Soluble nano microneedle as well as preparation method and application thereof

Abstract

The invention discloses a soluble nano microneedle as well as a preparation method and application thereof, and relates to the field of nano microneedles. When the soluble nano microneedle is prepared, pyrrole, benzaldehyde, p-hydroxy benzaldehyde and 1, 6-dibromohexane react to prepare quaternized porphyrin; the preparation method comprises the following steps: preparing drug-loaded nano microspheres from a polylactic acid-glycolic acid copolymer and quaternized porphyrin through an emulsion method; and then preparing a polyvinyl alcohol solution and the drug-loaded nano-microspheres through a template method. The soluble nano microneedle prepared by the invention has a good drug release effect, high drug utilization rate and low irritation.

Description

Technical Field

[0001] The present invention relates to the field of nano - microneedles, and specifically to a soluble nano - microneedle and a preparation method thereof. Background Art

[0002] The materials of soluble microneedles are generally water - soluble polymers, which are hard when dry and can easily pierce the stratum corneum when attached to the skin. After piercing the skin, the tips of the needles absorb the liquid components of the dermis layer and dissolve to release drugs. Soluble microneedles generally use biodegradable materials, which can degrade spontaneously in the skin, avoiding harmful residues caused by the breakage of microneedles in the skin and having good biocompatibility. The thickness of the human stratum corneum is 15 - 20μm. Microneedles can pierce the stratum corneum and underlying tissues to deliver antigens to the epidermis or dermis, and they are short enough not to reach pain receptors, thus avoiding the generation of pain sensation. In addition, immunization using microneedles does not require professional medical staff, which can greatly reduce the burden on hospitals in the case of large - scale vaccination, and there will be no sharp needle waste after vaccination, which is a great psychological comfort for people afraid of needles.

[0003] However, for soluble microneedles, the drug distribution in the needle body will directly affect the drug release rate of microneedles in the skin. On the other hand, the drugs of soluble microneedles are basically distributed throughout the entire needle body. When piercing the skin, the drugs in the base part will be wasted. The soluble nano - microneedles prepared by the present invention have good drug release effects, high drug utilization rates, low irritation, and broad market prospects. Summary of the Invention

[0004] The purpose of the present invention is to provide a preparation method of soluble nano - microneedles to solve the problems existing in the prior art.

[0005] To solve the above - mentioned technical problems, the present invention provides the following technical solutions: A soluble nano - microneedle, wherein the soluble nano - microneedle is prepared by reacting pyrrole, benzaldehyde, p - hydroxybenzaldehyde, and 1,6 - dibromohexane to obtain quaternized porphyrin; preparing drug - loaded nanospheres from poly(lactic - co - glycolic acid) copolymer and quaternized porphyrin by an emulsion method; and then preparing them from a polyvinyl alcohol solution and the drug - loaded nanospheres by a template method.

