Programmed stepped release microneedle transdermal drug delivery patch as well as preparation method and application of programmed stepped release microneedle transdermal drug delivery patch

Abstract

The invention discloses a programmed stepped release microneedle transdermal drug delivery patch as well as a preparation method and application thereof, and relates to the technical field of medicines. The microneedle transdermal drug delivery patch comprises: a flexible substrate; the microneedles are arranged on the flexible substrate, a first medicine carrying area, a second medicine carrying area and a third medicine carrying area which are sequentially arranged in the direction from the needle tip to the needle root of each microneedle are arranged in each microneedle, and the release speed of the medicine in the first medicine carrying area, the release speed of the medicine in the second medicine carrying area and the release speed of the medicine in the third medicine carrying area are sequentially decreased. The invention provides a microneedle transdermal drug delivery patch with the functions of multilayer material construction, spatial partition drug loading, programmed stepped release and single-time application multi-stage drug delivery as well as a preparation method and application of the microneedle transdermal drug delivery patch. And a drug-loaded storage with clear spatial distribution is formed in the microneedle, so that the drug-loaded release sequence corresponds to the position of the microneedle structure, and programmed stepped release of the drug-loaded in the time dimension is realized.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a programmed step-release microneedle transdermal drug delivery patch, its preparation method, and its application. Background Technology

[0002] Microneedle transdermal drug delivery technology has gained widespread attention in recent years in fields such as vaccine delivery, chronic disease treatment, and biological drug delivery due to its advantages such as being minimally invasive, painless, allowing for self-administration, and avoiding gastrointestinal degradation. By loading drugs into microneedle structures and inserting them beneath the stratum corneum of the skin, drugs can be directly delivered into the skin's microcirculation system, thereby improving drug bioavailability and reducing systemic side effects.

[0003] However, in existing microneedle drug delivery technologies, most microneedle structures are typically composed of a single material, and drug release mainly depends on the dissolution or degradation process of the material. Their release kinetics usually exhibit a single mode; for example, rapidly dissolving microneedles primarily achieve rapid release over a short period, while sustained-release microneedles focus on sustained release over a long period. For many disease treatment scenarios, relying solely on a single release mode often fails to simultaneously meet the synergistic requirements of rapid onset of action and long-term maintenance of therapeutic concentrations. For instance, in the treatment of diseases such as diabetes, cardiovascular disease, and chronic pain management, drug delivery typically requires both rapid onset of action to relieve acute symptoms and long-term sustained release to maintain stable therapeutic concentrations. Traditional drug delivery methods usually require multiple injections or combinations of various dosage forms to achieve different release stages, which not only increases the complexity of patient medication but also reduces treatment adherence.

[0004] On the other hand, even in some existing composite microneedle technologies, although multiple materials or drug loadings are introduced, their internal structural designs are usually relatively simple. Most achieve drug release only through mixed loading or simple layered structures, making it difficult to precisely control the release sequence and rate of different drug loadings over time. In addition, during the microneedle preparation process, insufficient control over the material dissolution rate, crosslinking density, and spatial distribution can easily lead to unclear boundaries between different release stages, thus affecting the overall drug delivery effect.

[0005] Therefore, there is an urgent need for a method to construct a multi-stage release structure in a single microneedle transdermal drug delivery patch. By rationally designing the material degradation rate and spatial structure distribution, the drug can form a pre-set and controllable programmed release process in the time dimension, thereby achieving both rapid onset and long-lasting sustained-release therapeutic effects in a single application. Summary of the Invention

[0006] The purpose of this invention is to at least solve one of the technical problems existing in the prior art, and to provide a programmed step-release microneedle transdermal drug delivery patch, its preparation method and application.

[0007] To address the following technical problems existing in the prior art, the present invention offers the following solutions: (1) The problem of a single drug delivery mode in microneedles: In response to the problem that existing microneedle systems mostly use a single material or a single release mechanism, resulting in a fixed drug delivery mode and difficulty in simultaneously achieving rapid onset and long-term sustained release, the present invention constructs a multi-layer structure and a combination of multiple materials to achieve programmed step-by-step release of the drug in the time dimension. (2) The problem of difficulty in accurately controlling the order of drug delivery in multiple stages: In response to the problem that it is difficult to accurately control the different drug delivery sequences and release rates in existing composite microneedle structures, the present invention constructs a multi-layer drug delivery structure with different degradation rates and solubility characteristics inside the microneedle, so that the drug delivery process occurs step by step in a preset order. (3) The problem of stability and manufacturability of multi-layer microneedle structures: In response to the problem that multi-layer microneedles are prone to unstable layering, insufficient structural bonding strength, or uneven drug delivery during the preparation process, the present invention improves the stability and preparation consistency of the multi-layer structure through layer-by-layer filling, gradient centrifugation, and interface bonding control methods. (4) The problem that complex dosing regimens are difficult to achieve with a single dosage form: In view of the problem that existing complex dosing regimens usually require multiple administrations or the combined use of multiple formulations, the present invention uses a programmed step release microneedle structure to enable multi-stage dosing with a single patch, thereby simplifying the dosing process and improving patient compliance.

[0008] This invention proposes a microneedle transdermal drug delivery patch, its preparation method, and its application, which involves "multi-layer material construction, spatial partitioning drug loading, programmed step release, and single-application multi-stage drug delivery." The core of this invention lies in constructing a multi-layer drug loading structure with different dissolution rates and degradation characteristics, and forming a drug reservoir with a clear spatial distribution inside the microneedles, so that the drug release sequence corresponds to the position of the microneedle structure, thereby achieving programmed step release of the drug in the time dimension.

[0009] The technical solution of the present invention is as follows: In a first aspect, the present invention provides a programmed step-release microneedle transdermal drug delivery patch, the microneedle transdermal drug delivery patch comprising: Flexible substrate; A plurality of microneedles are disposed on the flexible substrate. Each microneedle has a cavity capable of containing a drug. The cavity includes a first drug-loading region, a second drug-loading region, and a third drug-loading region arranged sequentially along the direction from the tip to the root of the microneedle. The first drug-loading region contains a first drug, the second drug-loading region contains a second drug, and the third drug-loading region contains a third drug. The release rates of the first drug, the second drug, and the third drug decrease sequentially.

