Hydrogel Microneedle Patch Based on Three-Dimensional Skeletal Structure, Its Preparation Method, and Applications

Abstract

The present invention discloses a hydrogel microneedle patch based on a three-dimensional skeletal structure, the microneedle patch includes microneedles, the raw materials of the microneedles include polyvinyl alcohol and acrylic resin aqueous dispersion, and the acrylic resin aqueous dispersion is mixed with polyvinyl alcohol uniformly and molded to obtain the microneedles. The hydrogel microneedle patch has relatively high strength and excellent swelling and puncture performance. The present invention further discloses a preparation method and application of the hydrogel microneedle patch.

Description

Technical Field

[0001] The present invention relates to the field of transdermal administration technology. More specifically, it relates to a hydrogel microneedle patch based on a three-dimensional skeleton structure, a method for preparing the same, and applications thereof.

Background Art

[0002] A hydrogel microneedle is a microneedle technology that realizes needle body expansion by absorbing interstitial skin fluid in a body fluid environment, promotes drug release, but the substrate itself does not dissolve and can be completely removed after drug release is completed. By adjusting the cross-linking strength of the hydrogel network, controllable drug release can be realized, and it has advantages such as no in-vivo residue of the substrate and auxiliary materials after use and higher biosafety. Since it was first reported in 2010, hydrogel microneedles can rapidly absorb the expansion of tissue fluid after acting on the skin and can maintain the open state of skin microchannels for a long time, thus expanding its application fields. 1) Hydrogel microneedles can replace solid microneedles in single-crystalline silicon and be used as a transdermal penetration promoting device. 2) Hydrogel microneedles can be used in combination with conventional drug-loaded transdermal preparations to improve the effective transdermal drug delivery efficiency of conventional skin preparations such as aqueous solutions, emulsions, patches, and gels. 3) Hydrogel microneedles can be used as a drug carrier, directly carry active ingredients, have a large drug loading capacity, and can realize controllable drug release rate by controlling the degree of cross-linking inside the system. 4) Hydrogel microneedles can be used for the rapid detection and extraction of biomolecules in interstitial fluid and have significant advantages in efficiency and cost. Compared with solid microneedles of metal and single-crystalline silicon, hydrogel microneedles have better material toughness, and there is no need to worry about the risk of the needle tip breaking in the skin and remaining during use. Compared with dissolving microneedles, hydrogel microneedles do not dissolve or decompose in a body fluid environment, and there is no need to worry about the problem of polymer accumulation in the body due to long-term use, making its use more convenient, safe, and reliable.

[0003] The previously reported hydrogel microneedles are mostly cross-linked microneedles obtained by utilizing hydrogen bonding or ester formation reactions between polymer chains. The research group led by Jin Tuo at Shanghai Jiao Tong University prepared polyvinyl alcohol (PVA) hydrogel microneedles through a repeated freeze-thaw process of freezing at -20°C and thawing at 4°C, which can achieve effective delivery to biopolymer drugs. However, the preparation of these microneedles requires a cross-linking process of repeated freeze-thaw cycles, which is time-consuming and the process is complicated, not suitable for industrialized preparation. The research group led by Donnelly at Queen's University, UK, focused on the research of the process in which polymethyl vinyl ether / maleic anhydride copolymer (PMVE / MA) and polyethylene glycol (PEG) cross-link at a high temperature of 80°C or under microwave conditions to form esters, and prepared superhydrogel microneedles with a swelling ratio reaching 1600%, which can achieve transdermal delivery of drugs with different molecular weights. However, the ester formation cross-linking process of the microneedles must react for 24 h under the condition of 80°C or cross-link for 8 h in a microwave environment. The preparation efficiency of the microneedles is low, which is disadvantageous for mass production. Moreover, the high-temperature preparation conditions are likely to cause the destruction of drug stability and limit its drug application range.

Summary of the Invention

Problems to be Solved by the Invention

[0004] The first object of the present invention is to provide a hydrogel microneedle patch based on a three-dimensional skeleton structure. The hydrogel microneedle patch utilizes the skeleton structure of an acrylic resin aqueous dispersion to surround a polyvinyl alcohol gel with relatively low cohesive force, and polyvinyl alcohol imparts certain mechanical strength to the acrylic resin aqueous dispersion without mechanical strength, and prepares a hydrogel microneedle patch that simultaneously has excellent swelling performance and puncture performance.

[0005] The second object of the present invention is to provide a method for preparing a hydrogel micro-needle patch based on a three-dimensional skeletal structure. The method can prepare hydrogel micro-needles under natural drying acupuncture conditions, overcome the limitations on cross-linking conditions in the prior art, and has advantages such as a simple preparation process for the micro-needles, easy operation, and high acupuncture speed.

[0006] The third object of the present invention is to provide an application of a hydrogel micro-needle patch based on a three-dimensional skeletal structure.

Means for Solving the Problems

[0007] To achieve the above first object, the present invention adopts the following technical solution: A hydrogel micro-needle patch based on a three-dimensional skeletal structure, wherein the micro-needle patch includes micro-needles. The raw materials of the micro-needles include polyvinyl alcohol and an acrylic resin aqueous dispersion. The polyvinyl alcohol is uniformly mixed with the acrylic resin aqueous dispersion and molded to obtain the micro-needles.

[0008] Furthermore, in the micro-needle patch, the acrylate resin aqueous dispersion surrounds a gel formed of polyvinyl alcohol as a skeletal structure.

