Search

CN-122006097-A - Micro-needle transdermal drug delivery patch with programmed step release and preparation method and application thereof

CN122006097ACN 122006097 ACN122006097 ACN 122006097ACN-122006097-A

Abstract

The invention discloses a micro-needle transdermal drug delivery patch with programmed step release and a preparation method and application thereof, and relates to the technical field of medicines. The micro-needle transdermal drug delivery patch comprises a flexible substrate and a plurality of micro-needles arranged on the flexible substrate, wherein a first drug carrying area, a second drug carrying area and a third drug carrying area are sequentially arranged in the micro-needles along the direction from the needle tip to the needle root of the micro-needles, and the release speed of drugs in the first drug carrying area, drugs in the second drug carrying area and drugs in the third drug carrying area are sequentially reduced. The invention provides a microneedle transdermal drug delivery patch with multilayer material construction, space partition drug loading, programmed step release and single-application multi-stage drug delivery, and a preparation method and application thereof, by constructing a multilayer drug loading structure with different dissolution rates and degradation characteristics, and a medicine carrying reservoir with definite spatial distribution is formed inside the micro needle, so that the medicine carrying release sequence corresponds to the micro needle structure position, and the programmed step release of medicine carrying in the time dimension is realized.

Inventors

  • DAI JIYANG
  • YANG BIN

Assignees

  • 深圳市古方中药饮片有限公司

Dates

Publication Date
20260512
Application Date
20260324

Claims (10)