[0010] Optionally, the degradation time of the first drug in the body fluid environment is 0.01 min to 10 min, the degradation time of the second drug in the body fluid environment is 0.5 h to 12 h, and the degradation time of the third drug in the body fluid environment is 6 h to 7 d.

[0011] Optionally, the height of the microneedle is 400 μm-900 μm, the height of the first drug-loading area is 100 μm-150 μm, the height of the second drug-loading area is 100 μm-300 μm, the height of the third drug-loading area is 200 μm-400 μm, and the thickness of the flexible substrate is 20 μm-100 μm.

[0012] Optionally, the first drug contains a first therapeutic drug, a first carrier, and a solvent; the second drug contains a second therapeutic drug, a second carrier, and a solvent; and the third drug contains a third therapeutic drug, a third carrier, and a solvent. The degradation rates of the first carrier, the second carrier, and the third carrier decrease sequentially; the first carrier comprises a hydrogel material with high hydrophilicity and / or low intermolecular crosslinking density; the second carrier comprises a material that has been modified to form a controllable degradation structure after temperature / acid sensitivity modification; and the third carrier comprises a composite material formed after physical / chemical crosslinking treatment. The onset time of the first therapeutic drug is shorter than that of the second and third therapeutic drugs, respectively.

[0013] Optionally, the first carrier includes at least one of hyaluronic acid and polyvinylpyrrolidone; the second carrier includes at least one of gelatin and chitosan; and the third carrier includes at least one of PLGA microsphere-polyvinyl alcohol-sodium alginate composite material and sodium carboxymethyl cellulose-calcium chloride composite material. The first drug further contains glycerol and / or sorbitol, the second drug further contains glutaraldehyde, a natural cross-linking agent, a pH adjuster, and / or sodium glycerophosphate, and the third drug further contains nanocellulose and / or nanoclay.

[0014] Secondly, the present invention provides a method for preparing the aforementioned microneedle transdermal drug delivery patch, comprising the following steps: S1. Dissolve the first carrier and the first therapeutic drug in a solvent to obtain a first solution; The second carrier and the second therapeutic drug are dissolved in a solvent to obtain a second solution; The raw materials for preparing the third carrier and the third therapeutic drug are dissolved in a solvent and cross-linked to obtain the third solution; S2. The first solution is dropped into the microneedle array mold, and the first solution is centrifuged to enter the microneedle tip region, and pre-dried to form the first drug. The second solution is continued to be added dropwise into the microneedle array mold, and the second solution is used to fill the central region of the microneedles to form a second drug by a second centrifugation. The third solution is continued to be added dropwise into the microneedle array mold, and then vacuum-treated, dried at low temperature or with gradient temperature increase, so that the third solution is distributed in the microneedle root region and the basal layer to form the third drug. S3. Demold the microneedle array mold to obtain a microneedle array, and fix the microneedle array on a flexible substrate to form a microneedle transdermal drug delivery patch.

[0015] Optionally, in S1, the preparation method of the first solution includes: dissolving hyaluronic acid with a molecular weight of 10kDa-500kDa in phosphate buffer, adding a first therapeutic drug, and stirring at room temperature to form a homogeneous and transparent first solution; or, dissolving polyvinylpyrrolidone and the therapeutic drug in deionized water to form a transparent first solution; wherein the added mass of hyaluronic acid is 5% of the volume of phosphate buffer, the added mass of polyvinylpyrrolidone is 10% of the volume of deionized water, and the concentration of the therapeutic drug in the first solution is 1mg / mL-2mg / mL; The preparation method of the second solution includes: dissolving gelatin in warm water, adding the second therapeutic drug, stirring thoroughly to form a homogeneous solution, and maintaining the temperature at 37℃-40℃ before use to prevent premature gelation, thereby obtaining the second solution; or, dissolving chitosan in a 0.5%-1.5% volume fraction acetic acid solution, adding the second therapeutic drug, thereby obtaining the second solution; wherein the mass of gelatin added is 10% of the volume of warm water, the mass of chitosan added is 2% of the volume of acetic acid solution, and the concentration of the therapeutic drug in the second solution is 0.5mg / mL-1mg / mL.

[0016] Optionally, in S1, the method for preparing the third solution includes: PLGA was dissolved in dichloromethane, and a third therapeutic drug was added to form an organic phase. The organic phase was slowly added dropwise to an aqueous phase containing 1%–2% polyvinyl alcohol by mass, and emulsified at 8000 rpm–12000 rpm for 1 min–3 min to form an O / W emulsion. The mixture was magnetically stirred at room temperature for 2 h–4 h to evaporate the organic solvent and solidify the PLGA to form drug-loaded microspheres. After centrifugation, washing, and freeze-drying, drug-loaded PLGA microspheres with a particle size of 0.5 μm–5 μm were obtained. The drug-loaded PLGA microspheres were dispersed at a concentration of 5–20 mg / mL in a sodium alginate solution with a mass-volume concentration of 1.5–2.5% to form a third solution. Alternatively, sodium carboxymethyl cellulose is added to deionized water and magnetically stirred at room temperature until completely dissolved to obtain a CMC-Na solution with a mass-volume concentration of 3%; a third therapeutic drug is added to the CMC-Na solution to obtain a drug-loaded polymer solution; a calcium chloride solution with a mass-volume concentration of 0.1%-0.5% is slowly added dropwise to the drug-loaded polymer solution to crosslink and form a third solution.

[0017] Optionally, in S2, the speed of the first centrifugation is 3000 rpm-4000 rpm, and the centrifugation time of the first centrifugation is 5-10 minutes; The pre-drying temperature is 22℃-28℃, the pre-drying time is 1-2 hours, and the moisture content of the first drug after pre-drying is 20%-40%. The second centrifugation speed is 2000-3000 rpm, and the centrifugation time is 3-5 minutes; The pressure of the vacuum treatment is controlled below -0.08 MPa; The low-temperature drying temperature is 4℃-10℃, and the low-temperature drying time is 12h-24h.

[0018] Thirdly, the present invention provides the use of the microneedle transdermal drug delivery patch in the preparation of drugs for treating diabetes and / or cardiovascular diseases and / or chronic pain.

[0019] This invention has at least one of the following beneficial effects: First, by constructing a multilayer microneedle structure composed of materials with different degradation rates, the present invention enables drug release to no longer be limited to a single mode, but to form a well-defined programmed step release process in the time dimension, thereby achieving both rapid onset and long-lasting sustained-release therapeutic effects in a single microneedle transdermal drug delivery patch.

