A micro-needle transdermal administration preparation of a nutrient solution and a preparation method thereof

Abstract

The present application relates to the technical field of microneedle preparation, in particular to a kind of nutrient solution microneedle transdermal drug preparation and preparation method thereof, and the microneedle transdermal drug preparation includes insoluble backing and soluble microneedle needle body vertically connected to the backing.The soluble microneedle needle body includes soluble synthetic polymer material and active ingredient, the insoluble backing includes polypropylene, the soluble synthetic polymer material includes boric acid-phosphoric acid-polyvinyl alcohol, and the active ingredient is liposome-coated nutrient solution nanoparticles, and the liposome is modified with tannic acid-carboxymethyl chitosan.The prepared nutrient solution microneedle transdermal drug preparation has high drug loading capacity, high toughness and hardness, and the active ingredient is not easy to migrate to the backing, has sustained-release effect, and high bioavailability.

Description

Technical Field

[0001] This invention relates to the field of microneedle formulation technology, specifically to a microneedle transdermal drug delivery formulation of a nutrient solution and its preparation method. Background Technology

[0002] Compared to traditional drug delivery methods (oral and injection), transdermal drug delivery offers advantages such as avoiding the first-pass effect of the intestines and liver, safety, convenience, and being painless and non-invasive. However, currently, there are not many drugs available for transdermal delivery, mainly because traditional creams and patches are affected by the barrier effect of the stratum corneum, resulting in low rates and efficiency of transdermal drug penetration. Soluble microneedles are a novel transdermal drug delivery carrier that combines the advantages of subcutaneous injection and transdermal delivery. Drugs are encapsulated within needle-like protrusions, which penetrate the stratum corneum to form small channels, breaking down the barrier and allowing the drug to directly enter the skin, significantly improving transdermal absorption. Soluble microneedles are tiny, unlikely to reach subcutaneous nerves, and therefore do not cause significant pain; the tiny channels formed by puncture heal automatically within hours, without causing bleeding or trauma; and they are simple and convenient to use, allowing patients to administer the drug at home. Because of these advantages, soluble microneedles have become an effective carrier for solving the problem of transdermal delivery of poorly soluble drugs.

[0003] Existing soluble microneedles are mainly made by dissolving active drugs in water-soluble polymer materials and casting them into molds. Although soluble microneedles have high transdermal delivery efficiency, they still have some drawbacks and shortcomings: (1) Low drug loading, especially for drugs with poor water solubility, the drug loading is difficult to increase by increasing the drug concentration of the solution at the needle tip, and the amount of drug delivered to the site of action is still insufficient; (2) Microneedles made of tough materials have poor flatness and wrinkling, while microneedles made of brittle materials have greater hardness but are easy to break; (3) Active ingredients are prone to migrate to the backing; (4) Drug stability cannot be guaranteed, there is no sustained-release function, and poor permeability; (5) Low bioavailability. Therefore, how to develop a microneedle transdermal drug delivery formulation with high drug loading, toughness and mechanical properties, drug that is not easily retained in the backing, drug stability, sustained-release function, and improved bioavailability is an urgent technical problem to be solved. Summary of the Invention

[0004] This invention proposes a microneedle transdermal drug delivery formulation of nutrient solution and its preparation method. Boric acid-phosphate-polyvinyl alcohol is used as the soluble microneedle substrate, which is tough, not easily broken, and has increased mechanical strength, facilitating skin penetration. The nutrient solution is encapsulated with liposomes, improving permeability and bioavailability, and enhancing sustained-release properties. Ellagic acid-carboxymethyl chitosan is used to modify the liposomes, enhancing their solubility and stability. Simultaneously, the liposomes can form intermolecular hydrogen bonds with the boric acid-phosphate-polyvinyl alcohol substrate through ellagic acid-carboxymethyl chitosan, significantly enhancing the solubility of the liposomes in the substrate and increasing drug loading. Polypropylene is used as a poorly soluble backing, which is non-toxic and odorless, preventing the active ingredients in the needle from migrating to the backing.

[0005] This invention is achieved through the following technical solution: A microneedle transdermal drug delivery formulation for a nutrient solution includes a poorly soluble backing and soluble microneedles vertically connected to the backing.

[0006] Furthermore, the insoluble backing material includes polypropylene, and the soluble microneedle material includes boric acid-phosphate-polyvinyl alcohol and ellagic acid-carboxymethyl chitosan-modified nutrient solution liposomes.

[0007] Furthermore, the nutrient solution liposomes modified with ellagic acid-carboxymethyl chitosan are liposomes containing nutrient solution modified with ellagic acid-carboxymethyl chitosan.

[0008] Furthermore, the nutrient solution includes, but is not limited to, one or more active ingredients with therapeutic or health-promoting functions, in a solution or suspension prepared with deionized water.

[0009] This invention also provides a method for preparing a nutrient solution microneedle transdermal drug delivery formulation, comprising the following steps: S1: Boric acid-phosphoric acid-polyvinyl alcohol and anhydrous ethanol are thoroughly mixed in a mass ratio of 1:1 to obtain a soluble polymer substrate. S2: The soluble polymer substrate obtained in step S1 is mixed with the nutrient liposome modified with ellagic acid-carboxymethyl chitosan in a certain proportion, heated and dissolved to obtain soluble microneedle material. S3: Add the soluble microneedle material obtained in step S2 into the microneedle mold, centrifuge at 10000 rpm for 1-2 h, and then dry at 40-45°C under forced air conditions for 40-50 min; S4: Add 10%wt polypropylene anhydrous ethanol solution to the microneedle mold as a poorly soluble backing, continue drying for 8-10 h, demold, and obtain a microneedle transdermal drug delivery formulation of nutrient solution according to the present invention.

[0010] Furthermore, the mixing ratio of the soluble polymer substrate and the ellagic acid-carboxymethyl chitosan-modified nutrient liposomes in step S2 is determined according to the required dosage of active ingredients.

[0011] Further, the preparation method of boric acid-phosphate-polyvinyl alcohol in step S1 includes the following steps: i: Take phosphoric acid, polyvinyl alcohol and acetone in a mass ratio of 2:1:10, heat to 60-80°C and stir for 1-2 hours, dry in a vacuum drying oven at 60°C, and then grind into powder to obtain polyvinyl phosphate. ii: Prepare a 30 g / L polyvinyl phosphate solution by mixing the polyvinyl phosphate obtained in step i with deionized water; iii: Dissolve boric acid in anhydrous ethanol to prepare a 1.2 mol / L boric acid solution. Then add urea of ​​equal mass to the boric acid solution. Mix the boric acid solution and the polyvinyl phosphate solution obtained in step ii at a volume ratio of 1:1. Transfer the mixture to a reaction vessel and react at 70°C for 7 h. Remove the ethanol solution by rotary evaporation at 95°C and vacuum dry at 80°C for 1 h to obtain boric acid-phosphate-polyvinyl alcohol.