  1. 1. A micro-needle transdermal drug delivery patch with programmed step release, the microneedle transdermal drug delivery patch is characterized by comprising: a flexible substrate (1); The micro-needle (2) on the flexible substrate (1) is arranged in a plurality, a cavity capable of containing medicines is formed in the micro-needle (2), the cavity comprises a first medicine carrying area (21), a second medicine carrying area (22) and a third medicine carrying area (23) which are sequentially arranged along the direction from the needle tip of the micro-needle (2) to the needle root, the first medicine carrying area (21) contains first medicines, the second medicine carrying area (22) contains second medicines, the third medicine carrying area (23) contains third medicines, and the release speeds of the first medicines, the second medicines and the third medicines are sequentially reduced.
  2. 2. The transdermal microneedle patch of claim 1, wherein the first drug has a degradation time of 0.01min to 10min in a body fluid environment, the second drug has a degradation time of 0.5h to 12h in a body fluid environment, and the third drug has a degradation time of 6h to 7d in a body fluid environment.
  3. 3. The transdermal microneedle delivery patch according to claim 1, wherein the height of the microneedle (2) is 400-900 μm, the height of the first drug-carrying region (21) is 100-150 μm, the height of the second drug-carrying region (22) is 100-300 μm, the height of the third drug-carrying region (23) is 200-400 μm, and the thickness of the flexible substrate (1) is 20-100 μm.
  4. 4. A transdermal microneedle patch according to claim 1, wherein, The first medicament comprises a first therapeutic medicament, a first carrier and a solvent, the second medicament comprises a second therapeutic medicament, a second carrier and a solvent, and the third medicament comprises a third therapeutic medicament, a third carrier and a solvent; The degradation rates of the first carrier, the second carrier and the third carrier are sequentially reduced, the first carrier comprises hydrogel materials with high hydrophilicity and/or low intermolecular crosslinking density, the second carrier comprises materials with temperature-sensitive/acid-sensitive modified controllable degradation structures, and the third carrier comprises composite materials formed after physical/chemical crosslinking treatment; the first therapeutic agent has a shorter onset time than the second therapeutic agent and the third therapeutic agent in sequence.
  5. 5. The transdermal microneedle patch of claim 4, wherein, The first carrier comprises at least one of hyaluronic acid and polyvinylpyrrolidone, the second carrier comprises at least one of gelatin and chitosan, and the third carrier comprises at least one of PLGA microsphere-polyvinyl alcohol-sodium alginate composite material and carboxymethylcellulose sodium-calcium chloride composite material; The first medicament also contains glycerol and/or sorbitol, the second medicament also contains glutaraldehyde, a natural cross-linking agent, a pH regulator and/or sodium glycerophosphate, and the third medicament also contains nanocellulose and/or nanoclay.
  6. 6. A method of preparing a transdermal microneedle patch according to claim 1, comprising the steps of: S1, dissolving a first carrier and a first therapeutic drug in a solvent to obtain a first solution; dissolving a second carrier and a second therapeutic drug in a solvent to obtain a second solution; dissolving the raw materials for preparing the third carrier and the third therapeutic drug in a solvent, and obtaining a third solution through crosslinking; S2, the first solution is dripped into a microneedle array die, and enters a microneedle tip area through first centrifugation, and is pre-dried to form a first medicament; Continuously dripping the second solution into the microneedle array die, and filling the middle area of the microneedles with the second solution through second centrifugation to form a second medicament; Continuously dripping the third solution into the microneedle array die, performing vacuum treatment, and performing low-temperature drying or gradient heating drying to ensure that the third solution is distributed in the microneedle root area and the basal layer to form a third medicament; and S3, demolding the microneedle array mold to obtain a microneedle array, and fixing the microneedle array on a flexible substrate to form the microneedle transdermal drug delivery patch.
  7. 7. The process according to claim 6, wherein in S1, The preparation method of the first solution comprises the steps of dissolving hyaluronic acid with the molecular weight of 10kDa-500kDa in phosphate buffer solution, adding a first therapeutic drug, stirring at room temperature to form a uniform 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 the hyaluronic acid is 5% of the volume of the phosphate buffer solution, the added mass of the polyvinylpyrrolidone is 10% of the volume of the 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 comprises the steps of dissolving gelatin in warm water, adding a second therapeutic drug, fully stirring to form a uniform solution, and keeping the temperature at 37-40 ℃ to prevent gelation in advance before use to obtain the second solution, or dissolving chitosan in acetic acid solution with the volume fraction of 0.5-1.5% to obtain the second solution, and adding the second therapeutic drug, wherein the adding mass of gelatin is 10% of the volume of the warm water, the adding mass of chitosan is 2% of the volume of the acetic acid solution, and the concentration of the therapeutic drug in the second solution is 0.5-1 mg/mL.
  8. 8. The method according to claim 6, wherein in S1, the method for preparing the third solution comprises: Dissolving PLGA in methylene dichloride, adding a third therapeutic drug to form an organic phase, slowly dripping the organic phase into a water phase containing 1-2% of polyvinyl alcohol by mass fraction, emulsifying for 1min-3 min under the condition of 8000rpm-12000 rpm to form O/W emulsion, magnetically stirring for 2 h-4 h at room temperature to volatilize an organic solvent, solidifying the PLGA to form drug-loaded microspheres, centrifuging, washing and freeze-drying to obtain the drug-loaded PLGA microspheres with the particle size of 0.5-5 mu m, dispersing the drug-loaded PLGA microspheres in a sodium alginate solution with the mass volume concentration of 1.5-2.5% by mass concentration of 5-20 mg/mL to form a third solution; Or adding sodium carboxymethylcellulose into deionized water, magnetically stirring at room temperature until the sodium carboxymethylcellulose is completely dissolved to obtain CMC-Na solution with the mass and volume concentration of 3%, adding a third therapeutic drug into the CMC-Na solution to obtain drug-loaded polymer solution, slowly dropwise adding calcium chloride solution with the mass and volume concentration of 0.1% -0.5% into the drug-loaded polymer solution, and crosslinking to form a third solution.
  9. 9. The process according to claim 6, wherein in S2, The speed of the first centrifugation is 3000rpm-4000 rpm, and the centrifugation time of the first centrifugation is 5-10 minutes; the temperature of the pre-drying is 22-28 ℃, the time of the pre-drying is 1-2 hours, and the water content of the first medicine after the pre-drying is 20-40%; The speed of the second centrifugation 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 12-24 hours.
  10. 10. Use of the transdermal microneedle patch of claim 1 for the preparation of a medicament for the treatment of diabetes and/or cardiovascular diseases and/or chronic pain.