[0009] Furthermore, the mass ratio of the polyvinyl alcohol to the acrylic resin aqueous dispersion is 5 to 50:0.1 to 10.

[0010] Furthermore, as can be understood, the structure of the micro-needles includes a needle tip and a base, and the needle tip and the base may be integrally formed or separately formed.

[0011] Furthermore, the hydrogel micro-needle patch further includes a backing. The backing is combined with the base.

[0012] Furthermore, functional additives, active substances, etc. can be added to the hydrogel microneedle patch according to actual needs. Exemplarily, in the hydrogel microneedle patch, the backing is a hollow aqueous adhesive patch, which serves to fix the microneedles to the skin, and the active substance can be added to the intermediate cavity, that is, the active substance directly contacts the microneedle base. Another one uses an adhesive sponge backing. The backing itself has good adhesiveness and also has drug-carrying properties and can carry the active substance.

[0013] Furthermore, the polyvinyl alcohol is high alcohol degree-of-hydrolysis polyvinyl alcohol. Furthermore, the alcohol degree of hydrolysis of the polyvinyl alcohol is 98% or more.

[0014] The acrylic resin aqueous dispersion is an aqueous system in which water is used as a dispersion medium and the acrylic resin is dispersed in water in the form of solid or semi-solid spherical or quasi-spherical particles with a size of 100 to 1000 nm, and it swells limitedly in a biological medium to form a dense three-dimensional skeletal structure. High alcohol degree-of-hydrolysis and high molecular weight polyvinyl alcohol is a swelling hydrogel material. In the process of drying the microneedle solution onto the needles, hydrogen bonding forces are formed within and between polyvinyl alcohol molecules. After encountering water, some polyvinyl alcohol forms hydrogen bonds with water molecules, weakening the hydrogen bonding within the polyvinyl alcohol molecules, reducing the cohesive force of the microneedles, and after swelling in water, the microneedles gel and cannot be completely taken out from the skin. Based on the properties of the above two types of materials, the present invention uniformly mixes the two, uses the skeletal structure of the acrylic resin aqueous dispersion to surround the polyvinyl alcohol gel with relatively low cohesive force, and polyvinyl alcohol imparts certain mechanical strength to the acrylic resin aqueous dispersion without mechanical strength, preparing a hydrogel microneedle preparation that simultaneously has excellent swelling performance and puncture performance.

[0015] Furthermore, the acrylic resin aqueous dispersion system is a mixture of one or several of acrylic resin, emulsifier, preservative, alkalizing agent, organic solvent and purified water.

[0016] Furthermore, the acrylic resin is a mixture of one or more selected from ethyl acrylate, methyl methacrylate, trimethylamine ethyl chloride methacrylate, methyl acrylate, and methacrylic acid.

[0017] Furthermore, the emulsifier is a mixture of one or more selected from stearyl alcohol polyether-2, nonylphenol ethoxylate, sodium lauryl sulfate, and polysorbate 80.

[0018] Furthermore, the preservative is a mixture of one or more selected from sorbic acid, benzoic acid, dehydroacetic acid, and methyl paraben.

[0019] Furthermore, the alkalizing agent is a mixture of one or more selected from sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, and ethanolamine.

[0020] Furthermore, the organic solvent is a mixture of one or more selected from ethanol and butanediol.

[0021] Furthermore, in the acrylic resin aqueous dispersion, the acrylic resin is a mixture of one or more selected from an ethyl acrylate and methyl methacrylate copolymer with a molar ratio of 2:1, a methacrylic acid, methyl acrylate, and methyl methacrylate copolymer with a molar ratio of 1:1:1, an ethyl acrylate, methyl methacrylate, and trimethylaminoethyl methacrylate chloride copolymer with a molar ratio of 1:2:0.1, an ethyl acrylate, methyl methacrylate, and trimethylaminoethyl methacrylate chloride copolymer with a molar ratio of 1:2:0.2, and a methacrylic acid and ethyl acrylate copolymer with a molar ratio of 1:1.

[0022] Furthermore, the micron needle further contains porogen.

[0023] Furthermore, the porogen is located in the acrylic resin aqueous dispersion and / or polyvinyl alcohol.

[0024] Furthermore, the mass percentage content of porogen in the micro-needle is 0.1 to 10 wt%.

[0025] Furthermore, the porogen is one or a mixture of several selected from polyvinylpyrrolidone, calcium hydrogen phosphate, sodium bicarbonate, sodium carbonate, trehalose, fructose, sorbitol, mannitol, xylitol, galactose, magnesium chloride, calcium chloride, and zinc chloride.

[0026] The porogen is a small molecule substance that can be eluted from the three-dimensional skeleton. Thus, it is advantageous for expanding the network gaps inside the micro-needles, forming a larger drug delivery space. For drugs with large molecular weights such as proteins, larger channels are advantageous for the rapid transport of drugs. By controlling the degree of cross-linking of PVA, the density of the three-dimensional network is controlled to realize the control of the drug delivery rate. On the other hand, by controlling the use of the porogen, the control of drug delivery with different properties is realized. Also, in the infrared cross-linking process, when the degree of PVA cross-linking increases, curling may occur at the edges of the micro-needles. When polyvinylpyrrolidone is added, it not only functions as a porogen but also can improve the flatness of the micro-needles.