[0006] A preparation method of a soluble nano - microneedle, comprising the following preparation steps: (1) Mix benzaldehyde, p-hydroxybenzaldehyde, and propionic acid evenly and stir while heating to 130 °C. Dropwise add a pyrrolepropionic acid solution that is 7 - 9 times the mass of benzaldehyde. Continue heating under reflux for 4 - 6 h. After cooling to room temperature, add methanol that is 40 - 60 times the mass of benzaldehyde. Let it stand at 4 °C for 10 - 14 h, then filter by suction. Separate the solid by silica gel column chromatography to obtain Compound 1. Mix Compound 1, 1,6-dibromohexane, anhydrous potassium carbonate, and N,N-dimethylformamide evenly and stir at room temperature for 22 - 26 h. Add dichloromethane that is 70 - 90 times the mass of Compound 1. Extract with deionized water. Dry the organic phase with anhydrous sodium sulfate, filter, and remove the solvent by rotary evaporation. Separate the solid by silica gel column chromatography to obtain Compound 2. Mix Compound 2, tetrahydrofuran, a 30% (mass concentration) aqueous solution of trimethylamine, and chloroform evenly and heat under reflux at 40 - 50 °C for 10 - 14 h. Cool to room temperature and remove the solvent by rotary evaporation. Add methanol that is 3 - 5 times the mass of Compound 2 and hexane that is 40 - 60 times the mass of Compound 2. Let it stand for 16 - 20 h, centrifuge to separate the precipitate, and dry to obtain the quaternized porphyrin. (2) Add an oil phase that is 0.1 - 0.2 times the mass of the aqueous phase to the aqueous phase. The stirring rate of the aqueous phase is 550 - 650 r / min to prepare a pre-emulsion. Ultrasonic for 30 min, continue stirring for 10 - 14 h, centrifuge to separate the precipitate, wash the precipitate with deionized water 3 - 5 times, and freeze-dry to obtain the drug-loaded nanoparticles. (3) Mix polyvinyl alcohol, sucrose, and ultrapure water in a mass ratio of 4:3:16 to prepare a polyvinyl alcohol solution. Mix the nanoparticles and the polyvinyl alcohol solution in a mass ratio of 1:(10 - 15) to prepare a drug-loaded nanoparticle solution. Spread the drug-loaded nanoparticle solution evenly above the template cavity, evacuate for 15 min, scrape off the excess solution, then spread another layer of polyvinyl alcohol solution, evacuate for 30 min, dry, and demold to obtain the product.

[0007] As an optimization, the preparation method of the pyrrolepropionic acid solution described in step (1) is: Mix freshly distilled pyrrole and propionic acid in a volume ratio of 3:1.

[0008] As an optimization, the mass ratio of benzaldehyde, p-hydroxybenzaldehyde, and propionic acid described in step (1) is 1:(3.4 - 3.6):(40 - 50).

[0009] As an optimization, the mass ratio of Compound 1, 1,6-dibromohexane, anhydrous potassium carbonate, and N,N-dimethylformamide described in step (1) is 1:(2 - 3):(1.5 - 2.5):(70 - 90).

[0010] As an optimization, the mass ratio of Compound 2, tetrahydrofuran, a 30% (mass concentration) aqueous solution of trimethylamine, and chloroform described in step (1) is 1:(40 - 60):(40 - 50):(20 - 30).

[0011] As an optimization, the preparation method of the oil phase described in step (2) is as follows: Mix poly (lactic-co-glycolic acid), quaternized porphyrin, and dichloromethane according to a mass ratio of 1: (0.08 - 0.12): (25 - 35), and ultrasonicate for 15 minutes to obtain the oil phase; the preparation method of the aqueous phase is as follows: Mix polyvinyl alcohol and deionized water according to a mass ratio of 1: (250 - 350) to obtain the aqueous phase.

[0012] As an optimization, the template specifications described in step (3) are as follows: The height is 500 μm, the needle base diameter is 350 μm, the distance between adjacent needles is 550 μm, and the needle cavity sheet is a square array close to 1 cm × 1 cm.

[0013] Compared with the prior art, the beneficial effects achieved by the present invention are as follows: When preparing the soluble nano - microneedles of the present invention, pyrrole, benzaldehyde, p - hydroxybenzaldehyde, and 1,6 - dibromohexane are reacted to obtain quaternized porphyrin; poly (lactic - co - glycolic acid) and quaternized porphyrin are used to prepare drug - loaded nanospheres through an emulsion method; then polyvinyl alcohol solution and drug - loaded nanospheres are prepared through a template method.

