Microneedle for treating periodontitis as well as preparation method and application of microneedle

Abstract

The invention discloses a microneedle for treating periodontitis as well as a preparation method and application of the microneedle, the active ingredient of the microneedle is a compound with osteogenesis and anti-inflammatory effects, and the compound is mesoporous silica loaded with alpha-ketoglutaric acid; the mass ratio of the mesoporous silica to the alpha-ketoglutaric acid is (1: 4)-(4: 1). The modified SiO2 with a unique spike structure is used as a carrier of the alpha KG, and the modified SiO2 and the alpha KG are compounded together in a carrying manner and jointly act on an affected part, so that cell membrane defensive lines of various cells such as macrophages and bone mesenchymal stem cells are easily broken through, and efficient immunoregulation and bone metabolism regulation effects are achieved in vivo. And a synergistic effect is generated in the aspect of osteogenesis and anti-inflammation.

Description

Technical Field

[0001] The present invention specifically relates to a microneedle for treating periodontitis and a preparation method and use thereof. Background Art

[0002] Periodontitis, also known as destructive periodontal disease, is a chronic inflammatory disease that affects approximately 11.2% of patients worldwide. The periodontal inflammatory state can destroy periodontal supporting tissues such as the alveolar bone, causing loose teeth or even tooth loss. Currently, the treatment of periodontitis mainly relies on surgical scaling combined with the use of antibiotics. The main purpose of surgical treatment is to remove infected lesions, but it is difficult to take into account the subsequent tissue regeneration and cannot target the precise regulation of the inflammatory cell state inside the periodontium. How to provide a non-surgical, non-antibiotic sequential treatment of inflammation and promote osteogenesis in a periodontitis treatment program is the current focus of research.

[0003] α-Ketoglutaric acid (αKG) is an important short-chain carboxylic acid molecule that is widely present in organisms. It plays a key role in connecting the carbon-nitrogen cycle in cells and is a key node in carbon-nitrogen metabolism. Studies have shown that αKG can improve osteoarthritis by regulating mitochondrial autophagy and oxidative stress. CN118021782A discloses a gel with α-ketoglutaric acid as an active ingredient for the treatment of periodontitis. Due to the complex metabolic pathway of αKG, the need for cofactors and the influence of the physiological environment on its absorption and distribution, its bioavailability is limited. The effect of applying it to the affected area in the form of a gel is not satisfactory, and the patient benefits are limited.

[0004] Mesoporous silica (SiO2) is a nanomaterial with a unique pore structure. Its pore size is usually between 2 and 50 nanometers. It has a high specific surface area and an ordered pore structure, high loading capacity and good biocompatibility, making it an ideal drug carrier. As a silicon-containing bioactive material, SiO2 itself also has multiple functions, such as participating in the regulation of the physiological processes of bone formation and bone calcification, and plays an important role in bone metabolism. However, SiO2 itself also has the problem of low bioavailability. When used as a drug carrier, it also faces the problems of pore blockage and drug leakage during controlled release, which will affect the efficacy of the drug.

[0005] There is no report on the use of mesoporous silica and α-ketoglutaric acid in combination for the treatment of periodontitis. Summary of the invention

[0006] To solve the above problems, the present invention provides a composite material with osteogenic and anti-inflammatory effects, which is mesoporous silica loaded with α-ketoglutaric acid;

[0007] The mass ratio of the mesoporous silica to α-ketoglutaric acid is 1:4 to 4:1.

[0008] Furthermore, the mass ratio of the mesoporous silica to α-ketoglutaric acid is 1:4; and / or: the mesoporous silica is mesoporous silica with a spike structure, and the particle size is 500nm to 1μm.