[0012] Furthermore, the synthesis reaction equation for the boric acid-phosphate polyvinyl alcohol is as follows: ; .

[0013] Furthermore, the method for preparing the ellagic acid-carboxymethyl chitosan-modified nutrient solution liposomes described in step S2 includes the following steps: I: Dissolve soybean lecithin, cholesterol and vitamin E in anhydrous ethanol at a mass ratio of 8:2:1 to prepare a lipid solution with soybean lecithin, cholesterol and vitamin E concentrations of 40 mg / mL, 10 mg / mL and 5 mg / mL, respectively. II: The lipid solution obtained in step I is subjected to rotary evaporation under reduced pressure to remove the organic solvent and obtain a lipid film, which is then uniformly adhered to the container wall. III: Pour 1%wt nutrient solution into the container containing the lipid film in step II. The volume ratio of nutrient solution to lipid solution is 5:4. Perform ultrasonic emulsification and mixing, and disperse in ice water at 200W power for 2-3 minutes to obtain a liposome suspension. IV: Weigh out ellagic acid-carboxymethyl chitosan and dissolve it in an equal volume of 1% acetic acid solution to prepare an ellagic acid-carboxymethyl chitosan acetic acid solution with a concentration of 30 mg / mL. Stir for 14 h. Slowly add the liposome suspension prepared in step III to the ellagic acid-carboxymethyl chitosan acetic acid solution at a dropping rate of 0.5 mL / min. Continue stirring for 2-3 hours to obtain the liposome solution. V: Add 15% (w / w) of mannose-lactose freeze-drying protectant to the liposome solution obtained in step IV, pre-freeze in a -80°C freezer for 24 h, the mass ratio of mannose to lactose in the freeze-drying protectant is 1:1, after pre-freezing quickly transfer to a freeze dryer, reduce the pressure to 0.2 Mbar, and freeze-dry under vacuum at -80°C for 24 h to obtain freeze-dried powder, thus preparing ellagic acid-carboxymethyl chitosan modified nutrient liposomes.

[0014] Furthermore, the preparation of ellagic acid-carboxymethyl chitosan in step IV includes the following steps: (1) Dissolve a certain amount of ellagic acid in DMSO to prepare a 0.1 g / mL solution, add 1 / 2 the weight of succinic anhydride of ellagic acid, stir at 40 °C for 12-24 h to obtain mixed solution I; (2) Add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC·HCl and N-hydroxysuccinimide NHS to DMSO to prepare solutions with EDC·HCl concentrations of 1 mol / L and NHS concentrations of 1.2 mol / L, respectively, to obtain mixed solution II; (3) Mix solution I and mixed solution II at a volume ratio of 5:1. After 30-40 min, add twice the volume of carboxymethyl chitosan aqueous solution with a concentration of 25 mg / mL. Stir at room temperature for 18-22 h, dialyze with deionized water for 4 days, and freeze dry to obtain ellagic acid-carboxymethyl chitosan.

[0015] Furthermore, the synthesis reaction equation for the ellagic acid-carboxymethyl chitosan is as follows: ; .

[0016] Compared with the prior art, the present invention has the following beneficial effects: (1) In this invention, boric acid-phosphoric acid-polyvinyl alcohol is prepared by reacting polyvinyl alcohol, phosphoric acid and boric acid as a soluble microneedle substrate. Polyvinyl alcohol is a tough material that is not easy to break, but its strength is not enough, its flatness is not ideal, and it is easy to wrinkle. Using brittle materials can solve the problem of insufficient strength, but it is easy to break. Boric acid-phosphoric acid-polyvinyl alcohol is tough and not easy to break, and has strong mechanical strength and high hardness, making it easy to penetrate the skin. In addition, boric acid groups can form hydrogen bonds with other molecules.

[0017] (2) In this invention, the nutrient solution is encapsulated with liposomes, which makes it easier to transport in the human body, facilitates absorption and utilization, and improves bioavailability. Liposomes can encapsulate hydrophilic or hydrophobic active ingredients and can serve as carriers for biomolecular active ingredients, as well as unstable and poorly soluble active ingredients. This avoids the decrease or loss of activity of active ingredients due to endogenous enzyme cleavage in the body, or their rapid clearance by the body's immune system. At the same time, it can prevent the decrease in activity of active ingredients when the body environment is unstable. This invention prepares liposomes to encapsulate the nutrient solution. Liposomes have good controlled-release ability and enhance sustained-release properties. Their lipid solubility is conducive to dissolving poorly soluble active ingredients, expanding the selection range of active ingredients. They can also fuse with stratum corneum lipids, improve permeability, and enhance the transdermal delivery efficiency of active ingredients. The encapsulation of liposomes can improve the stability of active ingredients and improve their bioavailability.

[0018] (3) In this invention, ellagic acid-carboxymethyl chitosan is prepared by reacting ellagic acid and carboxymethyl chitosan. The liposomes are modified by ellagic acid-carboxymethyl chitosan, which enhances the solubility and stability of the liposomes and improves the encapsulation rate of the active ingredients. At the same time, the liposomes can form intermolecular hydrogen bonds with the boric acid-phosphate-polyvinyl alcohol needle substrate through ellagic acid-carboxymethyl chitosan, which significantly enhances the solubility of the liposomes in the needle substrate and increases the drug loading.

[0019] (4) This invention uses polypropylene as the backing material for soluble microneedles. Normally, only the active ingredient at the needle tip can enter the skin with the soluble microneedle, while the remaining active ingredient remains on the backing. By using polystyrene as a poorly soluble backing and assembling it with a water-soluble needle tip, the migration of the drug to the backing layer can be significantly reduced because the needle tip and backing material are immiscible. In addition, polypropylene is non-toxic, odorless, relatively safe, and lightweight, making it suitable as a backing material. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only for this invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 The infrared spectrum of ellagic acid-carboxymethyl chitosan described in Example 3 of this invention; Figure 2 This is an electron micrograph of the nutrient solution liposomes modified with ellagic acid-carboxymethyl chitosan as described in Example 3 of the present invention; Figure 3 The mechanical strength test diagrams are of the microneedle formulations described in Examples 1-3 (a) and Comparative Example 1 (b) of the present invention; a: Microneedle formulations of Examples 1-3; b: Microneedle formulation of Comparative Example 1; Figure 4 The figures show the experimental results of transdermal water loss of the microneedle formulations described in Examples 1-3 and Comparative Example 2 of this invention; Figure 5 The diagram shows the drug loading efficiency of the microneedle formulations described in Example 4 and Comparative Examples 3-6 of this invention. Figure 6 This is a graph showing the cumulative drug release rate of the microneedle formulations described in Example 5 and Comparative Examples 7-8 of the present invention; Figure 7 This is a skin absorption rate diagram of the microneedle formulations described in Example 4 and Comparative Examples 3-6 of the present invention. Detailed Implementation

[0022] To make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited to the following embodiments.