[0014] Poly (lactic - co - glycolic acid) and quaternized porphyrin are used to prepare drug - loaded nanospheres through an emulsion method. Quaternized porphyrin has a conjugated large π - bond and good light absorption properties, and can convert light energy into heat energy. Under the irradiation of near - infrared light, it can effectively absorb light energy to generate heat, thereby promoting the dissolution of polyvinyl alcohol and improving the drug release performance of the soluble nano - microneedles; poly (lactic - co - glycolic acid) coats quaternized porphyrin. On the one hand, poly (lactic - co - glycolic acid) is a biocompatible material and has good compatibility with the human body. On the other hand, coating quaternized porphyrin with poly (lactic - co - glycolic acid) can reduce the toxicity of quaternary ammonium salts to cells. Quaternized porphyrin is positively charged and can bind to negatively charged proteins, so it is toxic to healthy cells. Using poly (lactic - co - glycolic acid) as the coating layer can isolate the contact between quaternized porphyrin and negatively charged proteins, thereby reducing its cytotoxicity and irritation. Specific embodiments

[0015] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0016] Example 1:

[0017] A preparation method of soluble nano - microneedles includes the following preparation steps: (1) Mix freshly distilled pyrrole and propionic acid in a volume ratio of 3:1 to obtain a pyrrole propionic acid solution; stir benzaldehyde, p-hydroxybenzaldehyde, and propionic acid in a mass ratio of 1:3.4:40 and heat to 130 °C, then add a pyrrole propionic acid solution 7 times the mass of benzaldehyde dropwise, continue heating under reflux for 4 h, cool to room temperature, add methanol 40 times the mass of benzaldehyde, let stand at 4 °C for 10 h, filter by suction, and separate the solid by silica gel column chromatography to obtain Compound 1; mix Compound 1, 1,6-dibromohexane, anhydrous potassium carbonate, and N,N-dimethylformamide in a mass ratio of 1:2:1.5:70, stir at room temperature for 2 h, add dichloromethane 70 times the mass of Compound 1, extract with deionized water, dry the organic phase with anhydrous sodium sulfate, filter, rotary evaporate to remove the solvent, and separate the solid by silica gel column chromatography to obtain Compound 2; mix Compound 2, tetrahydrofuran, a 30% aqueous solution of trimethylamine by mass concentration, and chloroform in a mass ratio of 1:40:40:20, heat under reflux at 40 °C for 10 h, cool to room temperature, rotary evaporate to remove the solvent, add methanol 3 times the mass of Compound 2 and hexane 40 times the mass of Compound 2, let stand for 16 h, centrifuge to separate the precipitate, and dry to obtain quaternized porphyrin; (2) Mix poly(lactic-co-glycolic acid), quaternized porphyrin, and dichloromethane in a mass ratio of 1:0.08:25, and ultrasonicate for 15 min to obtain an oil phase; mix polyvinyl alcohol and deionized water in a mass ratio of 1:250 to obtain an aqueous phase; add an oil phase 0.1 times the mass of the aqueous phase to the aqueous phase, and stir the aqueous phase at a rate of 550 r / min to obtain a pre-emulsion, ultrasonicate for 30 min, continue stirring for 10 h, centrifuge to separate the precipitate, wash the precipitate 3 times with deionized water, and freeze-dry to obtain drug-loaded nanospheres; (3) Mix polyvinyl alcohol, sucrose, and ultrapure water in a mass ratio of 4:3:16 to obtain a polyvinyl alcohol solution, mix the drug-loaded nanospheres and the polyvinyl alcohol solution in a mass ratio of 1:10 to obtain a drug-loaded nanosphere solution, evenly coat the drug-loaded nanoparticle solution above the template cavity, evacuate for 15 min, scrape off the excess solution, then evenly coat another layer of polyvinyl alcohol solution, evacuate for 30 min, dry and demold to obtain.

[0018] Example 2:

[0019] A preparation method of soluble nanoneedles, comprising the following preparation steps: (1) Mix freshly distilled pyrrole and propionic acid in a volume ratio of 3:1 to obtain a pyrrole propionic acid solution; Stir benzaldehyde, p-hydroxybenzaldehyde, and propionic acid in a mass ratio of 1:3.5:45 and heat to 130 °C, then dropwise add a pyrrole propionic acid solution 8 times the mass of benzaldehyde, continue heating under reflux for 5 h, cool to room temperature, add methanol 50 times the mass of benzaldehyde, place at 4 °C for 12 h, filter by suction, and separate the solid by silica gel column chromatography to obtain Compound 1; Mix Compound 1, 1,6-dibromohexane, anhydrous potassium carbonate, and N,N-dimethylformamide in a mass ratio of 1:2.5:2:80, stir at room temperature for 24 h, add dichloromethane 80 times the mass of Compound 1, extract with deionized water, dry the organic phase with anhydrous sodium sulfate, filter, rotary evaporate to remove the solvent, and separate the solid by silica gel column chromatography to obtain Compound 2; Mix Compound 2, tetrahydrofuran, 30% by mass aqueous trimethylamine solution, and chloroform in a mass ratio of 1:50:45:25, heat under reflux at 45 °C for 12 h, cool to room temperature, rotary evaporate to remove the solvent, add methanol 4 times the mass of Compound 2 and hexane 50 times the mass of Compound 2, let stand for 18 h, centrifuge to separate the precipitate, and dry to obtain quaternized porphyrin; (2) Mix poly(lactic-co-glycolic acid), quaternized porphyrin, and dichloromethane in a mass ratio of 1:0.1:30, sonicate for 15 min to obtain an oil phase; Mix polyvinyl alcohol and deionized water in a mass ratio of 1:300 to obtain an aqueous phase; Add an oil phase 0.15 times the mass of the aqueous phase to the aqueous phase, stir the aqueous phase at a rate of 600 r / min to obtain a pre-emulsion, sonicate for 30 min, continue stirring for 12 h, centrifuge to separate the precipitate, wash the precipitate 4 times with deionized water, and freeze-dry to obtain drug-loaded nanospheres; (3) Mix polyvinyl alcohol, sucrose, and ultrapure water in a mass ratio of 4:3:16 to obtain a polyvinyl alcohol solution, mix the drug-loaded nanospheres and the polyvinyl alcohol solution in a mass ratio of 1:12.5 to obtain a drug-loaded nanosphere solution, evenly coat the drug-loaded nanoparticle solution above the template cavity, evacuate for 15 min, scrape off the excess solution, then evenly coat another layer of polyvinyl alcohol solution, evacuate for 30 min, dry and demold to obtain.

[0020] Example 3:

[0021] A method for preparing soluble nanoneedles, comprising the following preparation steps: (1) Mix freshly distilled pyrrole and propionic acid in a volume ratio of 3:1 to obtain a pyrrole propionic acid solution; stir benzaldehyde, p-hydroxybenzaldehyde, and propionic acid in a mass ratio of 1: 3.6: 50 and heat to 130 °C, then drop in a pyrrole propionic acid solution 9 times the mass of benzaldehyde, continue heating under reflux for 6 h, cool to room temperature, add methanol 60 times the mass of benzaldehyde, place at 4 °C for 14 h, filter by suction, and separate the solid by silica gel column chromatography to obtain Compound 1; mix Compound 1, 1,6-dibromohexane, anhydrous potassium carbonate, and N,N-dimethylformamide in a mass ratio of 1: 3: 2.5:90, stir at room temperature for 26 h, add dichloromethane 90 times the mass of Compound 1, extract with deionized water, dry the organic phase with anhydrous sodium sulfate, filter, rotary evaporate to remove the solvent, and separate the solid by silica gel column chromatography to obtain Compound 2; mix Compound 2, tetrahydrofuran, a 30% (mass concentration) aqueous solution of trimethylamine, and chloroform in a mass ratio of 1:60: 50: 30, heat under reflux at 50 °C for 14 h, cool to room temperature, rotary evaporate to remove the solvent, add methanol 5 times the mass of Compound 2 and hexane 60 times the mass of Compound 2, let stand for 20 h, centrifuge to separate the precipitate, and dry to obtain quaternized porphyrin; (2) Mix poly(lactic-co-glycolic acid), quaternized porphyrin, and dichloromethane in a mass ratio of 1: 0.12: 35, and ultrasonicate for 15 min to obtain an oil phase; mix polyvinyl alcohol and deionized water in a mass ratio of 1: 350 to obtain an aqueous phase; add an oil phase 0.2 times the mass of the aqueous phase to the aqueous phase, stir the aqueous phase at a rate of 650 r / min to obtain a pre-emulsion, ultrasonicate for 30 min, continue stirring for 14 h, centrifuge to separate the precipitate, wash the precipitate 5 times with deionized water, and freeze-dry to obtain drug-loaded nanospheres; (3) Mix polyvinyl alcohol, sucrose, and ultrapure water in a mass ratio of 4:3:16 to obtain a polyvinyl alcohol solution, mix the drug-loaded nanospheres and the polyvinyl alcohol solution in a mass ratio of 1: 15 to obtain a drug-loaded nanosphere solution, evenly coat the drug-loaded nanoparticle solution above the template cavity, evacuate for 15 min, scrape off the excess solution, then evenly coat another layer of polyvinyl alcohol solution, evacuate for 30 min, dry and demold to obtain the product.