[0009] The present invention also provides a method for preparing the above-mentioned composite, comprising the following steps:

[0010] 1) Take a cationic surfactant and a sodium hydroxide solution, add water and stir, then add tetraethyl orthosilicate and cyclohexane and stir, centrifuge, and collect a white emulsion;

[0011] 2) taking the white emulsion obtained in step 1), washing with water and ethanol to obtain a precipitate, dispersing the precipitate in acetone, refluxing at 40-60° C. for 8-16 hours, collecting the precipitate, washing with ethanol, and drying to obtain mesoporous silica;

[0012] 3) Dissolve α-ketoglutaric acid in water, adjust the pH value to neutral, add the mesoporous silica obtained in step 2) according to the ratio, stir at room temperature for 8 to 24 hours and then centrifuge to obtain the product.

[0013] Furthermore, in step 1), the mass volume ratio of the cationic surfactant, sodium hydroxide solution, water, tetraethyl orthosilicate and cyclohexane is 0.5-2.5 g: 0.2-1 mL: 40-60 ml: 2-5 mL: 14-18 mL, preferably 1 g: 0.8 mL: 50 ml: 4 mL: 16 mL; the temperature of adding water and stirring is 50-70° C. for 1.5-2.5 hours; the temperature of adding tetraethyl orthosilicate and cyclohexane and stirring is 50-70° C. for 40-50 hours;

[0014] Furthermore, the concentration of the sodium hydroxide solution is 0.1 M; the water is deionized water; and the cationic surfactant is hexadecyltrimethylammonium bromide.

[0015] Furthermore, the amount of acetone used in step 2) is the same as the amount of water used in step 1).

[0016] Furthermore, in step 3), the mass volume ratio of the α-ketoglutaric acid to water is 1-4 g:50 ml.

[0017] The present invention also provides a use of the above-mentioned complex in preparing a drug for treating periodontitis, wherein the drug has anti-inflammatory and / or osteogenesis effects.

[0018] The present invention also provides a medicine for treating periodontitis, which is a preparation prepared by taking the above-mentioned complex as an active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients.

[0019] Furthermore, the preparation is an oral administration preparation; the oral administration preparation is a solution, a paste, a patch, or a powder; and the patch includes microneedles.

[0020] Furthermore, the microneedle is prepared from the following raw materials in parts by weight:

[0021] 2-6 parts of the aforementioned mesoporous silica loaded with α-ketoglutaric acid, 100-500 parts of gelatin, 1-5 parts of a photoinitiator, and 500-1500 parts of water;

[0022] Preferred:

[0023] 4 parts of the aforementioned mesoporous silica loaded with α-ketoglutaric acid, 200 parts of gelatin, 2 parts of a photoinitiator, and 1000 parts of water.

[0024] Furthermore, the photoinitiator includes phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt.

[0025] The present invention also provides a method for preparing the aforementioned microneedle, comprising the following steps:

[0026] Weigh the mesoporous silica loaded with α-ketoglutaric acid, gelatin, a photoinitiator and water according to the proportion, mix them, pour them into a mold, centrifuge, solidify, dry and demould to obtain the product;

[0027] The mold is a PDMS mold; and the curing is performed by irradiating with an ultraviolet lamp.

[0028] Finally, the present invention provides a use of the aforementioned microneedle in preparing a drug for treating periodontitis, characterized in that the drug has anti-inflammatory and / or osteogenesis effects.

[0029] The composite with osteogenic and anti-inflammatory effects of the present invention uses modified SiO2 with a unique spike structure as a carrier of αKG, and the modified SiO2 and αKG are compounded together in a carrying manner, and act together on the affected area, which is easy to break through the cell membrane defense line of various cells, such as macrophages and bone mesenchymal stem cells, and play a highly efficient immunomodulatory and bone metabolism regulating role in the body. Cell experiments have confirmed that: at the same dosage, compared with the use of SiO2 or αKG alone, the use of SiO2@αKG can form more calcium nodules in bone cells under inflammatory conditions, and it is statistically significant, and the osteogenic and anti-inflammatory effects are significantly improved, resulting in a synergistic effect. Applying SiO2@αKG to the periodontal affected area by microneedle administration can efficiently deliver the active ingredient SiO2@αKG, further improving the therapeutic effect of periodontitis.