[0023] It should be noted that, unless otherwise specified, all chemical reagents involved in this invention were purchased through commercial channels.

[0024] Example 1: This example provides a method for preparing a microneedle transdermal drug delivery formulation of a nutrient solution, mainly including the following steps: Preparation of boric acid-phosphoric acid-polyvinyl alcohol: i: Mix 100 g of phosphoric acid, 50 g of polyvinyl alcohol and 500 g of acetone, heat to 80°C and stir for 2 h, dry in a vacuum drying oven at 60°C, and then grind into powder to obtain polyvinyl phosphate. ii: Prepare a 30 g / L polyvinyl phosphate solution by mixing the polyvinyl phosphate obtained in step i with deionized water; iii: Dissolve boric acid in anhydrous ethanol to prepare a 1.2 mol / L boric acid solution. Then add urea of ​​the same mass as boric acid to the boric acid solution. Mix 1 L of boric acid solution and 1 L of polyvinyl phosphate solution obtained in step ii evenly, transfer to a reaction vessel, react at 70°C for 7 h, remove the ethanol solution by rotary evaporation at 95°C, and vacuum dry at 80°C for 1 h to obtain boric acid-phosphate-polyvinyl alcohol.

[0025] Preparation of ellagic acid-carboxymethyl chitosan: (1) Dissolve 10 g of ellagic acid in 100 mL of DMSO to prepare a 0.1 g / mL solution, add 5 g of succinic anhydride, and stir at 40 °C for 24 h to obtain mixed solution I; (2) Add 0.1 mol L of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC·HCl and 0.12 mol L of N-hydroxysuccinimide NHS to 100 mL of DMSO to prepare solutions with EDC·HCl concentrations of 1 mol / L and NHS concentrations of 1.2 mol / L, respectively, to obtain mixed solution II; (3) Mix 100 mL of mixed solution I and 20 mL of mixed solution II. After 40 min, add 200 mL of carboxymethyl chitosan aqueous solution with a concentration of 25 mg / mL. Stir at room temperature for 22 h, dialyze with deionized water for 4 days, and freeze dry to obtain ellagic acid-carboxymethyl chitosan.

[0026] Preparation of nutrient solution liposomes modified with ellagic acid-carboxymethyl chitosan: I: Dissolve 4 g of soybean lecithin, 1 g of cholesterol and 0.5 g of vitamin E in anhydrous ethanol to prepare a lipid solution with soybean lecithin, cholesterol and vitamin E concentrations of 40 mg / mL, 10 mg / mL and 5 mg / mL, respectively. II: The lipid solution obtained in step I is subjected to rotary evaporation under reduced pressure to remove the organic solvent and obtain a lipid film, which is then uniformly adhered to the container wall. III: Mix 0.5 g colchicine and 0.76 g paclitaxel with 125 mL deionized water to prepare a suspension. Pour the suspension into the container containing the lipid film from step II, perform ultrasonic emulsification and mixing, and disperse in ice water at 200 W power for 3 min to obtain a liposome suspension. IV: Weigh out ellagic acid-carboxymethyl chitosan and dissolve it in an equal volume of 1% wt acetic acid solution to prepare an ellagic acid-carboxymethyl chitosan acetic acid solution with a concentration of 30 mg / mL. Stir for 14 h. Slowly add the liposome suspension prepared in step III to the ellagic acid-carboxymethyl chitosan acetic acid solution at a dropping rate of 0.5 mL / min. Continue stirring for 3 hours to obtain the liposome solution. V: Add 15% (w / w) of mannose-lactose freeze-drying protectant to the liposome solution obtained in step IV, pre-freeze in a -80°C freezer for 24 h, the mass ratio of mannose to lactose in the freeze-drying protectant is 1:1, after pre-freezing quickly transfer to a freeze dryer, reduce the pressure to 0.2 Mbar, and freeze-dry under vacuum at -80°C for 24 h to obtain freeze-dried powder, thus preparing ellagic acid-carboxymethyl chitosan modified nutrient liposomes.

[0027] Preparation of microneedle transdermal drug delivery formulations for nutrient solutions: S1: Mix 1 g of boric acid-phosphoric acid-polyvinyl alcohol with 1 g of anhydrous ethanol thoroughly to obtain a soluble polymer substrate; S2: Mix 1 g of the soluble polymer substrate obtained in step S1 with 1 g of nutrient liposome modified with ellagic acid-carboxymethyl chitosan, heat and dissolve to obtain soluble microneedle material. S3: Add 50 μL of the soluble microneedle material obtained in step S2 into the microneedle mold, centrifuge at 10000 rpm for 2 h, and then dry at 45°C under forced air for 50 min. S4: Add 450 μL of 10%wt polypropylene anhydrous ethanol solution to the microneedle mold as a poorly soluble backing, continue drying for 10 h, demold, and obtain a 15*10 array (12 mm*8 mm in length and width) microneedle formulation. Each microneedle array has 150 needles, which is the microneedle transdermal drug delivery formulation of nutrient solution.

[0028] Example 2: This example provides a method for preparing a microneedle transdermal drug delivery formulation of a nutrient solution, mainly including the following steps: Preparation of boric acid-phosphoric acid-polyvinyl alcohol: i: Mix 100 g of phosphoric acid, 50 g of polyvinyl alcohol and 500 g of acetone, heat to 60°C and stir for 1 h, dry in a vacuum drying oven at 60°C, and then grind into powder to obtain polyvinyl phosphate. ii: Prepare a 30 g / L polyvinyl phosphate solution by mixing the polyvinyl phosphate obtained in step i with deionized water; iii: Dissolve boric acid in anhydrous ethanol to prepare a 1.2 mol / L boric acid solution. Then add urea of ​​the same mass as boric acid to the boric acid solution. Mix 1 L of boric acid solution and 1 L of polyvinyl phosphate solution obtained in step ii evenly, transfer to a reaction vessel, react at 70°C for 7 h, remove the ethanol solution by rotary evaporation at 95°C, and vacuum dry at 80°C for 1 h to obtain boric acid-phosphate-polyvinyl alcohol.