[0020] Secondly, by constructing a drug-loaded structure with spatial partitions inside the microneedle, the present invention allows different drugs or different doses of drugs to be distributed in the needle tip, needle body, and needle root regions respectively, thereby making the drug release sequence correspond to the microneedle dissolution sequence, thus improving the controllability and stability of the drug release process.

[0021] Furthermore, this invention achieves stable preparation of multilayer microneedles through layer-by-layer filling and gradient centrifugation processes, effectively avoiding delamination or structural damage during the preparation and demolding of multilayer structures, and improving the structural stability and preparation consistency of the microneedle array.

[0022] Finally, this invention, through a programmed step-release design, enables complex multi-stage drug delivery protocols to be achieved through a single microneedle patch application, thereby reducing the number of doses administered to patients, improving medication adherence, and helping to maintain more stable blood drug concentrations, thus improving therapeutic efficacy and safety. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of the structure of the programmed step-release microneedle transdermal drug delivery patch in a preferred embodiment of the present invention; Figure 2 This is a schematic diagram of the microneedles in the programmed step-release microneedle transdermal drug delivery patch in a preferred embodiment of the present invention; Reference numerals: 1. Flexible substrate; 2. Microneedle; 21. First drug loading area; 22. Second drug loading area; 23. Third drug loading area. Detailed Implementation

[0024] To make the technical problems solved, the technical solutions, and the beneficial effects of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0025] To address the core issues of existing microneedle drug delivery systems, such as the single release mode, difficulty in controlling the release sequence, and the inability to achieve complex drug delivery regimens with a single dosage form, this invention proposes a composite microneedle transdermal drug delivery system and its preparation method, which involves "multi-layer material construction—spatial partitioned drug loading—programmed step-release—single-application multi-stage drug delivery." The core of this invention lies in constructing multi-layered drug-loaded structures with different dissolution rates and degradation characteristics, and forming drug reservoirs with a clear spatial distribution within the microneedles. This ensures that the drug release sequence corresponds to the position of the microneedle structure, thereby achieving programmed step-release of the drug over time. The specific concept is as follows: 1. Conceptualization of Multilayer Drug-Loading Material System This invention constructs a multilayer drug delivery system by selecting hydrogel or polymer materials with different dissolution rates and degradation characteristics. Rapidly dissolving materials are used to achieve initial rapid drug release, moderately degrading materials are used to achieve sustained release, and sustained-release materials are used to achieve long-term sustained release, thus forming a multi-stage release basis at the material level.

[0026] 2. Microneedle Spatial Partitioning Drug Delivery Structure Concept During the microneedle preparation process, different materials and drug loading are distributed in the microneedle tip, body and root areas through layer-by-layer filling and gradient centrifugation. This makes the drug loading form clear partitions in the spatial structure, so that the drug release order corresponds to the dissolution order after the microneedle is inserted into the skin.

[0027] 3. Programmed step-by-step release concept By controlling the material dissolution rate, cross-linking density, and drug loading, the materials of each layer of the microneedle are sequentially dissolved or degraded in the body fluid environment, thereby forming a programmed step release process of "rapid release - medium-speed release - long-term sustained release", so that the drug loading concentration changes over time to form a stable and controllable release curve.

[0028] 4. Concept of multi-stage drug delivery with single application By integrating multiple release phases into the same microneedle transdermal drug delivery patch, patients can achieve multi-stage drug delivery effects with a single application, thus replacing traditional treatment methods that require multiple administrations or the combined use of multiple formulations.

[0029] 5. Adjustable release kinetics concept By adjusting the thickness of each layer of material, the degree of cross-linking, and the drug concentration ratio, the release time and release dose at each stage can be flexibly adjusted according to the treatment needs of different diseases, making the microneedle system of the present invention applicable to a variety of disease treatment scenarios.

[0030] The solution of the present invention is as follows: An embodiment of the present invention provides a programmed step-release microneedle transdermal drug delivery patch, the microneedle transdermal drug delivery patch comprising: Flexible substrate 1; A plurality of microneedles 2 are disposed on the flexible substrate 1. Each microneedle 2 has a cavity inside which can accommodate a drug. The cavity includes a first drug-loading region 21, a second drug-loading region 22 and a third drug-loading region 23 arranged sequentially along the direction from the tip to the root of the microneedle 2. The first drug-loading region 21 contains a first drug, the second drug-loading region 22 contains a second drug and the third drug-loading region 23 contains a third drug. The release rates of the first drug, the second drug and the third drug decrease sequentially.

[0031] This invention constructs a multilayer drug-loaded structure with different dissolution rates and degradation characteristics, and forms a drug reservoir with a clear spatial distribution inside the microneedle, so that the drug release sequence corresponds to the position of the microneedle structure, thereby realizing the programmed step release of the drug in the time dimension.

[0032] In some embodiments, the degradation time of the first drug in the body fluid environment is 0.01 min to 10 min, the degradation time of the second drug in the body fluid environment is 0.5 h to 12 h, and the degradation time of the third drug in the body fluid environment is 6 h to 7 d.

[0033] In some embodiments, the height of the microneedle 2 is 400 μm-900 μm, the height of the first drug-loading region 21 is 100 μm-150 μm, the height of the second drug-loading region 22 is 100 μm-300 μm, the height of the third drug-loading region 23 is 200 μm-400 μm, and the thickness of the flexible substrate 1 is 20 μm-100 μm.

[0034] In some embodiments, the first drug comprises a first therapeutic drug, a first carrier, and a solvent; the second drug comprises a second therapeutic drug, a second carrier, and a solvent; the third drug comprises a third therapeutic drug, a third carrier, and a solvent; and the degradation rates of the first carrier, the second carrier, and the third carrier decrease sequentially.

[0035] In some embodiments, the first carrier comprises a hydrogel material with high hydrophilicity and / or low intermolecular crosslinking density, the second carrier comprises a material that has been modified to form a controllable degradation structure after temperature / acid sensitivity modification, and the third carrier comprises a composite material formed after physical / chemical crosslinking treatment.

[0036] In some embodiments, the onset time of the first therapeutic drug is shorter than that of the second therapeutic drug and the third therapeutic drug, respectively.