[0030] The periodontal microneedle process of the present invention is simple and safe, and is suitable for large-scale industrial production; it is easy to use and can be used for periodontal therapy through extremely simplified local administration at home, and is suitable for market promotion.

[0031] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0032] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Mesoporous silica with spike structure (a) and microneedle array (b);

[0034] Figure 2 Images of SiO2 with normal structure and spike structure being engulfed by macrophages (green represents SiO2, red represents raw cytoskeleton, and blue represents raw cell nucleus);

[0035] Figure 3 Alizarin red staining (represents bone formation ability, red represents calcium nodules) SiO2@αKG has the best bone formation effect when the SiO2:αKG dosage is 1:4 (the left picture shows the calcium nodules dyed red. The more calcium nodules, the better the mineralization effect, that is, the best bone formation effect. The absorption peak of these mineral calcium nodules at 562nm after being dissolved by cetylpyridinium chloride, the larger the value, the more minerals);

[0036] Figure 4 Alizarin red staining after different treatments under inflammatory conditions; upper figure: Alizarin red staining under light microscopy, in which calcium nodules are red, and the more calcium nodules there are, the better the mineralization effect, that is, the best osteogenesis effect; the lower figure is the absorption peak at 562nm, and the larger the value, the more minerals there are.

[0037] Figure 5 Alizarin red staining after co-culture of microneedles containing or without SiO2@αKG and bone mesenchymal stem cells (BMSC). DETAILED DESCRIPTION

[0038] The raw materials, reagents and equipment used in the specific embodiments of the present invention are obtained by commercial purchase.

[0039] Example 1. Preparation of mesoporous silica loaded with α-ketoglutaric acid according to the present invention

[0040] (I) Preparation and characterization of mesoporous silica

[0041] 1) Take 1 g of hexadecyltrimethylammonium bromide (CTAB) and 0.8 mL of 0.1 M NaOH, add them to 50 mL of deionized water, stir at 60°C and 150 rpm for 2 hours, then add 4 mL of tetraethyl orthosilicate (TEOS) and 16 mL of cyclohexane, stir at 60°C and 150 rpm for 48 hours, and collect the white emulsion by centrifugation;

[0042] 2) Take the white emulsion, wash with water and ethanol to obtain a precipitate, then disperse the precipitate in 50 mL of acetone, reflux at 50° C. for 12 h, remove CTAB, wash with ethanol, and dry to obtain a white precipitate, which is mesoporous silica (SiO2) with a spike structure;

[0043] Electron microscopy observation of mesoporous silica. Figure 1 Electron microscopy images show that the mesoporous silica is uniform in size, with an average particle size of 500nm–1μm and a unique spike structure.

[0044] (II) Preparation of mesoporous silica loaded with α-ketoglutaric acid

[0045] 3) Take αKG, add water to dissolve it, adjust the pH value to neutral with NaOH (1M), and then add SiO2 obtained in step 2) to make the ratio of SiO2, αKG and water be 1g:4g:50ml. Finally, stir at room temperature for 12h and collect the precipitate by centrifugation to obtain mesoporous silica loaded with α-ketoglutaric acid (SiO2@αKG).

[0046] Example 2: Preparation of mesoporous silica loaded with α-ketoglutaric acid according to the present invention

[0047] (I) Preparation of mesoporous silica

[0048] 1) Take 1 g of hexadecyltrimethylammonium bromide (CTAB) and 0.8 mL of 0.1 M NaOH, add them to 50 mL of deionized water, stir at 60°C and 50 rpm for 2 hours, then add 4 mL of tetraethyl orthosilicate (TEOS) and 16 mL of cyclohexane, stir at 60°C and 50 rpm for 48 hours, and collect the white emulsion by centrifugation;