[0029] Preparation of ellagic acid-carboxymethyl chitosan: (1) Dissolve 10 g of ellagic acid in 100 mL of DMSO to prepare a 0.1 g / mL solution, add 5 g of succinic anhydride, and stir at 40 °C for 24 h to obtain mixed solution I; (2) Add 0.1 mol L of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC·HCl and 0.12 mol L of N-hydroxysuccinimide NHS to 100 mL of DMSO to prepare solutions with EDC·HCl concentrations of 1 mol / L and NHS concentrations of 1.2 mol / L, respectively, to obtain mixed solution II; (3) Mix 100 mL of mixed solution I and 20 mL of mixed solution II. After 30 min, add 200 mL of carboxymethyl chitosan aqueous solution with a concentration of 25 mg / mL. Stir at room temperature for 18 h, dialyze with deionized water for 4 days, and freeze dry to obtain ellagic acid-carboxymethyl chitosan.

[0030] Preparation of nutrient solution liposomes modified with ellagic acid-carboxymethyl chitosan: I: Dissolve 4 g of soybean lecithin, 1 g of cholesterol and 0.5 g of vitamin E in anhydrous ethanol to prepare a lipid solution with soybean lecithin, cholesterol and vitamin E concentrations of 40 mg / mL, 10 mg / mL and 5 mg / mL, respectively. II: The lipid solution obtained in step I is subjected to rotary evaporation under reduced pressure to remove the organic solvent and obtain a lipid film, which is then uniformly adhered to the container wall. III: Mix 0.5 g colchicine and 0.76 g paclitaxel with 125 mL deionized water to prepare a suspension. Pour the suspension into the container containing the lipid film from step II, perform ultrasonic emulsification and mixing, and disperse in ice water at 200 W power for 2 min to obtain a liposome suspension. IV: Weigh out ellagic acid-carboxymethyl chitosan and dissolve it in an equal volume of 1% wt acetic acid solution to prepare an ellagic acid-carboxymethyl chitosan acetic acid solution with a concentration of 30 mg / mL. Stir for 14 h. Slowly add the liposome suspension prepared in step III to the ellagic acid-carboxymethyl chitosan acetic acid solution at a dropping rate of 0.5 mL / min. Continue stirring for 2 hours to obtain the liposome solution. V: Add 15% (w / w) of mannose-lactose freeze-drying protectant to the liposome solution obtained in step IV, pre-freeze in a -80°C freezer for 24 h, the mass ratio of mannose to lactose in the freeze-drying protectant is 1:1, after pre-freezing quickly transfer to a freeze dryer, reduce the pressure to 0.2 Mbar, and freeze-dry under vacuum at -80°C for 24 h to obtain freeze-dried powder, thus preparing ellagic acid-carboxymethyl chitosan modified nutrient liposomes.

[0031] Preparation of microneedle transdermal drug delivery formulations for nutrient solutions: S1: Mix 1 g of boric acid-phosphoric acid-polyvinyl alcohol with 1 g of anhydrous ethanol thoroughly to obtain a soluble polymer substrate; S2: Mix 1 g of the soluble polymer substrate obtained in step S1 with 1 g of nutrient liposome modified with ellagic acid-carboxymethyl chitosan, heat and dissolve to obtain soluble microneedle material. S3: Add 50 μL of the soluble microneedle material obtained in step S2 into the microneedle mold, centrifuge at 10000 rpm for 1 h, and then dry at 40°C under forced air for 40 min. S4: Add 450 μL of 10%wt polypropylene anhydrous ethanol solution to the microneedle mold as a poorly soluble backing, continue drying for 8 h, demold, and obtain a 15*10 array (12 mm*8 mm in length and width) microneedle formulation. Each microneedle array has 150 needles, which is the microneedle transdermal drug delivery formulation of nutrient solution.

[0032] Example 3: This example provides a method for preparing a microneedle transdermal drug delivery formulation of a nutrient solution, mainly including the following steps: Preparation of boric acid-phosphoric acid-polyvinyl alcohol: i: Mix 100 g of phosphoric acid, 50 g of polyvinyl alcohol and 500 g of acetone, heat to 70°C and stir for 1.5 h, dry in a vacuum drying oven at 60°C, and then grind into powder to obtain polyvinyl phosphate ester; ii: Prepare a 30 g / L polyvinyl phosphate solution by mixing the polyvinyl phosphate obtained in step i with deionized water; iii: Dissolve boric acid in anhydrous ethanol to prepare a 1.2 mol / L boric acid solution. Then add urea of ​​equal mass to the boric acid solution. Mix 1 L of boric acid solution and 1 L of polyvinyl phosphate solution obtained in step ii at a volume ratio of 1:1. Transfer the mixture to a reaction vessel and react at 70°C for 7 h. Remove the ethanol solution by rotary evaporation at 95°C and dry under vacuum at 80°C for 1 h to obtain boric acid-phosphate-polyvinyl alcohol.

[0033] Preparation of ellagic acid-carboxymethyl chitosan: (1) Dissolve 10 g of ellagic acid in 100 mL of DMSO to prepare a 0.1 g / mL solution, add 5 g of succinic anhydride, and stir at 40 °C for 18 h to obtain mixed solution I; (2) Add 0.1 mol L of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC·HCl and 0.12 mol L of N-hydroxysuccinimide NHS to 100 mL of DMSO to prepare solutions with EDC·HCl concentrations of 1 mol / L and NHS concentrations of 1.2 mol / L, respectively, to obtain mixed solution II; (3) Mix 100 mL of mixed solution I and 20 mL of mixed solution II. After 35 min, add 200 mL of carboxymethyl chitosan aqueous solution with a concentration of 25 mg / mL. Stir at room temperature for 20 h, dialyze with deionized water for 4 days, and freeze dry to obtain ellagic acid-carboxymethyl chitosan.