[0027] To achieve the above second object, the present invention adopts the following technical solution: A method for preparing a hydrogel micro-needle patch based on a three-dimensional skeleton structure, comprising: preparing an aqueous solution of polyvinyl alcohol; after dissolving the aqueous solution of polyvinyl alcohol at a high temperature, adding an acrylic resin aqueous dispersion, uniformly mixing to obtain a mixed aqueous solution, removing bubbles, molding, and cross-linking to obtain the hydrogel micro-needle patch.

[0028] Furthermore, the cross-linking process is one selected from infrared irradiation cross-linking, physical freeze-thaw cross-linking, chemical agent cross-linking, annealing treatment cross-linking, microwave-assisted cross-linking, and radiation cross-linking.

[0029] Furthermore, in the infrared irradiation crosslinking, the infrared irradiation light wavelength is 1000 to 5000 nm.

[0030] Furthermore, in the mixed aqueous solution, the mass percentage content of polyvinyl alcohol is 5 to 50 wt%.

[0031] Furthermore, in the mixed aqueous solution, the mass percentage content of the acrylic resin aqueous dispersion is 0.1 to 10 wt%.

[0032] To achieve the above-mentioned third object, the present invention further protects the application of the above hydrogel microneedle patch in the transdermal delivery of the active substance.

[0033] Furthermore, the transdermal delivery method includes using a transdermal penetration enhancer device, combining with a drug-loaded patch, or directly loading one type of drug.

[0034] The present invention further protects the application of the above hydrogel microneedle patch in the extraction of biomolecules in skin interstitial fluid.

[0035] Furthermore, the hydrogel microneedle patch can exert a skin perforation effect, function as a transdermal penetration enhancer device, and promote the transdermal penetration of the active ingredient. The specific usage method can refer to the usage method of conventional solid microneedles of metals and single-crystalline silicon, and the description is omitted here.

[0036] Furthermore, the hydrogel microneedle patch can be used in combination with a solution, emulsion, cream, gel, or patch carrying the active ingredient. The specific usage method can refer to the usage method of conventional hydrogel microneedle patches, and the description is omitted here.

[0037] Furthermore, the hydrogel microneedle patch can directly load the active ingredient to achieve intradermal administration.

[0038] Furthermore, the hydrogel microneedle patch can absorb tissue fluid, thereby realizing the extraction of biomolecules in the skin interstitial fluid.

[0039] Furthermore, the active substance is one or more selected from small molecule drugs, traditional Chinese medicine extracts, polypeptides, proteins, and vaccines.

Advantages of the Invention

[0040] In the hydrogel microneedle patch provided by the present invention, a polyvinyl alcohol gel with relatively low cohesive force is surrounded by using the skeletal structure of an acrylic resin aqueous dispersion. Also, polyvinyl alcohol imparts a certain strength to the acrylic resin aqueous dispersion without mechanical strength, and a hydrogel microneedle preparation having excellent swelling performance and puncture performance is prepared. In the preparation method of the present invention, due to the selection of the specific acrylic resin aqueous dispersion and polyvinyl alcohol, it becomes possible to adopt a new cross-linking method, and hydrogel microneedles can be prepared under natural drying and needling conditions. The microneedle preparation process has advantages such as being simple, easy to operate, and having a high needling speed.

Brief Description of the Drawings

[0041] The specific embodiments of the present invention will be described in more detail with reference to the following drawings.

Figure 1

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Figure 10

Mode for Carrying Out the Invention

[0042] To explain the present invention more clearly, the present invention will be further described below in conjunction with preferred embodiments and drawings. Similar components in the drawings are denoted by the same reference numerals. It will be understood by those skilled in the art that the content specifically described below is illustrative rather than restrictive, and the protection scope of the present invention should not be limited thereby.

[0043] (Example 1) Preparation and puncture effect of hydrogel microneedle patch Weigh 17 mL of ultrapure water using a female cylinder, add 2.2 g (11 wt%) of polyvinyl alcohol, place it in an oven at 90 °C for high-temperature dissolution to obtain an aqueous polyvinyl alcohol solution. Weigh 0.8 g (4 wt%) of an acrylic resin aqueous dispersion (a copolymer of ethyl acrylate and methyl methacrylate with a molar ratio of 2:1), add it to the aqueous polyvinyl alcohol solution, stir uniformly to remove bubbles, use the mold method to prepare micro needles, dry the micro needles to form a film, and then obtain a patch of the hydrogel micro needles. The schematic diagram of the structure of the hydrogel micro needle patch is as shown in Figure 2a, and the schematic diagrams of its structure and internal structure after absorbing body fluid and swelling are as shown in Figure 2b.

[0044] Place the hydrogel micro needle patch on a stereomicroscope to observe the topography of the micro needles, and test the skin puncture performance of the micro needles by an in vitro puncture test on ex vivo porcine skin. The specific operation is as follows: Take out the frozen ex vivo porcine skin (depilated, skin thickness 600 μm) from a refrigerator at -20 °C, thaw it naturally at room temperature, then cut out a 1 cm × 1 cm area using a scalpel, absorb the moisture on the stratum corneum side of the skin using filter paper, and lay it on the surface of the silica gel mold with the stratum corneum side facing up. Act on the skin with the micro needles for 20 s using a needle feeding device (20 N / cm2), peel off the micro needles, and stain the skin with 4 mg / mL trypan blue dye for 30 min. After the staining is completed, wipe off the excess dye on the skin surface using a cotton swab, observe that a complete pinhole array is formed on the skin, and the results are shown in Figures 3 and 4. The prepared hydrogel micro needles have a complete needle body topography, sharp needle tips, are plump, and have good skin puncture properties.