[0049] 2) taking the white emulsion, washing with water and ethanol to obtain a precipitate, dispersing the precipitate in 50 mL of acetone, refluxing at 50° C. for 12 h, removing CTAB, washing with ethanol, and drying to obtain a white precipitate, which is mesoporous silica with a spike structure;

[0050] (II) Preparation of mesoporous silica loaded with α-ketoglutaric acid

[0051] 3) Take αKG, add water to dissolve it, adjust the pH value to neutral with NaOH (1M), and then add SiO2 obtained in step 2) to make the ratio of SiO2, αKG and water be 1g:1g:50ml. Finally, stir at room temperature for 12h and collect the precipitate by centrifugation to obtain mesoporous silica loaded with α-ketoglutaric acid (SiO2@αKG).

[0052] Example 3 Preparation of mesoporous silica loaded with α-ketoglutaric acid according to the present invention

[0053] (I) Preparation of mesoporous silica

[0054] 1) Take 1 g of hexadecyltrimethylammonium bromide (CTAB) and 0.8 mL of 0.1 M NaOH, add them to 50 mL of deionized water, stir at 60°C and 300 rpm for 2 hours, then add 4 mL of tetraethyl orthosilicate (TEOS) and 16 mL of cyclohexane, stir at 60°C and 300 rpm for 48 hours, and collect the white emulsion by centrifugation;

[0055] 2) taking the white emulsion, washing with water and ethanol to obtain a precipitate, dispersing the precipitate in 50 mL of acetone, refluxing at 50° C. for 12 h, removing CTAB, washing with ethanol, and drying to obtain a white precipitate, which is mesoporous silica with a spike structure;

[0056] (II) Preparation of mesoporous silica loaded with α-ketoglutaric acid

[0057] 3) Take αKG, add water to dissolve it, adjust the pH value to neutral with NaOH (1M), and then add SiO2 obtained in step 2) to make the ratio of SiO2, αKG and water be 4g:1g:50ml. Finally, stir at room temperature for 12h and collect the precipitate by centrifugation to obtain mesoporous silica loaded with α-ketoglutaric acid (SiO2@αKG).

[0058] Example 4 Preparation of microneedles of the present invention

[0059] Take the SiO2@αKG prepared in Example 1, gelatin, photoinitiator (phenyl (2,4,6-trimethylbenzoyl) lithium phosphate) and deionized water according to the formula ratio (0.004g: 0.2g: 0.002g: 1mL) and mix them to obtain a microneedle mixed solution, then pour it into the microneedle mold of the PDMS mold, centrifuge it, and cure it under ultraviolet light to form an array of microneedles. Dry to remove moisture, demold, and obtain periodontal microneedles.

[0060] Example 5 Preparation of microneedles of the present invention

[0061] Take the SiO2@αKG prepared in Example 2, gelatin, photoinitiator (phenyl (2,4,6-trimethylbenzoyl) lithium phosphate) and deionized water according to the formula ratio (0.004g: 0.2g: 0.002g: 1mL) and mix them to obtain a microneedle mixed solution, then pour it into the microneedle mold of the PDMS mold, centrifuge it, and cure it under ultraviolet light to form an array of microneedles. Dry to remove moisture, demold, and obtain periodontal microneedles.

[0062] Example 6 Preparation of microneedles of the present invention

[0063] Take the SiO2@αKG prepared in Example 3, gelatin, photoinitiator (phenyl (2,4,6-trimethylbenzoyl) lithium phosphate) and deionized water according to the formula ratio (0.004g: 0.2g: 0.002g: 1mL) and mix them to obtain a microneedle mixed solution, then pour it into the microneedle mold of the PDMS mold, centrifuge it, and cure it under ultraviolet light to form an array of microneedles. Dry to remove moisture, demold, and obtain periodontal microneedles.