[0037] In some embodiments, the first carrier includes at least one of hyaluronic acid and polyvinylpyrrolidone; the second carrier includes at least one of gelatin and chitosan; and the third carrier includes at least one of PLGA microsphere-polyvinyl alcohol-sodium alginate composite material and sodium carboxymethyl cellulose-calcium chloride composite material.

[0038] In some embodiments, the first drug further includes glycerol and / or sorbitol, the second drug further includes glutaraldehyde, a natural crosslinking agent, a pH adjuster, and / or sodium glycerophosphate, and the third drug further includes nanocellulose and / or nanoclay.

[0039] Another embodiment of the present invention provides a method for preparing a programmed step-release microneedle transdermal drug delivery patch, comprising the following steps: S1. Dissolve the first carrier and the first therapeutic drug in a solvent to obtain a first solution; The second carrier and the second therapeutic drug are dissolved in a solvent to obtain a second solution; The raw materials for preparing the third carrier and the third therapeutic drug are dissolved in a solvent and cross-linked to obtain the third solution; S2. The first solution is dropped into the microneedle array mold, and the first solution is centrifuged to enter the microneedle tip region, and pre-dried to form the first drug. The second solution is continued to be added dropwise into the microneedle array mold, and the second solution is used to fill the central region of the microneedles to form a second drug by a second centrifugation. The third solution is continued to be added dropwise into the microneedle array mold, and then vacuum-treated, dried at low temperature or with gradient temperature increase, so that the third solution is distributed in the microneedle root region and the basal layer to form the third drug. S3. Demold the microneedle array mold to obtain a microneedle array, and fix the microneedle array on a flexible substrate to form a microneedle transdermal drug delivery patch.

[0040] The preparation method of the present invention is simple. Through operations such as molding, centrifugation, pre-drying, and vacuum treatment, multiple drugs can be loaded effectively, and the release sequence and release rate of different drugs in the time dimension can be precisely controlled.

[0041] In some embodiments, the method specifically includes the following steps: S1. Preparation of multilayer programmed drug-loaded hydrogel system This step aims to construct multilayer drug-loaded structures with different degradation rates, solubility gradients, and release sequences, providing a material basis for subsequent programmed step release.

[0042] By controlling the dissolution rate, cross-linking density, and drug distribution location of each layer of material, a programmed step release mode of "rapid release - medium-speed release - long-acting sustained release" is formed sequentially.

[0043] S11. Prepare a rapid-release drug-loaded solution. Highly swollen and rapidly dissolving hydrogel materials were selected as the first-layer carrier to achieve rapid drug release in the initial stage.

[0044] The fast-release layer material preferably has high hydrophilicity and low intermolecular crosslinking density, so that it can dissolve or disintegrate rapidly within 1-10 minutes in a body fluid environment.

[0045] Specific example 1: Weigh hyaluronic acid (HA, molecular weight 10kDa-500kDa, 5% w / v) and dissolve it in phosphate buffer (PBS, pH 7.4), and add lidocaine (1 mg / mL) as a model drug. Stir magnetically for 30 minutes at room temperature to form a homogeneous and transparent rapid drug release solution.

[0046] If necessary, aseptic filtration can be performed through a 0.22 μm filter membrane to improve the stability of the formulation.

[0047] Specific example 2: Polyvinylpyrrolidone (PVP, 10% w / v) and the anti-inflammatory drug ibuprofen (2 mg / mL) are dissolved in deionized water to form a transparent drug-loaded solution. This material can dissolve rapidly in the body fluid environment.

[0048] In some embodiments, 1-3% by mass of glycerol or sorbitol may be added as a plasticizer to improve the mechanical strength after molding.

[0049] S12. Prepare medium-release drug-loaded solution. Hydrogel materials with moderate degradation rates are selected, or controlled degradation structures are formed through temperature- and acid-sensitive modification, to construct the second-stage release layer. The degradation time of the moderate-rate release layer material is preferably 30 minutes to 12 hours, so as to form a second release stage that is clearly different from the rapid-release layer.

[0050] Specific example 1: Weigh out gelatin (10% w / v) and dissolve it in warm water at 40°C. Add the antibiotic moxifloxacin (1 mg / mL), stir thoroughly to form a homogeneous solution, and keep it at 37-40°C before use to prevent premature gelation.

[0051] In some embodiments, 0.05%-0.2% glutaraldehyde or the natural crosslinking agent Genipin may be added as a mild crosslinking agent to adjust gel stability.

[0052] Specific Example 2: Chitosan (2% w / v) was dissolved in a 1% acetic acid solution and an anti-inflammatory peptide loading solution (0.5 mg / mL) was added to obtain a homogeneous medium-release drug loading solution.

[0053] The gelation rate can be adjusted by changing the pH value or by adding sodium glycerophosphate.

[0054] The solution pH is preferably adjusted to 6.2-6.8 so that it forms a stable but gradually degradable gel structure in the body fluid environment.

[0055] S13. Preparation of a long-acting sustained-release drug delivery system Select polymeric materials with slow degradation rates or composite materials that have undergone physical / chemical cross-linking treatment to construct long-acting sustained-release layers and achieve continuous drug delivery.

[0056] The degradation cycle of the long-acting sustained-release layer material is preferably 12 hours to 7 days to maintain a stable blood drug concentration.

[0057] Specific Example 1: The PLGA microspheres were prepared via an emulsion-solvent evaporation method. Specifically, PLGA (lactide:glycolic acid = 50:50–75:25, molar ratio) was dissolved in dichloromethane, and dexamethasone (3–10% of the PLGA mass, preferably 5%) was added to form an organic phase. This organic phase was then slowly added dropwise to an aqueous phase containing 1–2% polyvinyl alcohol (PVA), and emulsified at 10,000 rpm for 2 min to form an O / W emulsion. The emulsion was magnetically stirred at room temperature for 2–4 h to evaporate the organic solvent, allowing the PLGA to solidify and form drug-loaded microspheres. After centrifugation, washing, and freeze-drying, dexamethasone-loaded PLGA microspheres with a particle size of 0.5–5 μm were obtained. The resulting microspheres were dispersed at a concentration of 5–20 mg / mL in a 2% (w / v) sodium alginate solution to form a long-acting sustained-release drug delivery system.

[0058] Specific example 2: Weigh 3 g of sodium carboxymethyl cellulose (CMC-Na) and add it to 100 mL of deionized water. Stir magnetically for 30-60 min at room temperature until completely dissolved to obtain a CMC-Na solution with a mass-volume concentration of 3% (w / v).

