Controlled-release drug-release microneedle with good biocompatibility and preparation method of controlled-release drug-release microneedle

Abstract

The invention discloses a controlled-release drug-release microneedle with good biocompatibility and a preparation method thereof, and the preparation method comprises the following steps: S1, dissolving a sustained-release drug in a molding material solution to obtain a sustained-release needle body solution; dissolving an instantaneous drug in the forming material solution to obtain an instantaneous drug layer solution; the forming material solution comprises 16wt%-19wt% of a polyvinyl alcohol solution; s2, providing a microneedle mold, wherein the microneedle mold comprises needle body cavities distributed in an array and a backing cavity communicated with the open ends of the needle body cavities; adding a sustained-release needle body solution into the needle body cavity to fill the needle body cavity with the sustained-release needle body solution, and then adding a backing layer solution into the backing cavity to obtain a drug-release microneedle precursor; the backing layer solution is prepared from 20wt%-22wt% of a polyvinyl alcohol solution; s3, repeatedly freezing and thawing the drug release microneedle precursor for m times, wherein m is greater than 1; and removing the microneedle mold, applying an instantaneous drug layer solution on the surface of the sustained-release needle body, and freezing and crosslinking to obtain the controlled-release drug-release microneedle with good biocompatibility. The controlled-release drug-release microneedle with good biocompatibility provided by the invention can flexibly load different drugs according to clinical flexible drug use requirements, enables the drugs to be released in different sequences and rates, and solves the technical problem of single drug administration mode of the existing microneedle.

Description

Technical Field

[0001] The present invention relates to the technical field of medical drug delivery, and in particular to a controlled-release drug-releasing microneedle with good biocompatibility and a preparation method thereof. Background Art

[0002] The concept of microneedle was first proposed by Martin S. in 1976. It consists of a needle body with a certain strength and a supporting backing. As a minimally invasive method, microneedle has been widely used in tumor drug delivery and has significant advantages over traditional injection drug delivery:

[0003] The traditional method of administering cancer drugs by injection has relatively serious systemic toxicity. While being toxic to tumor tissue, cancer drugs are also toxic to other organs in the body. This defect is relatively fatal. Patients will experience serious toxic side effects after taking cancer drugs for a long time, and in severe cases, the patient may fall into a coma.

[0004] The height and diameter of the microneedles are both in the micron range, so they can be targeted to penetrate the local tumor site for targeted drug delivery, significantly reducing the toxic side effects of tumor drugs on other organs in the body, and having less systemic toxicity. In addition, since the microneedles are targeted to the tumor site, a small dose of drug loaded on the microneedles can produce a higher drug concentration at the tumor site, and its drug utilization rate is significantly higher than that of traditional injection drug delivery.

[0005] However, as clinical tumor drug administration schemes become more flexible, different drugs often need to be administered to patients in different orders and frequencies. However, the existing microneedle drug administration method is relatively single and can no longer meet this demand. Summary of the invention

[0006] The purpose of the present invention is to solve the technical problem that the existing microneedles cannot apply drugs to patients in different orders and at different frequencies.

[0007] In order to achieve the above object, the present invention provides a method for preparing a controlled-release drug-releasing microneedle with good biocompatibility, comprising the following steps:

[0008] Step S1, preparing the solution:

[0009] The sustained-release drug is dissolved in the molding material solution to obtain a sustained-release needle solution; the instantaneous drug is dissolved in the molding material solution to obtain an instantaneous drug layer solution; the molding material solution comprises: 16wt%-19wt% polyvinyl alcohol solution.

[0010] Step S2, preparing drug-releasing microneedle precursors:

[0011] A microneedle mold is provided, wherein the microneedle mold comprises a needle body cavity distributed in an array, and a backing cavity connected to the open end of the needle body cavity; the sustained-release needle body solution is added into the needle body cavity so that the sustained-release needle body solution fills the needle body cavity, and next, a backing layer solution is added into the backing cavity to obtain a drug-releasing microneedle precursor; the backing layer solution comprises: 20wt%-22wt% polyvinyl alcohol solution.