[0022] Comparative Example 1: A preparation method of soluble nanoneedles, comprising the following preparation steps: (1) Mix polyvinyl alcohol, sucrose, and ultrapure water in a mass ratio of 4:3:16 to obtain a polyvinyl alcohol solution, mix the drug-loaded nanospheres and the polyvinyl alcohol solution in a mass ratio of 1:12.5 to obtain a drug-loaded nanosphere solution, evenly coat the drug-loaded nanoparticle solution above the template cavity, evacuate for 15 min, scrape off the excess solution, then evenly coat another layer of polyvinyl alcohol solution, evacuate for 30 min, dry and demold to obtain the product.

[0023] Comparative Example 1: A preparation method of soluble nano - microneedles, comprising the following preparation steps: (1) Mix freshly distilled pyrrole and propionic acid in a volume ratio of 3:1 to obtain a pyrrole - propionic acid solution; Stir benzaldehyde, p - hydroxybenzaldehyde, and propionic acid in a mass ratio of 1:3.5:45 and heat to 130 °C. Drop in a pyrrole - propionic acid solution 8 times the mass of benzaldehyde, continue heating under reflux for 5 h. After cooling to room temperature, add methanol 50 times the mass of benzaldehyde, place at 4 °C for 12 h, filter by suction, and separate the solid by silica gel column chromatography to obtain compound 1; Mix compound 1, 1,6 - dibromohexane, anhydrous potassium carbonate, and N,N - dimethylformamide in a mass ratio of 1:2.5:2:80, stir at room temperature for 24 h, add dichloromethane 80 times the mass of compound 1, extract with deionized water, dry the organic phase with anhydrous sodium sulfate, filter, rotary evaporate to remove the solvent, and separate the solid by silica gel column chromatography to obtain compound 2; Mix compound 2, tetrahydrofuran, a 30% (mass concentration) aqueous solution of trimethylamine, and chloroform in a mass ratio of 1:50:45:25, heat under reflux at 45 °C for 12 h, cool to room temperature, rotary evaporate to remove the solvent, add methanol 4 times the mass of compound 2 and hexane 50 times the mass of compound 2, let stand for 18 h, centrifuge to separate the precipitate, and dry to obtain quaternized porphyrin; (3) Mix polyvinyl alcohol, sucrose, and ultrapure water in a mass ratio of 4:3:16 to obtain a polyvinyl alcohol solution. Mix quaternized porphyrin and the polyvinyl alcohol solution in a mass ratio of 1:12.5 to obtain a quaternized porphyrin solution. Spread the quaternized porphyrin solution evenly above the template cavity, evacuate for 15 min, scrape off the excess solution, then spread another layer of polyvinyl alcohol solution, evacuate for 30 min, dry and demold to obtain the product.