[0059] Subsequently, the peptide loading was added to the CMC-Na solution to achieve a final peptide concentration of 0.5 mg / mL. For example, 50 mg of the peptide loading was added to 100 mL of the solution, and the mixture was gently stirred for 10-20 min to ensure thorough and uniform dispersion, thus obtaining the drug-loaded polymer solution.

[0060] Subsequently, a 0.1%-0.5% (w / v) calcium chloride solution (CaCl2) is slowly added dropwise as a cross-linking agent to induce ionic cross-linking between the CMC-Na molecular chains, thereby forming a stable sustained-release gel structure. The amount of calcium ion solution added is preferably 5%-20% of the volume of the CMC-Na solution; for example, 5-20 mL of calcium ion solution is added to 100 mL of drug-loaded solution, and the reaction is carried out under slow stirring for 5-10 min to form a uniform, slightly cross-linked network.

[0061] In some embodiments, 1%-5% (w / v) of nanocellulose or nanoclay may be added to the above system as a structural reinforcing agent, for example, 1-5 g of nanocellulose or nanoclay may be added to 100 mL of the system to further improve the stability of the gel structure and prolong the drug release cycle.

[0062] The resulting system can be used as a long-acting sustained-release drug delivery material in microneedle structures.

[0063] S2. Constructing a programmatic ladder-structured microneedle array This step aims to construct drug-loaded compartments with different release phases inside the microneedles through multi-layer molding, layer-by-layer filling, and gradient centrifugation processes.

[0064] By controlling the spatial distribution of different materials in the microneedle tip, needle body, and needle root region, the correspondence between the spatial structure and the time release sequence is realized, thereby forming a programmed step release structure.

[0065] S21. Fabrication of microneedle array mold A standard microneedle array mold was prepared using microfabrication technology.

[0066] Specific example: A mold with inverted conical microneedle grooves was prepared using PDMS material. Each groove was 600 μm high, the needle tip diameter was about 20 μm, and the array density was 10×10.

[0067] In some embodiments, the microneedle height can be set to 400-900 μm, and the array density is 5×5 to 20×20.

[0068] The mold needs to be plasma treated before use to enhance its surface hydrophilicity.

[0069] The plasma treatment time is preferably 30-120 seconds.

[0070] S22, Fill the first layer (fast release layer) The rapid release drug-loaded solution obtained in step S11 is dropped into the mold and centrifuged to allow it to enter the microneedle tip region.

[0071] Specific example: Add 50 μL of rapid release drug loading solution to the PDMS mold and centrifuge at 3000-4000 rpm for 5-10 minutes to concentrate the drug solution into the needle tip area.

[0072] Then pre-dry at 25°C for 1-2 hours to allow some of the solvent to evaporate and fix the position.

[0073] This step ensures that the rapid release layer is mainly distributed in the 0-150 μm region at the microneedle tip, thereby preferentially contacting body fluids and rapidly releasing the drug after insertion into the skin.

[0074] S23, Fill the second layer (medium-speed release layer). After the first layer has been initially dried, a medium-release drug-loaded solution is added to form the second release stage.

[0075] Specific example: The drug-loaded solution obtained from S12 is dropped into the mold and centrifuged at 2000-3000 rpm for 3-5 minutes to fill the central structure of the microneedles.

[0076] Care should be taken to control the moisture content between the two layers to ensure that appropriate molecular chain entanglement is generated at the interface and to prevent delamination during demolding.

[0077] The moisture content of the first layer is preferably controlled at 20%-40% to enhance the interfacial bonding strength.

[0078] S24. Fill with the third layer (long-lasting sustained-release layer). Finally, a sustained-release layer material is filled in to form the microneedle substrate and the main drug storage structure.

[0079] Specific example: Add the sustained-release drug loading system obtained by S13 into the mold and perform vacuum treatment (pressure controlled below -0.08MPa) to remove air bubbles.

[0080] Then dry for 12-24 hours under low temperature (4-10℃) or gradient temperature conditions.

[0081] This step ensures that the long-acting sustained-release layer is mainly distributed in the microneedle root region and basal layer, thereby forming the main drug reservoir.

[0082] S3. Form a complete microneedle transdermal drug delivery patch and achieve programmed stepwise release. This step aims to integrate the microneedle array with the flexible substrate to form a complete transdermal drug delivery patch.

[0083] The resulting microneedle array structure exhibits a spatial gradient structure from the needle tip to the substrate, consisting of a fast-release layer, a medium-release layer, and a long-acting sustained-release layer.

[0084] S31. Demolding to obtain a multi-layered microneedle array After the material has completely cured, it is carefully demolded from the PDMS mold to obtain a microneedle array with a multi-layer structure.

[0085] Specific example: After drying, gently bend the mold to obtain a three-layer microneedle array with a height of approximately 600 μm. The breaking force of the resulting microneedles is preferably greater than 0.1 N / needle to ensure successful penetration of the stratum corneum. After demolding, the microneedles should be stored in a desiccator with the relative humidity controlled below 20%.

[0086] S32, Combined with flexible patch substrate The microneedle array is fixed on a flexible substrate to form a microneedle transdermal drug delivery patch.

[0087] Specific example: Select medical-grade polyurethane (PU) film or acrylic pressure-sensitive adhesive as the substrate, and fix the microneedle array to the central region of the substrate by hot pressing, UV curing, or directly utilizing the residual adhesiveness of the third layer material. The substrate thickness is preferably 20-100 μm to balance flexibility and mechanical support.

[0088] S33, Implementing programmed step-by-step release When microneedles penetrate the skin, the materials in each layer dissolve or degrade sequentially, thus forming a programmed stepwise release process for the drug-loaded substance, releasing it in a time-sequential manner. The first layer of material (distributed at the needle tip) dissolves rapidly, enabling initial rapid drug release; The second layer of material (distributed in the middle section of the needle body) gradually degrades, achieving a medium-speed continuous release; The third layer of slow-release material (distributed in the needle root and substrate) degrades over a long period of time, achieving long-term slow release.

[0089] In a bodily fluid environment, the typical release times of the three-layer structure are as follows: Phase 1: Rapid release within 0-10 minutes; Phase Two: Continuous release from 30 minutes to 12 hours; Phase 3: 12 hours to 7 days of long-lasting sustained release.

[0090] The above structural design enables programmed stepwise drug delivery under single-application conditions.