[0012] Step S3, preparing controlled-release drug-releasing microneedles with good biocompatibility:

[0013] The drug-releasing microneedle precursor is repeatedly frozen and thawed m times, m>1, so that the sustained-release needle body solution forms a sustained-release needle body, the backing layer solution forms a backing layer, and the sustained-release needle body and the backing layer are cross-linked and bonded; the microneedle mold is removed, and the transient drug layer solution is applied to the surface of the sustained-release needle body, and the controlled-release drug-releasing microneedle with good biocompatibility is obtained by freeze-crosslinking.

[0014] Optionally, the sustained-release drug includes at least one of sorafenib, PD-1 antibody drug, PD-L1 antibody drug, albumin paclitaxel, and gemcitabine; the transient drug includes at least one of 5-fluorouracil, oxaliplatin, folinic acid, and irinotecan.

[0015] Optionally, in step S3, repeatedly freezing and thawing the drug-releasing microneedle precursor m times means: freezing and cross-linking the drug-releasing microneedle precursor for 6 to 8 hours, then thawing for 1 to 4 hours, repeating m times, where m is 2 or 3.

[0016] Optionally, during the repeated freezing and thawing process of the drug-releasing microneedle precursor, the temperature for freezing and cross-linking is -20°C to -80°C, and the temperature for thawing is -2°C to -6°C.

[0017] Optionally, the backing layer solution further comprises: 14 wt % to 16 wt % of polyvinyl pyrrolidone.

[0018] The present invention also provides a controlled-release drug-releasing microneedle with good biocompatibility prepared according to the above-mentioned preparation method, and the controlled-release drug-releasing microneedle comprises: a backing layer and a plurality of sustained-release needle bodies distributed in an array; the sustained-release needle bodies are fixed to one side of the backing layer, the interior of the sustained-release needle bodies is loaded with sustained-release drugs, and the exterior of the sustained-release needle bodies is coated with a transient drug layer; the interior of the transient drug layer is loaded with transient drugs; the release rate of the transient drugs is greater than the release rate of the sustained-release drugs.

[0019] Optionally, the porosity of the sustained-release needle body is smaller than the porosity of the transient drug layer.

[0020] Optionally, the sustained-release needle body is a cone, the length of the sustained-release needle body is 600 μm to 800 μm, and the diameter of the end surface of the sustained-release needle body is 200 μm to 400 μm.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] (1) The drug-releasing microneedles provided by the present invention can control the order of administration of different drugs:

[0023] The present invention prepares a sustained-release needle body (loaded with sustained-release drugs) first, and then prepares a transient drug layer (loaded with transient drugs) on the outside of the sustained-release needle body, so that the transient drug layer is coated on the outside of the sustained-release needle body. With this arrangement, after the microneedle pierces the body, the drugs in the external transient drug layer will be released first, and after the drugs in the transient drug layer are partially released, the drugs in the sustained-release needle body begin to be released. Therefore, for drugs that need to be administered first, they can be loaded in the transient drug layer; for drugs that need to be administered later, they can be loaded in the sustained-release needle body, thereby controlling the administration order of different drugs.

[0024] (2) The drug-releasing microneedles provided by the present invention can control the administration rate of different drugs:

[0025] The present invention makes the porosity of the sustained-release needle body smaller than that of the instantaneous drug layer by making the freeze-thaw times of the polyvinyl alcohol solution in the sustained-release needle body greater than that of the polyvinyl alcohol solution in the instantaneous drug layer during the preparation process, thereby making the drug release rate of the sustained-release needle body smaller than that of the instantaneous drug layer:

[0026] Polyvinyl alcohol solution will form multiple microcrystalline areas in the frozen state. These microcrystalline areas will serve as physical cross-linking points when thawed to form a three-dimensional network structure. As the number of freeze-thaw cycles increases during the preparation of the sustained-release needle, the number of microcrystalline areas formed in the sustained-release needle will gradually increase, making the three-dimensional network structure formed in the sustained-release needle more compact, and the porosity of the sustained-release needle decreases, thereby slowing down the release rate of the sustained-release drug loaded in the sustained-release needle.