[0045] (Example 2) Preparation of a hydrogel micro needle patch containing porogen - trehalose Weigh 16.2 mL of ultrapure water using a female cylinder, add 2.4 g (12 wt%) of polyvinyl alcohol, place it in an oven at 90 °C and dissolve it at a high temperature to obtain an aqueous polyvinyl alcohol solution. Weigh 1.4 g (7 wt%) of an acrylic resin aqueous dispersion (a copolymer of ethyl acrylate and methyl methacrylate with a molar ratio of 2:1) and add it to the aqueous polyvinyl alcohol solution, stir it uniformly, remove the bubbles, Prepare micro needles using the mold method. After drying and forming a film of the micro needles, place them in a phosphate buffer solution with pH = 7.4, swell them at 37 °C for 8 h, take them out and observe. Compare the topographical changes of the micro needles before and after swelling. The results are shown in Figure 5. As a result, it shows that after swelling for 8 h, the water absorption volume of the micro needles increases significantly, but the microstructures such as the needle tip are still good, indicating that the micro needles have good swelling performance.

[0046] (Examples 3 - 14) Preparation of hydrogel micro needle patches containing other types of porogens Based on the method for preparing the micro needles in Example 2, combine the hydrogel micro needle formulations containing different types of porogens in Table 1 to prepare a micro needle solution, and obtain a series of hydrogel micro needle patches. Place the micro needles of each formulation in a phosphate buffer solution with pH = 7.4, and observe whether the needle tip integrity is maintained after swelling at 37 °C for 8 h to determine whether the micro needles have swelling performance. The results are shown in Table 1, indicating that the hydrogel micro needles of each formulation all have good in vitro swelling properties.

[0047]

Table 1

[0048] (Example 15) Preparation of infrared crosslinked hydrogel micro needle patches Using a female cylinder, 16.2 mL of ultrapure water was weighed, 2.8 g (14 wt%) of polyvinyl alcohol was added, and it was placed in an oven at 90 °C for high-temperature dissolution to obtain an aqueous polyvinyl alcohol solution. 1 g (5 wt%) of an acrylic resin aqueous dispersion (a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate with a molar ratio of 1:1:1) was weighed and added to the aqueous polyvinyl alcohol solution, stirred uniformly to remove bubbles, and a micro-needle was prepared using the mold method. After drying and film-forming the micro-needle, it was placed under an infrared lamp with a wavelength of 2400 - 3500 nm and irradiated at 70 °C for 1 minute to promote cross-linking. The non-infrared-crosslinked micro-needles and the infrared-crosslinked micro-needles were taken, weighed respectively, then put into a phosphate buffer solution with pH = 7.4, swollen at 37 °C for 8 h, taken out, the moisture on the surface of the micro-needles was absorbed using filter paper, weighed again, and the formula: swelling ratio = (weight of micro-needle after swelling - weight of micro-needle before swelling) / weight of micro-needle before swelling * 100% was used to calculate the influence of infrared cross-linking on the swelling ratio of the micro-needles. The results are shown in Table 2. As a result, the swelling ratio of the micro-needles in the infrared cross-linking group decreased significantly, indicating that infrared irradiation further improved the cohesive force between polyvinyl alcohol molecules, formed more hydrogen bonds, thereby reducing the swelling ratio of the micro-needles. Based on the existing network formed by PVA and the aqueous dispersion, it was discovered that PVA itself can achieve self-cross-linking by infrared light irradiation. PVA is controlled within the network skeleton of the aqueous dispersion, ensuring that it still has a complete needle shape after swelling. However, due to the gel properties of PVA in reality, a small amount of PVA may dissolve into the solvent medium. If further control of PVA elution is desired, a higher degree of cross-linking can be achieved by further strengthening the cross-linking between PVA molecules.

[0049]

Table 2

[0050] (Example 16) Preparation of a Freeze-Thaw Cross-Linked Hydrogel Micro-Needle Patch Weigh 16.8 mL of ultrapure water using a female cylinder, add 3 g (15 wt%) of polyvinyl alcohol, place it in an oven at 90 °C for high-temperature dissolution to obtain an aqueous polyvinyl alcohol solution. Weigh 0.2 g (1 wt%) of an acrylic resin aqueous dispersion (a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate with a molar ratio of 1:1:1), add it to the aqueous polyvinyl alcohol solution, stir uniformly to remove bubbles, and use the mold method to prepare micro needles. After molding the micro needles, place the mold in a refrigerator at -20 °C for 8 h of freezing treatment, and then place it in a refrigerator at 4 °C for 8 h of melting treatment. After performing the above cycle twice, a crosslinked hydrogel micro needle patch was obtained. Take the non-crosslinked micro needles by freeze-thaw and the crosslinked micro needles by freeze-thaw, weigh them respectively, then place them in a phosphate buffer solution with pH = 7.4, swell at 37 °C for 8 h, take them out, absorb the moisture on the surface of the micro needles using filter paper, weigh again, and use the formula: swelling ratio = (weight of micro needles after swelling - weight of micro needles before swelling) / weight of micro needles before swelling * 100% to calculate the influence of freeze-thaw crosslinking on the swelling ratio of micro needles. The results are shown in Table 3. As a result, the swelling ratio of micro needles by freeze-thaw crosslinking decreased significantly. Repeating freeze-thaw improved the cohesive force between polyvinyl alcohol molecules, formed more hydrogen bonds, and thereby decreased the swelling ratio of micro needles. Based on the existing network formed by PVA and the aqueous dispersion, it was discovered that PVA itself can achieve self-crosslinking by repeated freeze-thaw treatment. PVA is controlled within the network skeleton of the aqueous dispersion and still guarantees having a complete needle shape after swelling. However, due to the gel properties of PVA in reality, a small amount of PVA may dissolve into the solvent medium. If further control of PVA elution is desired, a higher crosslinking degree can be achieved by further strengthening the crosslinking between PVA molecules.