[0091] Another embodiment of the present invention provides the use of a programmed step-release microneedle transdermal drug delivery patch in the preparation of drugs for treating diabetes and / or cardiovascular diseases.

[0092] The microneedle transdermal drug delivery patch of the present invention contains a first drug-loading region, a second drug-loading region, and a third drug-loading region. These three regions are respectively loaded with a fast-release drug, a medium-release drug, and a long-acting sustained-release drug, thereby enabling its use in the treatment of diseases such as diabetes, cardiovascular disease, and chronic pain management.

[0093] 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 specific embodiments.

[0094] Example 1 This embodiment provides a programmed stepwise release microneedle transdermal drug delivery patch for the treatment of diabetes, the specific scheme of which is as follows: like Figure 1 As shown, the programmed step-release microneedle transdermal drug delivery patch of this embodiment includes a flexible substrate 1 and a plurality of microneedles 2 disposed on the flexible substrate 1, the microneedles 2 being vertically disposed on the substrate 1. Figure 2 As shown, the microneedle 2 has a cavity inside that can accommodate drugs. The cavity includes a first drug loading area 21, a second drug loading area 22 and a third drug loading area 23 arranged sequentially along the direction from the tip to the root of the microneedle 2. The first drug loading area 21, the second drug loading area 22 and the third drug loading area 23 are respectively loaded with insulin.

[0095] In this embodiment, the first drug-loading region 21 is a fast-release layer (needle tip layer), the second drug-loading region 22 is a medium-release layer (needle body layer), and the third drug-loading region 23 is a long-acting sustained-release layer (needle root layer).

[0096] The specific formulation and preparation method of the microneedle transdermal drug delivery patch in this embodiment are as follows: In this embodiment, a programmable step-release microneedle array with a three-layer structure is constructed, and the materials and drug formulations of each layer are as follows.

[0097] (1) Rapid release layer (needle tip layer) Material: Hyaluronic acid (HA, molecular weight approximately 200 kDa); Rapid-acting insulin Insulin Lispro; formula: Preparation method: Add 5 g of hyaluronic acid to 100 mL of PBS buffer (pH 7.4) and stir magnetically until completely dissolved; add 100 mg of Insulin Lispro to bring the final concentration to 1 mg / mL, and add 2 g of glycerol as a plasticizer. Continue stirring for 20 min to form a homogeneous drug-loaded solution.

[0098] This layer is used to achieve rapid insulin release within 5–10 minutes after microneedles are inserted into the skin.

[0099] (2) Medium-speed release layer (needle body layer) Material: Gelatin; Short-acting human insulin (Regular Insulin); formula: Preparation method: Dissolve 10 g of gelatin in 100 mL of 40℃ deionized water, then add 100 mg of regularinsulin and 0.1 g of Genipin as a crosslinking agent, and stir for 15 min to obtain a homogeneous drug-loaded solution.

[0100] This layer gradually degrades in the body fluid environment within 30 minutes to 6 hours, and is used to maintain stable postprandial blood glucose levels.

[0101] (3) Long-acting sustained-release layer (needle root layer) Material: PLGA microspheres (LA:GA=65:35); Long-acting insulin, insulin galagine; Sodium alginate; PLGA microsphere formulation: 100 mg of PLGA was dissolved in 2 mL of dichloromethane, and long-acting insulin (5% of the PLGA mass) was added to form an organic phase. This organic phase was then slowly added dropwise to 20 mL of an aqueous phase containing 2% polyvinyl alcohol (PVA), and emulsified at 10,000 rpm for 2 min to form an O / W emulsion. The emulsion was then magnetically stirred at room temperature for 3 h to evaporate the organic solvent. After centrifugation, washing, and freeze-drying, drug-loaded PLGA microspheres were obtained.

[0102] Drug-loaded PLGA microspheres were dispersed at a concentration of 10 mg / mL in a 2% (w / v) sodium alginate solution to form a long-acting sustained-release system.

[0103] This layer gradually releases insulin in the body over 6 to 48 hours to maintain basal blood glucose levels.

[0104] II. Microneedle Array Structure Parameters The microneedle mold was prepared using PDMS, and the specific parameters are as follows: Total drug dosage: Total insulin dose per patch: 12 IU.

[0105] III. Preparation of Microneedle Transdermal Drug Delivery Patches Follow these steps: 1. Add the rapid release layer solution to the PDMS mold, centrifuge at 3000 rpm for 5 min to fill the needle tip area, and pre-dry at 25°C for 1 hour.

[0106] 2. Add the medium-speed release layer solution and centrifuge at 2000 rpm for 3 min to fill the middle section of the microneedles.

[0107] 3. Add PLGA microspheres / sodium alginate sustained-release system to form needle root and base structure.

[0108] 4. Dry at 4℃ for 12 h, then demold to obtain a three-layer microneedle array.

[0109] 5. Adhere the microneedle array to the medical PU flexible substrate to form a complete transdermal drug delivery patch.

[0110] Comparative Example 1 The difference from Example 1 is that there are only two microneedle structures (the needle body layer is removed); the specific structure is as follows: needle tip layer: HA + Insulin Lispro; needle root layer: PLGA microspheres + Insulin Glargine; the rest is the same as in Example 1.

[0111] Comparative Example 2 The difference from Example 1 is that there are only two microneedle structures (removing the needle tip layer). The specific structure is as follows: needle body layer: Gelatin + Regular insulin; needle root layer: PLGA microspheres + Insulin Glargine; the rest is the same as in Example 1.

[0112] Tests and Results: To verify the technical efficacy of the three-layer microneedle transdermal drug delivery patch of the present invention and the drug delivery patches of Comparative Examples 1 and 2 for diabetes, the following comparative experiments were designed.

[0113] The experimental animals were all STZ-induced diabetic mice with fasting blood glucose ≥16.7 mmol / L.

[0114] Each group has n = 10.

[0115] The dosage is standardized: 12 IU / kg insulin equivalent.