Description

Micro-needle transdermal drug delivery patch with programmed step release and preparation method and application thereof Technical Field The invention relates to the technical field of medicines, in particular to a micro-needle transdermal drug delivery patch with programmed step release and a preparation method and application thereof. Background The micro-needle transdermal drug delivery technology has the advantages of being minimally invasive, painless, self-drug delivery, gastrointestinal degradation avoidance and the like, and has recently received wide attention in the fields of vaccine delivery, chronic disease treatment, biological drug delivery and the like. By loading the drug carrier into the microneedle structure and penetrating below the stratum corneum, it is possible to achieve direct drug carrier entry into the skin microcirculation system, thereby improving drug carrier bioavailability and reducing systemic side effects. However, in existing microneedle drug delivery technologies, most microneedle structures are typically composed of a single material, drug delivery is primarily dependent on the dissolution or degradation process of the material, and its release kinetics typically exhibit a single pattern, e.g., fast dissolution microneedles primarily achieve rapid release over a short period of time, while slow release microneedles focus on sustained release over a long period of time. For many disease treatment scenarios, relying on a single release pattern alone tends to be difficult to meet the synergistic demands of both rapid onset and long-term maintenance of therapeutic concentrations. For example, in the treatment of diabetes, cardiovascular disease, and chronic pain management, drug delivery is often required to have the dual feature of both rapid onset of action to alleviate acute symptoms and long-term sustained release to maintain a stable therapeutic concentration. Traditional modes of administration typically require multiple injections or multiple dosage form combinations to achieve different release phases, which not only increases patient medication complexity, but also reduces treatment compliance. On the other hand, even in some existing compound microneedle technologies, although various materials or various drug carriers are introduced, the internal structural design is generally simpler, and release of drug carriers is mostly realized only by mixed loading or a simple layered structure, so that it is difficult to accurately control the release sequence and release rate of different drug carriers in the time dimension. In addition, in the microneedle preparation process, the insufficient control of the dissolution rate, the crosslinking density and the spatial distribution of the materials can easily cause the unclear limit between different release stages, thereby influencing the overall drug delivery effect. Therefore, a method for constructing a multi-stage release structure in a single microneedle transdermal drug delivery patch is needed, and a preset and controllable programmed release process is formed in the time dimension by reasonably designing the material degradation rate and the spatial structure distribution, so that the rapid onset and long-acting slow release treatment effect can be realized in one application process. Disclosure of Invention The invention aims to at least solve one of the technical problems in the prior art and provides a micro-needle transdermal drug delivery patch with programmed step release, and a preparation method and application thereof. Aiming at the problems that the existing microneedle system adopts single material or single release mechanism to lead to fixed drug-carrying release mode and difficult realization of quick acting and long-acting slow release simultaneously, the invention realizes programmed step release of drug-carrying in time dimension by constructing a multi-layer structure and multi-material combination. (2) Aiming at the problem that the release sequence and release rate of different drug carriers in the existing composite microneedle structure are difficult to accurately control, the invention builds a multi-layer drug carrier structure with different degradation rates and dissolution characteristics in the microneedle, so that the drug carrier release process occurs step by step according to the preset sequence. (3) Aiming at the problems of unstable layering, insufficient structural bonding strength or uneven drug carrying distribution in the preparation process of the multilayer microneedle, the invention improves the stability and the preparation consistency of the multilayer structure by adopting a layer-by-layer filling, gradient centrifugation and interface bonding regulation method. (4) Aiming at the problem that the existing complex dosing scheme usually needs multiple dosing or multiple preparations to be used jointly, the invention realizes multi-stage dosing by programming a step release micr