[0024] Test Example 1: Drug release test: Use human - simulated skin composed of gelatin hydrogel to test the drug release effect of soluble nano - microneedles. The preparation method of gelatin hydrogel is as follows: Dissolve 2.5 g of gelatin solution in 50 mL of ultrapure water at 60 °C to form a homogeneous and transparent solution. Slowly pour the prepared 5 w / v% gelatin solution into a petri dish while it is hot, and let it stand at room temperature for 12 h. When the gelatin forms an elastic and non - flowing state, it can be prepared for use. Pierce the soluble nano - microneedles prepared in each example and comparative example into the gelatin with appropriate pressure, and observe the dissolution situation after 10 min through a hand - held microscope. Take another portion of the soluble nano - microneedles prepared in each example and comparative example, pierce them into the gelatin with appropriate pressure, irradiate with a near - infrared laser, and observe the dissolution situation after 10 min through a hand - held microscope. The results are shown in Table 1.

[0025] Table 1 Dissolution rate (%) Dissolution rate after near-infrared irradiation (%) Example 1 94 98 Example 2 94 98 Example 3 92 99 Comparative Example 1 93 92 Comparative Example 2 92 92 From the comparison of the experimental data of Examples 1 to 3 and Comparative Examples 1 to 2 in Table 1, it can be found that the soluble nano - microneedles prepared by the present invention have good drug - release performance.

[0026] The difference between Comparative Example 1 and Example 2 is that quaternized porphyrin was not added. By comparison, the dissolution rate of Comparative Example 1 is better than that of Comparative Example 1 after near - infrared irradiation. This shows that quaternized porphyrin has a conjugated large π - bond and good light - absorption property, can convert light energy into heat energy, can effectively absorb light energy to generate heat under the irradiation of near - infrared light, thus promoting the dissolution of polyvinyl alcohol and improving the drug - release performance of the soluble nano - microneedles.

[0027] Test Example 2: Irritation test: Select healthy experimental mice, shave the hair at the same position, stick the soluble nano - microneedles prepared in each example and comparative example on the skin surface of the shaved mice, press for 5 min and then wait for 30 min, remove the soluble nano - microneedles, and observe the condition of the skin surface of the mice after 6 h. The results are shown in Table 2.

[0028] Table 2 Redness and swelling condition Example 1 No redness and swelling Example 2 No redness and swelling Example 3 No redness and swelling Comparative Example 1 No redness and swelling Comparative Example 2 Redness and swelling From the comparison of the experimental data of Examples 1 to 3 and Comparative Examples 1 to 2 in Table 2, it can be found that the soluble nano - microneedles prepared by the present invention have low irritation.

[0029] The difference between Comparative Example 2 and Example 2 is that quaternized porphyrin was not coated with poly(lactic - co - glycolic acid). By comparison, the irritation of Comparative Example 2 is greater than that of Examples 1 to 3. This shows that coating quaternized porphyrin with poly(lactic - co - glycolic acid) can reduce the toxicity of quaternary ammonium salts to cells. Quaternized porphyrin is positively charged and can bind to negatively charged proteins, so it is toxic to healthy cells. Using poly(lactic - co - glycolic acid) as the coating layer can isolate the contact between quaternized porphyrin and negatively charged proteins, thereby reducing its toxicity to cells and reducing irritation.

[0030] The specific embodiments described above have further detailed the purpose, technical solution and beneficial effects of the present invention. It should be understood that the above - mentioned are only specific embodiments of the present invention and are not used to limit the protection scope of the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A soluble nano - microneedle, characterized in that, The soluble nano - microneedles are prepared by reacting pyrrole, benzaldehyde, p - hydroxybenzaldehyde, and 1,6 - dibromohexane to obtain quaternized porphyrin; preparing drug - loaded nanospheres from poly(lactic - co - glycolic acid) copolymer and quaternized porphyrin by emulsion method; and then preparing them from polyvinyl alcohol solution and drug - loaded nanospheres by template method.