[0064] The beneficial effects of the present invention are further illustrated by test examples below:

[0065] Experimental Example 1 Study on the Microneedle of the Present Invention for the Treatment of Periodontitis

[0066] 1. Functional comparison between ordinary SiO2 and SiO2 with spike structure

[0067] Ordinary structure SiO2: Add 16 ml of 25% (w / v) hexadecyltrimethylammonium bromide solution and 90 mg of triethanolamine to 20 ml of water, gently stir at 60°C for 1 hour, then add 1.5 ml of ethyl silicate and 1 mL of cyclohexane to the solution, magnetically stir at 60°C for 24 hours, collect the precipitate by centrifugation, wash several times with water and ethanol, then disperse in 30 mL of acetone and reflux for 8 hours to remove hexadecyltrimethylammonium bromide, finally wash with ethanol and vacuum dry at 45°C for 8 hours.

[0068] SiO2 with spike structure: prepared according to Example 1.

[0069] The normal structure SiO2 and the spike structure SiO2 were labeled with FITC, mixed with αKG in a ratio of 1:4, stirred at room temperature for 12 hours, and then centrifuged to collect the precipitate to obtain mesoporous silica loaded with α-ketoglutaric acid (SiO2@αKG), and then RAW264.7 was used for cell phagocytosis experiments. The specific steps are:

[0070] Place the cell slide soaked in 75% alcohol in a 12-well plate and soak it in sterile PBS for later use. Prepare the cell suspension and adjust the RAW264.7 cell concentration to 1×10 5 / mL. A certain concentration of cell suspension and FITC-labeled SiO2@αKG nanoparticles (final concentration 20μg / mL) were added to the well plate, and the cells were incubated for different time periods, washed 3 times with preheated blank medium, fixed with 4% paraformaldehyde for 10 minutes, rinsed 3 times with PBS, and phalloidin was added. The cells were incubated in the incubator for 1 hour to stain the cytoskeleton. The cell nucleus was counterstained with DAPI working solution for 5 minutes, washed with PBS for 3 minutes, and the anti-fluorescence quenching sealing agent was used to seal the slices and then observed and photographed by laser confocal microscopy.

[0071] from Figure 2 The results of macrophage observations show that the spike-structured SiO2 enhances the interaction between nanomaterials and biological hosts with its unique topological structure. At the same time, the number of SiO2 with a spike structure (green fluorescence) entering cells is significantly higher than that of ordinary SiO2, and as time goes by, the number of nanoparticles entering the cells gradually increases (the green fluorescence in the cells gradually increases), indicating that the spike-structured SiO2 loaded with αKG is easier to enter macrophages than the ordinary structured SiO2 loaded with αKG. As a drug delivery carrier for αKG, the spike-structured SiO2 can efficiently carry αKG into macrophages, thereby promoting αKG to enter macrophages to regulate inflammation.

[0072] 2. Functional comparison of nanomaterial SiO2@αKG composites with different proportions of SiO2 and αKG

[0073] Take the SiO2@αKG prepared in Examples 1 to 3 respectively, add BMSC cells (bone mesenchymal stem cells) for co-culture, ensure that the concentration of the nanomaterial in the culture medium is 100 μg / ml, after 14 days, aspirate the culture medium in the wells, rinse with PBS 3 times, each time for 5 minutes; fix with 4% paraformaldehyde at room temperature for 30 minutes, add an appropriate amount of Alizarin Red staining solution to each well, and incubate at room temperature for 30 minutes in the dark; aspirate the staining solution, wash with double distilled water 2-3 times to remove incompletely bound dye, observe and take pictures under an inverted microscope, then add 10% cetylpyridinium chloride to dissolve the calcium nodules, and detect the absorption peak at 562nm.

[0074] Results Figure 3 ,from Figure 3 It can be seen that after treatment with SiO2@αKG synthesized at a ratio of 1:4, the calcium nodules (red) formed by BMSCs were significantly higher than those at other ratios. The same result was also shown by semi-quantitative statistics using cetylpyridinium chloride.