[0051] [Table 3]

[0052] (Example 17) Preparation of Chemically Crosslinked Hydrogel Microneedle Patches Using a graduated cylinder, 16.2 mL of ultrapure water was measured, 2.4 g (12 wt%) of polyvinyl alcohol was added, and it was placed in an oven at 90 °C for high-temperature dissolution to obtain an aqueous polyvinyl alcohol solution. 1.2 g (6 wt%) of an acrylic resin aqueous dispersion (a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate with a molar ratio of 1:1:1) was weighed and added to the aqueous polyvinyl alcohol solution. Further, 0.2 g (1 wt%) of glutaraldehyde as a crosslinking agent was added, and it was stirred uniformly to remove bubbles. Microneedles were prepared using the mold method. After the microneedles were formed, chemically crosslinked hydrogel microneedle patches were obtained. The uncrosslinked microneedles and the crosslinked microneedles were taken, weighed respectively, then placed in a phosphate buffer solution with pH = 7.4, and swollen at 37 °C for 8 h. They were taken out, and the moisture on the surface of the microneedles was absorbed using filter paper and weighed again. Using the formula: swelling ratio = (weight of microneedles after swelling - weight of microneedles before swelling) / weight of microneedles before swelling * 100%, the influence of crosslinking agent crosslinking on the swelling ratio of microneedles was calculated, and the results are shown in Table 4. As a result, the swelling ratio of microneedles in the crosslinked group decreased significantly, indicating that the chemical crosslinking agent can form chemical bonds with the hydroxyl groups of polyvinyl alcohol, improve the degree of crosslinking of the system, and thereby reduce the swelling ratio of microneedles. Based on the existing network formed by PVA and the aqueous dispersion, it was discovered that PVA itself can achieve self-crosslinking by a chemical crosslinking agent. PVA is controlled within the network skeleton of the aqueous dispersion and still guarantees having a complete needle shape after swelling. However, due to the gel properties of PVA in reality, a small amount of PVA may dissolve into the solvent medium. If it is desired to further control the elution of PVA, a higher degree of crosslinking can be achieved by further strengthening the crosslinking between PVA molecules.

[0053]

Table 4

[0054] (Example 18) Preparation of Microwave-Crosslinked Hydrogel Microneedle Patch Using a graduated cylinder, 15.9 mL of ultrapure water was measured, 4 g (20 wt%) of polyvinyl alcohol was added, and it was placed in an oven at 90 °C for high-temperature dissolution to obtain an aqueous polyvinyl alcohol solution. 0.1 g (0.5 wt%) of an acrylic resin aqueous dispersion (a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate with a molar ratio of 1:1:1) was weighed and added to the aqueous polyvinyl alcohol solution, stirred uniformly to remove bubbles, and microneedles were prepared using the mold method. After the microneedles were dried to form a film, they were placed in a microwave box and treated with microwaves for 10 minutes to promote crosslinking. The non-microwave-crosslinked microneedles and the crosslinked microneedles were taken, weighed respectively, then placed in a phosphate buffer solution with pH = 7.4, swollen at 37 °C for 8 h, taken out, the moisture on the surface of the microneedles was absorbed using filter paper, weighed again, and the formula: swelling ratio = (weight of microneedles after swelling - weight of microneedles before swelling) / weight of microneedles before swelling * 100% was used to calculate the influence of microwave crosslinking on the swelling ratio of microneedles. The results are shown in Table 5. As a result, the swelling ratio of the microneedles in the microwave crosslinking group decreased significantly. Microwave crosslinking further improved the cohesive force between polyvinyl alcohol molecules, formed more hydrogen bonds, thereby indicating that it reduced the swelling ratio of microneedles. Based on the existing network formed by PVA and the aqueous dispersion, it was discovered that PVA itself can achieve self-crosslinking by microwave treatment. PVA is controlled within the network skeleton of the aqueous dispersion and still guarantees having a complete needle shape after swelling. However, due to the gel properties of PVA in reality, a small amount of PVA may dissolve into the solvent medium. If further control of PVA elution is desired, a higher degree of crosslinking can be achieved by further strengthening the crosslinking between PVA molecules.