[0034] Preparation of nutrient solution liposomes modified with ellagic acid-carboxymethyl chitosan: I: Dissolve 4 g of soybean lecithin, 1 g of cholesterol and 0.5 g of vitamin E in anhydrous ethanol to prepare a lipid solution with soybean lecithin, cholesterol and vitamin E concentrations of 40 mg / mL, 10 mg / mL and 5 mg / mL, respectively. II: The lipid solution obtained in step I is subjected to rotary evaporation under reduced pressure to remove the organic solvent and obtain a lipid film, which is then uniformly adhered to the container wall. III: Mix 0.5 g colchicine and 0.76 g paclitaxel with 125 mL deionized water to prepare a suspension. Pour the suspension into the container containing the lipid film from step II, perform ultrasonic emulsification and mixing, and disperse in ice water at 200 W power for 2.5 min to obtain a liposome suspension. IV: Weigh out ellagic acid-carboxymethyl chitosan and dissolve it in an equal volume of 1% wt acetic acid solution to prepare an ellagic acid-carboxymethyl chitosan acetic acid solution with a concentration of 30 mg / mL. Stir for 14 h, and slowly add the liposome suspension obtained in step III to the ellagic acid-carboxymethyl chitosan acetic acid solution at a dropping rate of 0.5 mL / min. Continue stirring for 2.5 hours to obtain the liposome solution. V: Add 15% (w / w) of mannose-lactose freeze-drying protectant to the liposome solution obtained in step IV, pre-freeze in a -80°C freezer for 24 h, the mass ratio of mannose to lactose in the freeze-drying protectant is 1:1, after pre-freezing quickly transfer to a freeze dryer, reduce the pressure to 0.2 Mbar, and freeze-dry under vacuum at -80°C for 24 h to obtain freeze-dried powder, thus preparing ellagic acid-carboxymethyl chitosan modified nutrient liposomes.

[0035] Preparation of microneedle transdermal drug delivery formulations for nutrient solutions: S1: Mix 1 g of boric acid-phosphoric acid-polyvinyl alcohol with 1 g of anhydrous ethanol thoroughly to obtain a soluble polymer substrate; S2: Mix 1 g of the soluble polymer substrate obtained in step S1 with 1 g of nutrient liposome modified with ellagic acid-carboxymethyl chitosan, heat and dissolve to obtain soluble microneedle material. S3: Add 50 μL of the soluble microneedle material obtained in step S2 into the microneedle mold, centrifuge at 10000 rpm for 1.5 h, and then dry at 42°C under forced air for 45 min. S4: Add 450 μL of 10%wt polypropylene anhydrous ethanol solution to the microneedle mold as a poorly soluble backing, continue drying for 9 h, demold, and obtain a 15*10 array (12 mm*8 mm) microneedle formulation. Each microneedle array has 150 needles, which is the microneedle transdermal drug delivery formulation of nutrient solution.

[0036] The prepared ellagic acid-carboxymethyl chitosan was subjected to infrared spectroscopy, and the nutrient solution liposomes modified with ellagic acid-carboxymethyl chitosan were photographed using electron microscopy. Figure 1 The display shows 3474cm. -1 It is the -OH absorption peak of ellagic acid, 1720 cm⁻¹. -1 It is the absorption peak of C=O; 1617 cm⁻¹ -1 1617 cm -1 1617 cm -1 These are typical characteristic absorption peaks of the benzene ring. Figure 2 The experiment showed that granular ellagic acid-carboxymethyl chitosan-modified nutrient solution liposomes were prepared.

[0037] Example 4: This example provides a method for preparing a microneedle transdermal drug delivery formulation of a nutrient solution, the active ingredient of which is leonurine, and mainly includes the following steps: Preparation of boric acid-phosphoric acid-polyvinyl alcohol: i: Mix 100 g of phosphoric acid, 50 g of polyvinyl alcohol and 500 g of acetone, heat to 80°C and stir for 2 h, dry in a vacuum drying oven at 60°C, and then grind into powder to obtain polyvinyl phosphate. ii: Prepare a 30 g / L polyvinyl phosphate solution by mixing the polyvinyl phosphate obtained in step i with deionized water; iii: Dissolve boric acid in anhydrous ethanol to prepare a 1.2 mol / L boric acid solution. Then add urea of ​​the same mass as boric acid to the boric acid solution. Mix 1 L of boric acid solution and 1 L of polyvinyl phosphate solution obtained in step ii evenly, transfer to a reaction vessel, react at 70°C for 7 h, remove the ethanol solution by rotary evaporation at 95°C, and vacuum dry at 80°C for 1 h to obtain boric acid-phosphate-polyvinyl alcohol.

[0038] Preparation of ellagic acid-carboxymethyl chitosan: (1) Dissolve 10 g of ellagic acid in 100 mL of DMSO to prepare a 0.1 g / mL solution, add 5 g of succinic anhydride, and stir at 40 °C for 24 h to obtain mixed solution I; (2) Add 0.1 mol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC·HCl and 0.12 mol of N-hydroxysuccinimide NHS to 100 mL of DMSO to prepare solutions with EDC·HCl concentrations of 1 mol / L and NHS concentrations of 1.2 mol / L, respectively, to obtain mixed solution II; (3) Mix 100 mL of mixed solution I and 20 mL of mixed solution II. After 40 min, add 200 mL of 25 mg / mL carboxymethyl chitosan aqueous solution. Stir at room temperature for 22 h, then dialyze with deionized water for 4 days and freeze dry to obtain ellagic acid-carboxymethyl chitosan.

[0039] Preparation of Leonurus alkaloid liposomes modified with ellagic acid-carboxymethyl chitosan: I: Dissolve 4 g of soybean lecithin, 1 g of cholesterol and 0.5 g of vitamin E in 100 mL of anhydrous ethanol to prepare a lipid solution with soybean lecithin, cholesterol and vitamin E concentrations of 40 mg / mL, 10 mg / mL and 5 mg / mL respectively. II: The lipid solution obtained in step I is subjected to rotary evaporation under reduced pressure to remove the organic solvent and obtain a lipid film, which is then uniformly adhered to the container wall. III: Mix 1.26 g of leonurine with 125 mL of deionized water to prepare a suspension, pour it into the container containing the lipid film in step II, perform ultrasonic emulsification and mixing, and disperse it in ice water at 200 W power for 3 min to obtain a liposome suspension. IV: Weigh out ellagic acid-carboxymethyl chitosan and dissolve it in an equal volume of 1% acetic acid solution to prepare an ellagic acid-carboxymethyl chitosan acetic acid solution with a concentration of 30 mg / mL. Stir for 14 h, and slowly add the liposome suspension prepared in step III to the ellagic acid-carboxymethyl chitosan acetic acid solution at a dropping rate of 0.5 mL / min. Continue stirring for 3 hours to obtain the liposome solution. V: Add 15% (w / w) of mannose-lactose freeze-drying protectant to the liposome solution obtained in step IV, pre-freeze in a -80°C freezer for 24 h, the mass ratio of mannose to lactose in the freeze-drying protectant is 1:1, after pre-freezing quickly transfer to a freeze dryer, reduce the pressure to 0.2 Mbar, and freeze-dry under vacuum at -80°C for 24 h to obtain freeze-dried powder, thus preparing ellagic acid-carboxymethyl chitosan modified leonurine liposomes.