[0075] 3. Comparison of the effects of different functional ingredients

[0076] BMSC cells (bone mesenchymal stem cells) were treated with lipopolysaccharide (LPS) at a concentration of 200ng / ml, and then different nanomaterials (100μg / ml) were added in equal amounts for BMSC co-culture. Specifically, SiO2@αKG (prepared according to Example 1), mesoporous SiO2 with a spike structure (prepared according to Example 1) and α-ketoglutaric acid were taken respectively, and BMSC cells treated with LPS were added for co-culture as SSiO2@αKG group, SSiO2 group and αKG group. After 14 days, the culture medium in the wells was discarded, and PBS was rinsed 3 times, each time for 5min; 4% paraformaldehyde was fixed at room temperature for 30min, and an appropriate amount of alizarin red staining solution was added to each well, and incubated at room temperature for 30min away from light; the staining solution was discarded, and the cells were washed 2-3 times with double distilled water to remove the incompletely bound dyes, and observed and photographed under an inverted microscope. After that, 10% cetylpyridinium chloride was added to dissolve the calcium nodules, and the absorption peak at 562nm was detected. At the same time, normal BMSC cells and BMSC cells treated with LPS but not co-cultured with nanomaterials were used as controls.

[0077] Results Figure 4 ,from Figure 4 It can be seen that after LPS (lipopolysaccharide, inflammatory factor) treatment, BMSC cells have fewer calcium nodules (dyed red represents calcium nodules). Using α-ketoglutaric acid and mesoporous silica alone has a certain rescue effect, but it is not obvious. After treating cells with mesoporous silica loaded with α-ketoglutaric acid, the calcium nodules are significantly higher than those in other groups.

[0078] After Alizarin red staining, 10% cetylpyridinium chloride was used to dissolve the calcium nodules and the absorption peak at 562nm was detected. It can be clearly seen that under the action of equal amounts of nanomaterials, the SSiO2@αKG group had a more significant and statistically significant effect in promoting the formation of calcium nodules in cells under inflammatory conditions compared with the SSiO2 group and the αKG group. The osteogenesis ability was significantly improved, resulting in a synergistic effect.

[0079] 4. Verification of the efficacy of the microneedle in the treatment of periodontitis

[0080] The micron-sized needle tip of the microneedle penetrates the stratum corneum of the skin to form microchannels, which can directly deliver drugs to the epidermis or upper dermis, improving the penetration efficiency and bioavailability of drugs. Therefore, SiO2@αKG is made into microneedles to further verify its effect in treating periodontitis. Specifically:

[0081] BMSC cells were cultured using a transwell chamber, and the microneedles prepared in Example 4 and the microneedles without SiO2@αKG prepared in the same manner as Example 4 were placed in the upper chamber. After 14 days, alizarin red staining was used, and the formation of calcium nodules was observed by photographs and optical images to determine the effect of promoting osteogenesis.

[0082] Figure 5 It can be seen that the cell calcium nodules in the microneedle treatment group containing SiO2@αKG were significantly more than those in the microneedle control group without SiO2@αKG, which shows that SiO2@αKG made into a microneedle dosage form can still effectively promote the osteogenic differentiation of cells, which provides a feasible strategy for osteogenesis in periodontitis.

[0083] In summary, the present invention uses modified SiO2 with a unique spike structure as a carrier of αKG, and composites the modified SiO2 and αKG in a carrying manner, and acts on the affected area together, easily breaking through a variety of cells, such as macrophages, and the cell membrane defense line of bone mesenchymal stem cells, and exerting efficient immune regulation and bone metabolism regulation in vivo. Cell experiments have confirmed that: at the same dosage, compared with the use of SiO2 or αKG alone, the use of SiO2@αKG can form more calcium nodules in bone cells under inflammatory conditions, and it is statistically significant, and the osteogenic anti-inflammatory effect is significantly improved, resulting in a synergistic effect. Applying SiO2@αKG to the periodontal affected area through a microneedle administration method can enable the active ingredient SiO2@αKG to be efficiently delivered, further improving the therapeutic effect of periodontitis, and has practical promotion and application value.