[0055]

Table 5

[0056] (Example 19) Preparation of Electron Beam Irradiation Crosslinked Hydrogel Microneedle Patch Using a graduated cylinder, 15.2 mL of ultrapure water was measured, 3.2 g (16 wt%) of polyvinyl alcohol was added, and it was placed in an oven at 90 °C for high-temperature dissolution to obtain an aqueous polyvinyl alcohol solution. 1.6 g (8 wt%) of an acrylic resin aqueous dispersion (a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate with a molar ratio of 1:1:1) was weighed and added to the aqueous polyvinyl alcohol solution, stirred uniformly to remove bubbles, and microneedles were prepared using the mold method. After the microneedles were dried to form a film, they were irradiated with an electron beam for 20 minutes to promote crosslinking. Non-radiation-crosslinked microneedles and crosslinked microneedles were taken, weighed respectively, then placed in a phosphate buffer solution with pH = 7.4, swollen at 37 °C for 8 h, taken out, the moisture on the surface of the microneedles was absorbed using filter paper, weighed again, and the formula: swelling ratio = (weight of microneedles after swelling - weight of microneedles before swelling) / weight of microneedles before swelling * 100% was used to calculate the effect of radiation crosslinking on the swelling ratio of microneedles. The results are shown in Table 6. As a result, the swelling ratio of microneedles by the radiation crosslinking group decreased significantly. Radiation crosslinking formed hydroxyl radicals between the secondary and tertiary carbons in the polyvinyl alcohol molecular chain. After removing the radiation, chemical bond crosslinking was formed between the radicals through a two-group coupling reaction, thereby showing that the swelling ratio of microneedles was decreased. Based on the existing network formed by PVA and the aqueous dispersion, it was discovered that PVA itself can achieve self-crosslinking by electron beam irradiation. PVA is controlled within the network skeleton of the aqueous dispersion and still guarantees having a complete needle shape after swelling. However, due to the gel properties of PVA in reality, a small amount of PVA may dissolve into the solvent medium. If further control of the elution of PVA is desired, a higher degree of crosslinking can be achieved by further strengthening the crosslinking between PVA molecules.

[0057]

Table 6

[0058] (Example 20) Transdermal permeability of a hydrogel microneedle patch to an aqueous solution of an active ingredient as a transdermal penetration enhancer Using a measuring cylinder, 16.4 mL of ultrapure water was weighed, 2.4 g (12 wt%) of polyvinyl alcohol was added, and it was placed in an oven at 90 °C for high-temperature dissolution to obtain an aqueous polyvinyl alcohol solution. 1.2 g (6 wt%) of an acrylic resin aqueous dispersion (a copolymer of ethyl acrylate and methyl methacrylate with a molar ratio of 2:1) was weighed and added to the aqueous polyvinyl alcohol solution, stirred uniformly to remove bubbles, and microneedles were prepared using the mold method. After drying, a hydrogel microneedle patch was obtained. An aqueous solution with a mass content of azelaic acid and matrine of 1% and 1.3% respectively was prepared as the active ingredient solution. The hydrogel microneedles were attached to the stratum corneum side of ex vivo porcine skin, pressed for 20 seconds using a self-made needle feeding device (20 N / cm2), then the microneedle patch was removed, the skin was fixed to a transdermal cup, 100 μL of the aqueous active ingredient solution was added to the administration tank side, automatically sampled at regular intervals using a fully automatic transdermal meter, the drug content in the receiving tank was analyzed using high-performance liquid chromatography, the cumulative transdermal permeation rate of the drug was determined, and the results are shown in Figure 6. As a result, after using the hydrogel microneedle patch as a transdermal penetration enhancer, the administration microchannels on the skin surface could be effectively opened, promoting the transdermal permeation of the aqueous active ingredient solution. In a continuous 10-hour in vitro transdermal permeation test, the cumulative delivery rates of azelaic acid and matrine were 14.90 ± 3.77% and 12.30 ± 2.95% respectively. Also, a blank control group was set, the same volume of the active ingredient solution was dropped onto the untreated intact stratum corneum side, the skin was fixed to a transdermal cup in the same way for an in vitro transdermal permeability test. As a result, neither azelaic acid nor matrine in the blank control group could effectively penetrate the stratum corneum barrier and enter the receiving pool within 10 hours. The hydrogel microneedle patch could effectively exert the skin porosity effect and promote the transdermal delivery of the aqueous active ingredient solution.

[0059] (Example 21) Transdermal permeability of the combination of a hydrogel microneedle patch and an aqueous solution of an active ingredient Weighed 16.4 mL of ultrapure water using a measuring cylinder, added 2.4 g (12 wt%) of polyvinyl alcohol, placed it in an oven at 90 °C for high-temperature dissolution to obtain an aqueous polyvinyl alcohol solution. Weighed 1.2 g (6 wt%) of an acrylic resin aqueous dispersion (a copolymer of ethyl acrylate and methyl methacrylate with a molar ratio of 2:1) and added it to the aqueous polyvinyl alcohol solution, stirred uniformly, removed the bubbles, and prepared microneedles using the mold method. After drying, a hydrogel microneedle patch was obtained. An aqueous solution with a mass content of azelaic acid and matrine of 1% and 1.3% respectively was prepared as the active ingredient solution. The hydrogel microneedles were attached to the stratum corneum side of the in vitro porcine skin. After pressing for 20 seconds using a self-made needle feeding device (20 N / cm2), the microneedles were pierced into the skin. The skin with the microneedles attached was fixed in a transdermal cup, 100 μL of the aqueous active ingredient solution was added, automatically sampled at regular intervals using a fully automatic transdermal meter, and the drug content in the receiving tank was analyzed using high-performance liquid chromatography to determine the cumulative transdermal permeation rate of the drug. The results are shown in Figure 7. As a result, when using the hydrogel microneedle patch formulated with the aqueous active ingredient solution, effective permeation of the drug can be achieved, acting continuously for 10 h. The cumulative permeation rates of azelaic acid and matrine are 29.42 ± 2.43% and 27.51 ± 1.57% respectively. Water-soluble drugs with relatively poor transdermal permeability have good permeation efficiency in the field of transdermal delivery.