[0040] Preparation of microneedle transdermal drug delivery formulations of leonurine: S1: Boric acid-phosphoric acid-polyvinyl alcohol and anhydrous ethanol are thoroughly mixed in a mass ratio of 1:1 to obtain a soluble polymer substrate. S2: The soluble polymer substrate obtained in step S1 is mixed with the leonurine liposome modified with ellagic acid-carboxymethyl chitosan at a ratio of 20 mg leonurine per milliliter of soluble polymer substrate, and heated to dissolve to obtain soluble microneedle material. S3: Add 50 μL of the soluble microneedle material obtained in step S2 into the microneedle mold, centrifuge at 10000 rpm for 2 h, and then dry at 45°C under forced air for 50 min. S4: Add 450 μL of 10%wt polypropylene anhydrous ethanol solution to the microneedle mold as a poorly soluble backing, continue drying for 10 h, demold, and obtain a 15*10 array (12 mm*8 mm in length and width) microneedle formulation. Each microneedle array has 150 needles, which is the microneedle transdermal drug delivery formulation of leonurine.

[0041] Example 5: This example provides a method for preparing a microneedle transdermal drug delivery formulation of a nutrient solution, the active ingredient of which is nicotinamide mononucleotide. The steps are the same as in Example 4, except that nicotinamide mononucleotide is used instead of leonurine.

[0042] Comparative Example 1 is the same as Example 1, except that polyvinyl alcohol is used instead of boric acid-phosphate-polyvinyl alcohol.

[0043] Comparative Example 2 is the same as Example 1, except that polyvinylpyrrolidone is used instead of boric acid-phosphate-polyvinyl alcohol.

[0044] Comparative Example 3 is the same as Example 4, except that chitosan is used instead of carboxymethyl chitosan.

[0045] Comparative Example 4 is the same as Example 4, except that carboxymethyl chitosan is used instead of ellagic acid-carboxymethyl chitosan.

[0046] Comparative Example 5 is the same as Example 4, except that leonurine is used instead of ellagic acid-carboxymethyl chitosan modified leonurine liposomes.

[0047] Comparative Example 6 was the same as Example 4, except that a mannose-lactose freeze-drying protectant with a mass fraction of 15% of the liposome suspension was added to the liposome suspension, and the mixture was pre-frozen in a -80°C freezer for 24 h. The mass ratio of mannose to lactose in the freeze-drying protectant was 1:1. After pre-freezing, the mixture was quickly transferred to a freeze dryer, the pressure was reduced to 0.2 Mbar, and the mixture was vacuum freeze-dried at -80°C for 24 h to obtain freeze-dried powder, thus preparing Leonurus alkaloid liposomes.

[0048] Comparative Example 7 is the same as Example 5, except that carboxymethyl chitosan is used instead of ellagic acid-carboxymethyl chitosan.

[0049] Comparative Example 8 was the same as Example 5, except that a mannose-lactose lyophilization protectant with a mass fraction of 15% of the liposome suspension was added to the liposome suspension, and the mixture was pre-frozen in a -80°C freezer for 24 h. The mass ratio of mannose to lactose in the lyophilization protectant was 1:1. After pre-freezing, the mixture was quickly transferred to a freeze dryer, the pressure was reduced to 0.2 Mbar, and the mixture was vacuum freeze-dried at -80°C for 24 h to obtain lyophilized powder, thus preparing nicotinamide mononucleotide liposomes.

[0050] Comparative Example 9 is the same as Example 4, except that the soluble polymer matrix and the leonurine liposome modified with ellagic acid-carboxymethyl chitosan are mixed at a ratio of 2 mg leonurine per milliliter of soluble polymer matrix, heated to dissolve, and a soluble microneedle material is obtained. 500 μL of the soluble microneedle material is added to a microneedle mold, centrifuged at 10,000 rpm for 2 h, dried at 45°C under forced air for 10 h, and demolded to obtain a 15*10 array (12 mm*8 mm) microneedle formulation. Each microneedle array has 150 needles, which is the leonurine microneedle transdermal drug delivery formulation.

[0051] Comparative Example 10 was the same as Example 4, except that 450 μL of a 10%wt boric acid-phosphoric acid-polyvinyl alcohol anhydrous ethanol solution was added to the microneedle mold as a backing, and the mold was dried for another 10 h. After demolding, a 15*10 array (12 mm*8 mm in length and width) microneedle formulation was obtained, with 150 needles on each microneedle array, which is the microneedle transdermal drug delivery formulation of leonurine.

[0052] Performance testing I. Determination of Microneedle Mechanical Strength and Puncture Ability The microneedle formulations prepared in Examples 1-3 and Comparative Example 1 were placed with the needle body facing upwards on the test stage of a microneedle mechanical strength tester. An aluminum flat-bottomed probe (10 mm in diameter) was moved vertically downwards at a constant speed of 0.5 mm / min to the tip of the microneedle. When the applied force reached 30 N, the morphology of the microneedle was observed and photographed. The results are as follows: Figure 3 As shown in Table 1, a 10 μm thick aluminum foil was placed on a microneedle mold. The microneedle formulations from Examples 1-3 and Comparative Example 1 were then placed on the aluminum foil. A pressure of 20 N was applied to the back of the foil and held for 1 min. The aluminum foil was then removed and placed on white paper. The micropores on the aluminum foil were coated with a 2% methylene blue solution, and the number of stained pores on the white paper was counted. The puncture efficiency was calculated using the following formula: Puncture efficiency (%) = (Number of stained pores / Number of microneedles) * 100%.

[0053] Figure 3 The results showed that the needles in Examples 1-3 and Comparative Example 1 were bent, but no microneedles were found to break, indicating that the needles had sufficient toughness.

[0054] Table 1 Microneedle puncture efficiency

[0055] Table 1 shows that the microneedles of Examples 1-3 have higher puncture efficiency than Comparative Example 1, indicating that the boric acid-phosphate-polyvinyl alcohol used in this invention can enhance the mechanical strength of the needle body, making the needle body have higher hardness and easier to penetrate the skin.