[0116] Blood glucose testing times: 0 h, 0.5 h, 1 h, 3 h, 6 h, 12 h, 24 h Grouping: 1. Experimental group (three-layer structure microneedles of this invention) structure: Needle tip layer: HA + Insulin Lispro (rapid release); Needle body layer: Gelatin + Regular insulin (medium-rate release); Needle root layer: PLGA microspheres + Insulin Glargine (sustained release); Functions: Rapidly lowers blood sugar + continuously controls blood sugar + maintains long-term effects; 2. Comparative Experiment 1 (two-layer microneedle structure, needle body layer removed) structure: Needle tip layer: HA + Insulin Lispro; Needle root layer: PLGA microspheres + Insulin Glargine; Missing: Medium-rate release layer; Characteristics: Rapid blood sugar reduction in the early stage, but weak blood sugar control in the middle stage; 3. Comparative Experiment 2 (two-layer microneedle structure, needle tip layer removed) structure: Needle body layer: Gelatin + Regular insulin; Needle root layer: PLGA microspheres + Insulin Glargine; Missing: Fast Release layer; Characteristics: Slow onset of action, poor blood sugar control in the early stages; The experimental results are as follows: I. Results of mouse experiments The average blood glucose levels (mmol / L) for each group are shown in the table below: Experimental Results Analysis 1. Onset speed 0.5-hour blood glucose: Experimental group: 12.4 mmol / L; Comparative Experiment 1: 13.0 mmol / L Comparative Experiment 2: 17.2 mmol / L This demonstrates that the lack of a needle tip layer significantly reduces the onset of action.

[0117] 2. Mid-term blood glucose control 6-hour blood glucose: Experimental group: 7.5 mmol / L Comparative Experiment 1: 11.8 mmol / L Comparative Experiment 2: 9.6 mmol / L This demonstrates that the lack of a needle layer leads to a significant decrease in mid-term blood sugar control.

[0118] 3. Long-term maintenance capability 24-hour blood glucose: Experimental group: 8.1 mmol / L Comparative Experiment 1: 17.1 mmol / L Comparative Experiment 2: 14.2 mmol / L This demonstrates that the three-layer structure can maintain a stable blood sugar-lowering effect.

[0119] II. Blood glucose fluctuation range 24-hour blood glucose fluctuation range for each group: This demonstrates the clear three-layer structure, resulting in more stable blood sugar levels.

[0120] In summary, compared with Comparative Example 1 and Comparative Example 2, it can be seen that the microneedle transdermal drug delivery patch in Example 1, due to its fast-release layer, medium-release layer and long-acting sustained-release layer, can achieve multi-stage programmed drug delivery under a single microneedle patch application, thereby reducing the number of drug administrations and improving the stability of blood glucose control.

[0121] Example 2 The programmed step-release microneedle transdermal drug delivery patch prepared in Example 1 was used for the treatment of type 2 diabetes, and the application method is as follows: Application Background: In the treatment of type 2 diabetes, patients typically need to meet two insulin dosing requirements simultaneously: rapid pre-meal insulin administration to suppress rapid postprandial blood glucose spikes; and basal insulin maintenance to maintain stable blood glucose levels throughout the day. Current clinical treatment usually involves multiple subcutaneous insulin injections, which has the following problems: high injection frequency, poor patient compliance, and large fluctuations in blood glucose levels. Therefore, developing a delivery system that can simultaneously achieve rapid blood glucose reduction, sustained control, and basal maintenance in a single dose is of great significance.

[0122] Specific drug administration process: In this embodiment, the programmed step-release microneedle transdermal drug delivery patch comprises a three-layer structure: a needle tip layer, a needle body layer, and a needle root layer. The drug release time of each layer is designed according to the insulin delivery requirements, and the release process is as follows.

[0123] Before meals, patients apply the microneedle transdermal drug delivery patch to the surface of their abdominal skin and apply gentle pressure to allow the microneedle array to penetrate beneath the stratum corneum. Once the microneedles penetrate the skin, the materials in each layer dissolve or degrade sequentially within the interdermal fluid environment, thus creating a phased drug release process.

[0124] Phase 1: Rapid Release Phase (0–10 minutes) The hyaluronic acid (HA) rapid dissolution layer in the microneedle tip area dissolves rapidly in the interstitial fluid of the skin, releasing the fast-acting insulin Insulin Lispro loaded within it.

[0125] Function: Rapidly lowers postprandial blood glucose levels and controls postprandial blood glucose peaks. This process mimics the first phase of insulin secretion by pancreatic β cells.

[0126] Phase Two: Medium-Range Continuous Release Phase (30 minutes – 6 hours) The gelatin gel layer in the microneedle body gradually degrades in the body fluid environment, thereby continuously releasing the short-acting insulin (regular insulin) loaded therein.

[0127] Function: It continuously provides insulin during the postprandial blood glucose rise phase, maintains stable blood glucose levels, and prevents blood glucose from rising again. This phase is equivalent to the second phase of insulin secretion in the human body.

[0128] Phase 3: Long-lasting sustained-release phase (6 hours – 48 hours) The microneedle root region contains a PLGA microsphere sustained-release system that gradually degrades in the body and continuously releases long-acting insulin, insulin galgine.

[0129] Function: Provides a continuous basal insulin level, prevents blood glucose spikes at night or on an empty stomach, maintains a stable basal blood glucose concentration, and thus forms a stable basal insulin supply system.

[0130] In summary, the microneedle structure of this invention, by setting different release layers in space, enables drug release to form a stepwise change in the time dimension, thereby achieving the following effects in sequence: (1) rapid hypoglycemic phase: rapidly controlling postprandial blood glucose elevation; (2) continuous hypoglycemic phase: maintaining stable postprandial blood glucose; (3) basal maintenance phase: providing long-acting basal insulin levels. Therefore, by constructing a programmed stepwise release microneedle transdermal drug delivery patch, this invention achieves multi-stage insulin release under single-application conditions, thereby simulating the kinetic characteristics of human insulin secretion, reducing the number of drug administrations and improving the stability of blood glucose control.

[0131] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A programmed step-release microneedle transdermal drug delivery patch, characterized in that, The microneedle transdermal drug delivery patch includes: Flexible substrate (1); A plurality of microneedles (2) are disposed on the flexible substrate (1). The microneedles (2) have cavities inside that can accommodate drugs. The cavities include a first drug loading area (21), a second drug loading area (22) and a third drug loading area (23) arranged sequentially from the tip to the root of the microneedle (2). The first drug loading area (21) contains a first drug, the second drug loading area (22) contains a second drug, and the third drug loading area (23) contains a third drug. The release rates of the first drug, the second drug and the third drug decrease sequentially.