[0060] (Example 22) Transdermal permeability of the combination of a hydrogel microneedle patch and a gel preparation of an active ingredient Weigh 16.4 mL of ultrapure water using a female cylinder, add 2.4 g (12 wt%) of polyvinyl alcohol, place it in an oven at 90 °C for high-temperature dissolution to obtain an aqueous polyvinyl alcohol solution. Weigh 1.2 g (6 wt%) of an acrylic resin aqueous dispersion (a copolymer of ethyl acrylate and methyl methacrylate with a molar ratio of 2:1), add it to the aqueous polyvinyl alcohol solution, stir evenly, remove bubbles, use the mold method to prepare micro needles, and after drying, obtain a hydrogel micro needle patch. Affix the hydrogel micro needles to the stratum corneum side of the in vitro porcine skin, press for 20 seconds using a self-made needle feeding device (20 N / cm2), then pierce the skin with the micro needles, fix the skin with the micro needles affixed to a transdermal cup, add 100 μL of a commercially available 15 (wt)% azelaic acid gel to the administration tank side, automatically sample at regular intervals using a fully automatic transdermal meter, analyze the drug content in the receiving tank using a high-performance liquid chromatograph, determine the cumulative transdermal permeation rate of the drug, and show the results in Figure 8. As a result, when a commercially available azelaic acid gel preparation is formulated and used with a hydrogel micro needle patch, effective permeation of the drug can be achieved, it acts continuously for 10 h, the cumulative permeation amount of azelaic acid reaches 228 μg, and good transdermal penetration compared to the commercially available preparation can be achieved.

[0061] (Example 23) Transdermal permeability of a hydrogel micro needle patch directly loaded with azelaic acid and matrine Weigh 15.58 mL of ultrapure water using a female cylinder, add 2.4 g (12 wt%) of polyvinyl alcohol, place it in an oven at 90 °C for high-temperature dissolution to obtain an aqueous polyvinyl alcohol solution. Weigh 2 g (10 wt%) of polyvinylpyrrolidone and add it to the polyvinyl alcohol solution. Further weigh 0.02 g (0.1 wt%) of an acrylic resin aqueous dispersion (a copolymer of ethyl acrylate and methyl methacrylate with a molar ratio of 2:1) and add it to the aqueous polyvinyl alcohol solution. Stir uniformly to remove bubbles and obtain a micro-needle matrix solution. Prepare an aqueous solution of azelaic acid with a mass content of 1% and an aqueous solution of matrine with a mass content of 1.3%. After the two active ingredients are completely dissolved, mix the active ingredient solution with the micro-needle substrate solution to obtain a drug-loaded micro-needle solution. Remove bubbles, use the mold method to prepare micro-needles, and after drying, obtain hydrogel micro-needles loaded with azelaic acid and matrine. Place the micro-needles under an infrared irradiation lamp at 70 °C for 2 minutes to promote cross-linking of the micro-needles. Then attach the micro-needles to the stratum corneum side of the in vitro pig skin, press for 20 seconds using a self-made needle feeding device (20 N / cm2), pierce the micro-needles into the skin, fix the skin with the attached micro-needles to a transdermal cup, automatically sample at regular intervals using a fully automatic transdermal meter, analyze the drug content in the receiving pool using high-performance liquid chromatography, determine the cumulative transdermal permeation rate of the drug, and show the results in Figure 9. As a result, after continuous application for 10 h, the cumulative transdermal permeation rates of both azelaic acid and matrine base can reach more than 50%, and the two drugs can maintain good synchronous release.

[0062] (Example 24) The hydrogel micro-needle patch is used for the extraction of Propionibacterium acnes in skin acne. Weigh 16.4 mL of ultrapure water using a female cylinder, add 4 g (20 wt%) of polyvinyl alcohol, place it in an oven at 90 °C for high-temperature dissolution to obtain an aqueous polyvinyl alcohol solution. Weigh 0.4 g (2 wt%) of an acrylic resin aqueous dispersion (a copolymer of ethyl acrylate and methyl methacrylate with a molar ratio of 2:1), add it to the aqueous polyvinyl alcohol solution, stir uniformly to remove bubbles, use the mold method to prepare micro needles, and after drying, obtain a hydrogel micro needle patch. And the hydrogel micro needle patch was placed under an ultraviolet lamp and irradiated for sterilization overnight. Use an alcohol swab to disinfect the facial acne area of the volunteer suffering from acne, and then pierce the acne skin with a sterile hydrogel micro needle patch and continue to apply it for 3 minutes. After that, remove the micro needle patch, put the micro needles into a pre-prepared sterile thioglycolate liquid medium. At the same time, take a hydrogel micro needle that does not come into contact with the skin as a blank control and directly put it into the sterile thioglycolate liquid medium. Incubate the two culture solutions in an anaerobic environment at 37 °C for 72 h, take them out, observe whether there is bacterial growth in the media in the two culture bottles, and take a small amount of the media in each bottle and drop it on a sterile Columbia agar solid medium. Incubate the medium in an anaerobic environment at 37 °C for 72 h, take it out, observe the growth status of the colonies on the culture plate, compare it with the purchased Propionibacterium acnes strain as a positive control, and determine whether we have successfully extracted Propionibacterium acnes from the skin. The results are shown in Figure 9. As a result, after the hydrogel micro needles acted on the skin acne, an obvious turbidity phenomenon occurred in the thioglycolate liquid medium, indicating that bacteria grew. On the contrary, the medium of the hydrogel micro needle group that did not come into contact with the skin remained clear and no bacteria were present. Also, after inoculating the blood agar culture dish, white colonies grew on the agar in the hydrogel micro needle group after acting on the skin acne. The surface of the colonies was smooth and consistent with the colony morphology of the positive control group of Propionibacterium acnes, indicating that the hydrogel micro needle patch can be used for the extraction of Propionibacterium acnes in skin acne.