[0056] II. In vivo skin moisture loss experiment Generally, severely damaged skin exhibits higher transepidermal water loss values, while less damaged or intact skin exhibits lower transepidermal water loss values. One day prior to the experiment, the hair on the abdominal skin of male rats was shaved using a razor. After anesthetizing the rats with chloral hydrate, the microneedle formulations of Examples 1-3 and Comparative Example 2 were applied to the abdominal skin and removed after 5 minutes. Transepidermal water loss was recorded at each fixed time point (0, 1, 2, 3, 4, 5, and 6 h) using a transepidermal water loss meter. Skin adjacent to the microneedle application site served as a blank control. Transepidermal water loss values ​​are expressed in g / (m²). 2 •h) indicates that the TTEST function in Excel was used to determine the difference, and P<0.05 was considered a significant difference. The results are as follows: Figure 4 As shown.

[0057] Figure 4 The results showed that the transdermal water loss value gradually decreased over time. From 0 to 4 h, the transdermal water loss value of Examples 1-3 was significantly higher than that of the control group (P<0.05). From 5 h onwards, it was no longer significantly higher than that of the control group, indicating that the skin was gradually healing. The transdermal water loss value of Comparative Example 2 was still significantly higher than that of the control group at 6 h, indicating that its skin recovery speed was slower. The microneedle preparation of Comparative Example 2 caused greater damage to the skin. Combined with the results of the microneedle mechanical strength and puncture ability test, it shows that the boric acid-phosphate-polyvinyl alcohol of the present invention can make the needle body tough and hard, easy to penetrate the skin and will not cause great damage to the skin.

[0058] III. Drug Loading Determination The microneedle formulations prepared in Examples 4 and Comparative Examples 3-6 were carefully decapitated using a scalpel, and the needle tips were collected in centrifuge tubes. The needle tips were dissolved in 30% wt methanol aqueous solution, ultrasonically extracted for 30 min, and then filtered through a 0.22 μm filter. Finally, the content of leonurine in different microneedle formulations, i.e., the actual drug loading, was determined by high-performance liquid chromatography (HPLC). The chromatographic conditions were as follows: column: Agilent C18 column (4.6 mm * 250 mm, 5 μm); mobile phase: methanol:water = 70:30; flow rate: 1.0 mL / min; detection wavelength: 277 nm; column temperature: 30℃; injection volume: 20 μL. The results are shown in Table 2. The drug loading efficiency (%) was calculated using the formula (actual drug loading / theoretical drug loading) * 100%, and the results are as follows. Figure 5 As shown, ** indicates a statistically significant difference.

[0059] Table 2 Drug loading of microneedle formulations

[0060] Table 2 and Figure 5The results showed that the actual drug loading and drug loading efficiency of Example 4 were significantly higher than those of Comparative Examples 3-6, indicating that the microneedle formulation of the present invention has a high drug loading and can load poorly soluble substances. Ellagic acid-carboxymethyl chitosan modified liposomes can increase the drug loading because they can generate stronger hydrogen bond molecular forces with soluble polymer substrates.

[0061] IV. Release Rate Test Nicotinamide mononucleotide (NMN) was prepared by placing the three soluble microneedle tips obtained in Example 5 and Comparative Examples 7-8 into centrifuge tubes, adding PBS, and placing them in a water bath at 37°C. Every 1 hour, 1 mL of sample was taken and 1 mL of PBS solution was added. After filtration through a microporous membrane, the NMN content was determined by high-performance liquid chromatography (HPLC), and the cumulative release rate was calculated. The results are as follows: Figure 6 As shown, the release of nicotinamide mononucleotide in Example 5 was significantly slowed down, with a cumulative release rate of only 29.7% after 12 hours, effectively increasing the in vivo retention time. This indicates that the liposomes modified with ellagic acid-carboxymethyl chitosan of the present invention can enhance sustained-release properties.

[0062] V. Skin penetration test SD rats were anesthetized with 1 mL of 20% urethane, euthanized by cervical dislocation, and the hair on their abdomen was shaved. After 24 hours, the abdominal skin was peeled off, subcutaneous fat tissue was removed, and the skin was rinsed with physiological saline. The surface moisture was then blotted dry with filter paper to obtain rat skin. The rat skin was laid flat on a soft rubber plate, and the microneedle formulations of Examples 4 and Comparative Examples 3-6 were pressed with the thumb to allow the microneedles to penetrate the skin. The microneedle formulation and the skin were placed as a whole on the receiving pool, fixed with transparent tape, and then the supply pool was attached. A horseshoe was clamped on, and then PBS was added to the receiving pool as the receiving solution. Twelve hours later, the remaining microneedles on the mouse skin surface were scraped off with a scraper. The mouse skin surface was then washed with the receiving solution. The two were combined and diluted with an equal volume of receiving solution, and then methanol was added until the methanol mass fraction was 30%. The mixture was ultrasonically extracted for 30 minutes, then filtered through a 0.22 μm filter. The content of leonurine was determined by high-performance liquid chromatography (HPLC), which represents the amount of leonurine that did not penetrate the skin. The skin absorption rate of leonurine (%) was calculated as follows: [(Total leonurine in microneedles - Leonurine that did not penetrate the skin) / Total leonurine in microneedles] * 100%. Results are as follows... Figure 7 As shown, ** indicates a statistically significant difference. After 12 hours, the skin absorption rate of leonurine in Example 4 was 95%, which was significantly higher than that of Comparative Examples 3-6 (66.33-86.33%). This indicates that the microneedle formulation of the present invention has better transdermal ability, is more easily absorbed by the skin, and has high bioavailability.

[0063] VI. Drug loading capacity of backing and needle body The microneedle formulations prepared in Example 4 and Comparative Examples 9-10 were carefully cut off at the needle tip using a scalpel. The cut needle body and residual backing were collected in centrifuge tubes, dissolved in 30% wt methanol aqueous solution, and extracted by ultrasonication for 30 min. The mixture was then filtered through a 0.22 μm filter. Finally, the content of leonurine in different microneedle formulations was determined by high performance liquid chromatography (HPLC), and the drug loading of the backing and needle body of different microneedle formulations was obtained. The results are shown in Table 3.

