1), the stabilizer is one or more of polyglutamic acid, polyaspartic acid, polyacrylic acid, polymaleic acid, polyglutamic acid, polyvinyl phosphonic acid, carboxymethyl chitosan, ethylenediamine tetraacetic acid, sodium tripolyphosphate, sodium hexametaphosphate and sodium pyrophosphate;

the calcium salt is soluble calcium salt, and is selected from one or more of calcium chloride and/or its hydrate, calcium acetate and/or its hydrate, calcium lactate and/or its hydrate, calcium citrate and/or its hydrate, calcium bicarbonate, and calcium dihydrogen phosphate.

4. The method of claim 1, wherein: in the step 1), the metal ion salt additive is selected from one or more of nitrates, sulfates or chlorides of soluble silver, zinc, strontium, magnesium, copper, gallium, manganese, cerium, zirconium and titanium.

5. The method of claim 1, wherein: in the step 1) and the step 2), the gelling agent is any one or combination of more of methylcellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, acrylamide polymer, acrylic polymer, vinyl alcohol polymer, polyvinylpyrrolidone, polyethylene glycol, carboxymethyl chitosan, lignin, sodium alginate, agar, starch, collagen, hyaluronic acid and polypeptide compounds;

the solvent is deionized water, glycerol deionized water solution in any ratio and ethanol deionized water solution in any ratio.

6. The method of claim 1, wherein: in the step 2), the components in parts by weight are as follows: 50 to 500 portions of phosphate, 10 to 50 portions of fluoride, 50 to 200 portions of gel and 50 to 2000 portions of solvent.

7. The method of claim 1, wherein: in the step 2), the phosphate is soluble phosphate and is selected from one or more of sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, diammonium hydrogen phosphate, sodium phosphate, potassium phosphate and ammonium phosphate; the fluoride is any one or combination of stannous fluoride, sodium fluoride, potassium fluoride, silver fluoride, potassium monofluorophosphate and sodium fluosilicate.

8. The method of claim 1, wherein: the mixing in the step 3) is that the molar ratio of the calcium to the metal ions in the metal ion salt additive in the tooth mineralization and antibacterial dual-function gel is 1-10 by selecting the proportion of the gel agent i and the gel ii: 1; the molar ratio of the sum of the metal ions in the calcium and metal ion salt additive to the phosphorus is 1.3-2.1: 1.

9. a dental mineralization anti-bacterial dual function gel prepared by the method of any one of claims 1-8, wherein the active ingredient of the dental mineralization anti-bacterial dual function gel is a hybrid amorphous calcium phosphate having a particle size of 30-40nm and a spherical shape, and being doped with the metal ion and fluoride ion of the metal ion salt additive.

10. The use of the tooth-mineralization antibacterial bifunctional gel prepared by the method according to any one of claims 1 to 8 in the preparation of a tooth biomimetic-mineralization medicament, wherein the tooth biomimetic-mineralization medicament is a tooth leukoplakia prevention medicament, an early caries treatment medicament or a tooth desensitization treatment medicament.

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