2. The preparation method of a soluble nano microneedle according to claim 1, characterized in that, It includes the following preparation steps: (1) Mix and stir benzaldehyde, p - hydroxybenzaldehyde, and propionic acid and heat up to 130 °C, then drop in a pyrrole - propionic acid solution which is 7 - 9 times the mass of benzaldehyde, continue heating under reflux for 4 - 6 h, cool to room temperature, add methanol which is 40 - 60 times the mass of benzaldehyde, place at 4 °C for 10 - 14 h, filter by suction, and separate the solid by silica gel column chromatography to obtain Compound 1; mix Compound 1, 1,6 - dibromohexane, anhydrous potassium carbonate, and N,N - dimethylformamide, stir at room temperature for 22 - 26 h, add dichloromethane which is 70 - 90 times the mass of Compound 1, extract with deionized water, dry the organic phase with anhydrous sodium sulfate, filter, remove the solvent by rotary evaporation, and separate the solid by silica gel column chromatography to obtain Compound 2; mix Compound 2, tetrahydrofuran, 30% (mass concentration) aqueous trimethylamine solution, and chloroform, heat under reflux at 40 - 50 °C for 10 - 14 h, cool to room temperature, remove the solvent by rotary evaporation, add methanol which is 3 - 5 times the mass of Compound 2 and hexane which is 40 - 60 times the mass of Compound 2, let stand for 16 - 20 h, centrifuge to separate the precipitate, and dry to obtain quaternized porphyrin; (2) Add an oil phase which is 0.1 - 0.2 times the mass of the aqueous phase to the aqueous phase, with the stirring rate of the aqueous phase being 550 - 650 r / min to prepare a pre - emulsion, ultrasonicate for 30 min, continue stirring for 10 - 14 h, centrifuge to separate the precipitate, wash the precipitate with deionized water 3 - 5 times, and freeze - dry to obtain drug - loaded nanoparticles; (3) Mix polyvinyl alcohol, sucrose, and ultrapure water according to a mass ratio of 4:3:16 to prepare a polyvinyl alcohol solution, mix the nanoparticles and the polyvinyl alcohol solution according to a mass ratio of 1:(10 - 15) to prepare a drug - loaded nanoparticle solution, evenly coat the drug - loaded nanoparticle solution above the template cavity, evacuate for 15 min, scrape off the excess solution, then evenly coat another layer of polyvinyl alcohol solution, evacuate for 30 min, dry and demold to obtain the product.

3. The preparation method of a soluble nano-micro needle according to claim 2, characterized in that, The preparation method of the pyrrole - propionic acid solution described in step (1) is: mix freshly distilled pyrrole and propionic acid according to a volume ratio of 3:

1.

4. The preparation method of a soluble nano-microneedle according to claim 2, characterized in that, The mass ratio of benzaldehyde, p - hydroxybenzaldehyde, and propionic acid described in step (1) is 1:(3.4 - 3.6):(40 - 50).

5. The preparation method of a soluble nano-micro needle according to claim 2, characterized in that The mass ratio of Compound 1, 1,6 - dibromohexane, anhydrous potassium carbonate, and N,N - dimethylformamide described in step (1) is 1:(2 - ).

6. The preparation method of a soluble nano-micro needle according to claim 2, characterized in that, The mass ratio of Compound 2, tetrahydrofuran, 30% (mass concentration) aqueous trimethylamine solution, and chloroform described in step (1) is 1:(40 - 60):(40 - 50):(20 - 30).

7. The preparation method of a soluble nano microneedle according to claim 2, characterized in that, The preparation method of the oil phase described in step (2) is as follows: poly (lactic-co-glycolic acid), quaternized porphyrin, and dichloromethane are mixed evenly at a mass ratio of 1: (0.08 - 0.12): (25 - 35), and then ultrasonicated for 15 minutes to obtain the oil phase; the preparation method of the water phase is as follows: polyvinyl alcohol and deionized water are mixed evenly at a mass ratio of 1: (250 - 350) to obtain the water phase.

8. The preparation method of a soluble nano microneedle according to claim 2, characterized in that, The template specifications described in step (3) are as follows: the height is 500 μm, the needle base diameter is 350 μm, the distance between adjacent needles is 550 μm, and the needle cavity sheet is a square array close to 1 cm × 1 cm.

9. Use of the method for preparing soluble nano - microneedles according to any one of claims 1 - 8 in the preparation of nano - microneedles.