[0064] Table 3 Distribution of Leonurine in Different Microneedle Formulations

[0065] Table 3 shows that there was no significant difference in the total drug loading between Example 4 and Comparative Examples 9-10, but the distribution of the drug in the needle body and the backing was significantly different. In Example 1, all the drug loading was on the needle body. In Comparative Example 9, the drug loading on the backing was 30 times that on the needle body, indicating that most of the drug was concentrated on the backing. In Comparative Example 10, the drug loading on the needle body was 12 times that on the backing, indicating that the microneedle formulation in Comparative Example 10 could effectively concentrate the drug on the needle body, but due to diffusion, some of the drug would be distributed in the backing. These results indicate that the microneedle formulation of the nutrient solution of the present invention, due to the use of a poorly soluble backing, the method of drying the needle body first and then the backing, and the operation method of the needle body containing the drug and the backing not containing the drug, prevents the drug from migrating and diffusing to the backing, resulting in a high drug loading in the needle body.

[0066] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention (including the claims) is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in the details for the sake of brevity.

[0067] This invention is intended to cover all such substitutions, modifications, and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this invention should be included within the scope of protection of this invention.

Claims

1. A microneedle transdermal drug delivery formulation for a nutrient solution, characterized in that, It includes a poorly soluble backing and soluble microneedles vertically connected to the backing; The material used to prepare the insoluble backing includes polypropylene; The soluble microneedle body is prepared from boric acid-phosphate-polyvinyl alcohol and ellagic acid-carboxymethyl chitosan modified nutrient liposomes. The method for preparing a microneedle transdermal drug delivery formulation of a nutrient solution includes the following steps: S1: Boric acid-phosphoric acid-polyvinyl alcohol and anhydrous ethanol are thoroughly mixed in a mass ratio of 1:1 to obtain a soluble polymer substrate. S2: The soluble polymer substrate obtained in step S1 is mixed with the nutrient liposome modified with ellagic acid-carboxymethyl chitosan in a certain proportion, heated and dissolved to obtain soluble microneedle material. S3: Add the soluble microneedle material obtained in step S2 into the microneedle mold, centrifuge at 10000 rpm for 1-2 h, and then dry at 40-45°C under forced air conditions for 40-50 min; S4: Add a 10%wt polypropylene anhydrous ethanol solution to the microneedle mold as a poorly soluble backing, continue drying for 8-10 h, and then demold.

2. The microneedle transdermal drug delivery formulation of a nutrient solution according to claim 1, characterized in that, The ellagic acid-carboxymethyl chitosan modified nutrient solution liposomes are liposomes containing nutrient solution modified with ellagic acid-carboxymethyl chitosan.

3. The method for preparing a microneedle transdermal drug delivery formulation of a nutrient solution according to claim 2, characterized in that, The preparation method of boric acid-phosphate-polyvinyl alcohol described in step S1, Includes the following steps: i: Take phosphoric acid, polyvinyl alcohol and acetone in a mass ratio of 2:1:10, heat to 60-80°C and stir for 1-2 hours, dry in a vacuum drying oven at 60°C, and then grind into powder to obtain polyvinyl phosphate. ii: Prepare a 30 g / L polyvinyl phosphate solution by mixing the polyvinyl phosphate obtained in step i with deionized water; iii: Dissolve boric acid in anhydrous ethanol to prepare a 1.2 mol / L boric acid solution. Then add urea of ​​equal mass to the boric acid solution. Mix the boric acid solution and the polyvinyl phosphate solution obtained in step ii at a volume ratio of 1:

1. Transfer the mixture to a reaction vessel and react at 70°C for 7 h. Remove the ethanol solution by rotary evaporation at 95°C and vacuum dry at 80°C for 1 h to obtain boric acid-phosphate-polyvinyl alcohol.

4. The method for preparing a microneedle transdermal drug delivery formulation of a nutrient solution according to claim 3, characterized in that, The mixing ratio of the soluble polymer substrate and the nutrient liposome modified with ellagic acid-carboxymethyl chitosan in step S2 is determined according to the required dosage of active ingredients.

5. The method for preparing a microneedle transdermal drug delivery formulation of a nutrient solution according to claim 4, characterized in that, The preparation method of the nutrient solution liposomes modified with ellagic acid-carboxymethyl chitosan in step S2 includes the following steps: I: Dissolve soybean lecithin, cholesterol and vitamin E in anhydrous ethanol at a mass ratio of 8:2:1 to prepare a lipid solution with soybean lecithin, cholesterol and vitamin E concentrations of 40 mg / mL, 10 mg / mL and 5 mg / mL, respectively. II: The lipid solution obtained in step I is subjected to rotary evaporation under reduced pressure to remove the organic solvent and obtain a lipid film, which is then uniformly adhered to the container wall. III: Pour 1%wt nutrient solution into the container containing the lipid film in step II. The volume ratio of nutrient solution to lipid solution is 5:

4. Perform ultrasonic emulsification and mixing, and disperse in ice water at 200W power for 2-3 minutes to obtain a liposome suspension. IV: Weigh out ellagic acid-carboxymethyl chitosan and dissolve it in an equal volume of 1% acetic acid solution to prepare an ellagic acid-carboxymethyl chitosan acetic acid solution with a concentration of 30 mg / mL. Stir for 14 h. Slowly add the liposome suspension prepared in step III to the ellagic acid-carboxymethyl chitosan acetic acid solution at a dropping rate of 0.5 mL / min. Continue stirring for 2-3 hours to obtain the liposome solution. V: Add 15% (w / w) of mannose-lactose freeze-drying protectant to the liposome solution obtained in step IV, pre-freeze in a -80°C freezer for 24 h, the mass ratio of mannose to lactose in the freeze-drying protectant is 1:1, after pre-freezing quickly transfer to a freeze dryer, reduce the pressure to 0.2 Mbar, and freeze-dry under vacuum at -80°C for 24 h to obtain freeze-dried powder, thus preparing ellagic acid-carboxymethyl chitosan modified nutrient liposomes.

6. The method for preparing a microneedle transdermal drug delivery formulation of a nutrient solution according to claim 5, characterized in that, The preparation of ellagic acid-carboxymethyl chitosan in step IV includes the following steps: (1) Dissolve a certain amount of ellagic acid in DMSO to prepare a 0.1 g / mL solution, add 1 / 2 the weight of succinic anhydride of ellagic acid, stir at 40 °C for 12-24 h to obtain mixed solution I; (2) Add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC·HCl and N-hydroxysuccinimide NHS to DMSO to prepare solutions with EDC·HCl concentrations of 1 mol / L and NHS concentrations of 1.2 mol / L, respectively, to obtain mixed solution II; (3) Mix solution I and mixed solution II at a volume ratio of 5:

1. After 30-40 min, add twice the volume of carboxymethyl chitosan aqueous solution with a concentration of 25 mg / mL. Stir at room temperature for 18-22 h, dialyze with deionized water for 4 days, and freeze dry to obtain ellagic acid-carboxymethyl chitosan.

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