Claims

1. A composite having osteogenic and anti-inflammatory effects, characterized in that: It is mesoporous silica loaded with α-ketoglutaric acid; The mass ratio of the mesoporous silica to α-ketoglutaric acid is 1:4 to 4:

1.

2. The composite according to claim 1, characterized in that: The mass ratio of the mesoporous silica to α-ketoglutaric acid is 1:4; And / or: the mesoporous silica is a mesoporous silica with a spike structure, and the particle size is 500nm to 1μm.

3. A method for preparing the composite according to claim 1 or 2, characterized in that: The steps include: 1) Take a cationic surfactant and a sodium hydroxide solution, add water and stir, then add tetraethyl orthosilicate and cyclohexane and stir, centrifuge, and collect a white emulsion; 2) taking the white emulsion obtained in step 1), washing with water and ethanol to obtain a precipitate, dispersing the precipitate in acetone, refluxing at 40-60° C. for 8-16 hours, collecting the precipitate, washing with ethanol, and drying to obtain mesoporous silica; 3) Dissolve α-ketoglutaric acid in water, adjust the pH value to neutral, add the mesoporous silica obtained in step 2) according to the ratio, stir at room temperature for 8 to 24 hours and then centrifuge to obtain the product.

4. The method according to claim 3, characterized in that: Step 1) The mass volume ratio of the cationic surfactant, sodium hydroxide solution, water, tetraethyl orthosilicate and cyclohexane is 0.5-2.5g:0.2-1mL:40-60ml:2-5mL:14-18mL, preferably 1g:0.8mL:50ml:4mL:16mL; adding water and stirring at a temperature of 50-70°C for 1.5-2.5 hours; adding tetraethyl orthosilicate and cyclohexane and stirring at a temperature of 50-70°C for 40-50 hours; The concentration of the sodium hydroxide solution is 0.1M; the water is deionized water; the cationic surfactant is hexadecyltrimethylammonium bromide; And / or, the amount of acetone used in step 2) is the same as the amount of water used in step 1); And / or, in step 3), the mass volume ratio of α-ketoglutaric acid to water is 1-4 g:50 ml.

5. Use of the complex according to claim 1 or 2 in the preparation of a drug for treating periodontitis, characterized in that: The drug has anti-inflammatory and / or osteogenic effects.

6. A drug for treating periodontitis, which is a preparation prepared by using the complex according to claim 1 or 2 as an active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients; The preparation is an oral administration preparation; The oral administration preparation is a solution, an ointment, a patch, or a powder; the patch includes a microneedle.

7. The drug according to claim 6, characterized in that: The microneedle is prepared from the following raw materials in parts by weight: 2 to 6 parts of mesoporous silica loaded with α-ketoglutaric acid as claimed in claim 1 or 2, 100 to 500 parts of gelatin, 1 to 5 parts of photoinitiator, and 500 to 1500 parts of water; Preferred: 4 parts of mesoporous silica loaded with α-ketoglutaric acid as described in claim 1 or 2, 200 parts of gelatin, 2 parts of photoinitiator, and 1000 parts of water.

8. The drug according to claim 6, characterized in that: The photoinitiator includes phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt.

9. A method for preparing the microneedle according to any one of claims 6 to 8, characterized in that: The steps include: Weigh the mesoporous silica loaded with α-ketoglutaric acid, gelatin, a photoinitiator and water according to the proportion, mix them, pour them into a mold, centrifuge, solidify, dry and demould to obtain the product; The mold is a PDMS mold; and the curing is performed by irradiating with an ultraviolet lamp.

10. Use of the microneedle according to any one of claims 6 to 8 in preparing a drug for treating periodontitis, characterized in that: The drug has anti-inflammatory and / or osteogenic effects.

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