2. The microneedle transdermal drug delivery patch according to claim 1, characterized in that, The degradation time of the first drug in the body fluid environment is 0.01 min to 10 min, the degradation time of the second drug in the body fluid environment is 0.5 h to 12 h, and the degradation time of the third drug in the body fluid environment is 6 h to 7 d.

3. The microneedle transdermal drug delivery patch according to claim 1, characterized in that, The height of the microneedle (2) is 400 μm-900 μm, the height of the first drug-loading area (21) is 100 μm-150 μm, the height of the second drug-loading area (22) is 100 μm-300 μm, the height of the third drug-loading area (23) is 200 μm-400 μm, and the thickness of the flexible substrate (1) is 20 μm-100 μm.

4. The microneedle transdermal drug delivery patch according to claim 1, characterized in that, The first drug contains a first therapeutic drug, a first carrier, and a solvent; the second drug contains a second therapeutic drug, a second carrier, and a solvent; and the third drug contains a third therapeutic drug, a third carrier, and a solvent. The degradation rates of the first carrier, the second carrier, and the third carrier decrease sequentially; the first carrier comprises a hydrogel material with high hydrophilicity and / or low intermolecular crosslinking density; the second carrier comprises a material that has been modified to form a controllable degradation structure after temperature / acid sensitivity modification; and the third carrier comprises a composite material formed after physical / chemical crosslinking treatment. The onset time of the first therapeutic drug is shorter than that of the second and third therapeutic drugs, respectively.

5. The microneedle transdermal drug delivery patch according to claim 4, characterized in that, The first carrier includes at least one of hyaluronic acid and polyvinylpyrrolidone; the second carrier includes at least one of gelatin and chitosan; the third carrier includes at least one of PLGA microsphere-polyvinyl alcohol-sodium alginate composite material and sodium carboxymethyl cellulose-calcium chloride composite material. The first drug further contains glycerol and / or sorbitol, the second drug further contains glutaraldehyde, a natural cross-linking agent, a pH adjuster, and / or sodium glycerophosphate, and the third drug further contains nanocellulose and / or nanoclay.

6. The method for preparing the microneedle transdermal drug delivery patch according to claim 1, characterized in that, Includes the following steps: S1. Dissolve the first carrier and the first therapeutic drug in a solvent to obtain a first solution; The second carrier and the second therapeutic drug are dissolved in a solvent to obtain a second solution; The raw materials for preparing the third carrier and the third therapeutic drug are dissolved in a solvent and cross-linked to obtain the third solution; S2. The first solution is dropped into the microneedle array mold, and the first solution is centrifuged to enter the microneedle tip region, and pre-dried to form the first drug. The second solution is continued to be added dropwise into the microneedle array mold, and the second solution is used to fill the central region of the microneedles to form the second drug by a second centrifugation. The third solution is continued to be added dropwise into the microneedle array mold, and then vacuum-treated, dried at low temperature or with gradient temperature increase, so that the third solution is distributed in the microneedle root region and the basal layer to form the third drug. S3. Demold the microneedle array mold to obtain a microneedle array, and fix the microneedle array on a flexible substrate to form a microneedle transdermal drug delivery patch.

7. The preparation method according to claim 6, characterized in that, In S1, The preparation method of the first solution includes: dissolving hyaluronic acid with a molecular weight of 10kDa-500kDa in phosphate buffer, adding a first therapeutic drug, and stirring at room temperature to form a homogeneous and transparent first solution; or, dissolving polyvinylpyrrolidone and the therapeutic drug in deionized water to form a transparent first solution; wherein the added mass of hyaluronic acid is 5% of the volume of phosphate buffer, the added mass of polyvinylpyrrolidone is 10% of the volume of deionized water, and the concentration of the therapeutic drug in the first solution is 1mg / mL-2mg / mL; The preparation method of the second solution includes: dissolving gelatin in warm water, adding the second therapeutic drug, stirring thoroughly to form a homogeneous solution, and maintaining the temperature at 37℃-40℃ before use to prevent premature gelation, thereby obtaining the second solution; or, dissolving chitosan in a 0.5%-1.5% volume fraction acetic acid solution, adding the second therapeutic drug, thereby obtaining the second solution; wherein the mass of gelatin added is 10% of the volume of warm water, the mass of chitosan added is 2% of the volume of acetic acid solution, and the concentration of the therapeutic drug in the second solution is 0.5mg / mL-1mg / mL.

8. The preparation method according to claim 6, characterized in that, In S1, the method for preparing the third solution includes: PLGA was dissolved in dichloromethane, and a third therapeutic drug was added to form an organic phase. The organic phase was slowly added dropwise to an aqueous phase containing 1%–2% polyvinyl alcohol by mass, and emulsified at 8000 rpm–12000 rpm for 1 min–3 min to form an O / W emulsion. The mixture was magnetically stirred at room temperature for 2 h–4 h to evaporate the organic solvent and allow the PLGA to solidify into drug-loaded microspheres. After centrifugation, washing, and freeze-drying, drug-loaded PLGA microspheres with a particle size of 0.5 μm–5 μm were obtained. The drug-loaded PLGA microspheres were dispersed at a concentration of 5–20 mg / mL in a sodium alginate solution with a mass-volume concentration of 1.5–2.5% to form a third solution. Alternatively, sodium carboxymethyl cellulose is added to deionized water and magnetically stirred at room temperature until completely dissolved to obtain a CMC-Na solution with a mass-volume concentration of 3%; a third therapeutic drug is added to the CMC-Na solution to obtain a drug-loaded polymer solution; a calcium chloride solution with a mass-volume concentration of 0.1%-0.5% is slowly added dropwise to the drug-loaded polymer solution to crosslink and form a third solution.

9. The preparation method according to claim 6, characterized in that, In S2, The first centrifugation speed is 3000rpm-4000rpm, and the first centrifugation time is 5-10 minutes; The pre-drying temperature is 22℃-28℃, the pre-drying time is 1-2 hours, and the moisture content of the first drug after pre-drying is 20%-40%. The second centrifugation speed is 2000-3000 rpm, and the centrifugation time is 3-5 minutes; The pressure of the vacuum treatment is controlled below -0.08 MPa; The low-temperature drying temperature is 4℃-10℃, and the low-temperature drying time is 12h-24h.

10. The use of the microneedle transdermal drug delivery patch of claim 1 in the preparation of a drug for treating diabetes and / or cardiovascular disease and / or chronic pain.

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