[0063] The above embodiments of the present invention are merely examples for clearly explaining the present invention, and do not limit the embodiments of the present invention. For those skilled in the art, in addition to the above description, other different forms of changes or variations may be made. Here, it is impossible to cover all embodiments, and obvious changes or variations made by the technical solution of the present invention are included within the protection scope of the present invention.

Claims

1. A method for preparing a hydrogel micro-needle patch based on a three-dimensional skeletal structure, comprising: adding polyvinyl alcohol having an alcohol decomposition degree of 98% or more into ultrapure water, placing the ultrapure water in an oven at 90°C to dissolve the polyvinyl alcohol at a high temperature, and preparing an aqueous solution of polyvinyl alcohol; adding an acrylic resin aqueous dispersion into the aqueous solution of polyvinyl alcohol heated at 90°C, stirring uniformly to obtain a mixed aqueous solution, removing bubbles, preparing micro-needles using a mold method, drying the micro-needles to form a film, and then cross-linking to obtain the hydrogel micro-needle patch. Here, in the micro-needle patch, the acrylic resin aqueous dispersion surrounds a gel composed of polyvinyl alcohol as a skeletal structure. A method for preparing a hydrogel micro-needle patch based on a three-dimensional skeletal structure, characterized in that.

2. The method for preparing a hydrogel micro-needle patch based on a three-dimensional skeletal structure according to claim 1, wherein the acrylic resin aqueous dispersion is a mixture of one or more of acrylic resin, emulsifier, preservative, alkalizing agent, organic solvent, and purified water.

3. The acrylic resin is one selected from ethyl acrylate, methyl methacrylate, trimethylamine ethyl chloride methacrylate, methyl acrylate, and methacrylic acid. The emulsifier is one or a mixture of several selected from stearyl alcohol polyether-2, nonylphenol ethoxylate, sodium lauryl sulfate, and polysorbate-80. The preservative is one or a mixture of several selected from sorbic acid, benzoic acid, dehydroacetic acid, and methyl paraben. The alkalizing agent is one or a mixture of several selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, and ethanolamine. The organic solvent is one or a mixture of several selected from ethanol and butanediol. A method for preparing a hydrogel micro-needle patch based on a three-dimensional skeletal structure according to claim 2, characterized in that.

4. In the acrylic resin aqueous dispersion, the acrylic resin is one or a mixture of several selected from an ethyl acrylate and methyl methacrylate copolymer with a molar ratio of 2:1, a methacrylic acid, methyl acrylate and methyl methacrylate copolymer with a molar ratio of 1:1:1, an ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride copolymer with a molar ratio of 1:2:0.1, an ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride copolymer with a molar ratio of 1:2:0.2, and a methacrylic acid and ethyl acrylate copolymer with a molar ratio of 1:

1. The method for preparing a hydrogel micro-needle patch based on the three-dimensional skeleton structure according to claim 1 is characterized by this.

5. The micro-needles further contain a porogen, and the porogen is located in the acrylic resin aqueous dispersion and / or polyvinyl alcohol. The mass percentage content of the porogen in the micro-needles is 0.1 to 10 wt%. The method for preparing a hydrogel micro-needle patch based on the three-dimensional skeleton structure according to claim 1 is characterized by this.

6. The porogen is one or a mixture of several selected from polyvinylpyrrolidone, calcium hydrogen phosphate, sodium bicarbonate, sodium carbonate, trehalose, fructose, sorbitol, mannitol, xylitol, galactose, magnesium chloride, calcium chloride, and zinc chloride. The method for preparing a hydrogel micro-needle patch based on the three-dimensional skeleton structure according to claim 5 is characterized by this.

7. The cross-linking is one selected from infrared light irradiation cross-linking, physical freeze-thaw cross-linking, chemical agent cross-linking, annealing treatment cross-linking, microwave-assisted cross-linking, and radiation cross-linking. The method for preparing a hydrogel micro-needle patch based on the three-dimensional skeleton structure according to claim 1 is characterized by this.

8. The infrared light wavelength of the infrared light irradiation cross-linking is 1000 to 5000 nm. The method for preparing a hydrogel micro-needle patch based on the three-dimensional skeleton structure according to claim 7 is characterized by this.

9. In the mixed aqueous solution, the mass percentage content of polyvinyl alcohol is 5 to 50 wt%. In the mixed aqueous solution, the mass percentage content of the acrylic resin aqueous dispersion is 0.1 to 10 wt%, and the method for preparing the hydrogel micro needle patch based on the three-dimensional skeleton structure according to claim 1 is characterized by this.

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