[0027] Thus, for instantaneous drugs that need instantaneous administration (usually drugs with long efficacy, the efficacy of a single dose can last for a long time), they can be loaded in the instantaneous drug layer, and after the microneedle penetrates the body, the instantaneous drugs in the instantaneous drug layer are released instantly; for sustained-release drugs that need continuous administration (usually drugs with short efficacy, which require multiple continuous administrations), they can be loaded in the sustained-release drug layer so that the sustained-release drugs are continuously and slowly released.

[0028] (3) The drug-releasing microneedles provided by the present invention have excellent biosafety and biocompatibility:

[0029] Existing sustained-release microneedles are usually prepared from materials such as methacrylated gelatin (GelMA), which require the addition of photoinitiators such as 2-hydroxy-2-methyl-1-phenyl-1-propanone (HMP) during the preparation process to achieve crosslinking and curing. However, this photoinitiator is not biosafe, and the drug-releasing microneedles prepared from it have poor biosafety and are not suitable for use in vivo.

[0030] The present invention prepares the controlled-release drug-releasing microneedles of the present invention only by using polyvinyl alcohol. Polyvinyl alcohol has excellent biosafety and biocompatibility, and will cross-link with each other during the freeze-thaw process. The present invention adds polyvinyl alcohol to both the backing layer and the sustained-release needle body, so that the polyvinyl alcohol at the contact surface of the backing layer and the sustained-release needle body can cross-link with each other during the freeze-thaw process of preparing the microneedles, thereby cross-linking the backing layer and the sustained-release needle body, so that there is no need to add additional photoinitiators to cross-link and solidify the microneedles, or to add additional adhesive materials to bond the backing layer and the sustained-release needle body, and the biosafety and biocompatibility are relatively high.

[0031] The controlled-release drug-releasing microneedles with good biocompatibility provided by the present invention carry different drugs and can be applied to different diseases, including pancreatic tumors, skin tumors, intestinal tumors, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The figure is a flow chart of the preparation of the drug-releasing microneedles of the present invention.

[0033] Figure 2 This is a schematic structural diagram of the polytetrafluoroethylene microneedle mold used in the present invention.

[0034] Figure 3 Figure 2 is a graph showing changes in tumor size in mice in each experimental group of the present invention.

[0035] Figure 4 This is a comparison chart of the tumor sizes of mice in each experimental group of the present invention. DETAILED DESCRIPTION

[0036] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and embodiments.

[0037] Based on the background technology, in order to solve the technical problem that the existing microneedle drug delivery method is single and cannot meet the needs of clinical flexible drug use, the present invention provides a controlled-release microneedle with good biocompatibility. The microneedle can flexibly load different drugs according to the needs of clinical flexible drug use, and release the drugs in different orders and rates, thereby solving the technical problem that the existing microneedle drug delivery method is single.

[0038] The following is a specific description with reference to embodiments.

[0039] Example 1 Preparation of drug-releasing microneedles for the treatment of pancreatic cancer

[0040] The reagents and materials used in this example are all commercially available, as follows.

[0041] Backing layer

[0042] Polyvinyl alcohol: alcoholysis degree 86.5-89%, item number: P139538, manufacturer: Aladdin.

[0043] Sustained release needle

[0044] ① Sustained-release drugs (usually drugs with a short duration of efficacy that require multiple continuous administrations): Sorafenib, purchased from MCE.

[0045] ②Molding materials

[0046] Polyvinyl alcohol: alcoholysis degree 98-98.8%, item number: 30153084, manufacturer: Sinopharm Chemical Reagent Co., Ltd.

[0047] Transient drug layer

[0048] ① Instant drugs (usually drugs with long duration of efficacy, the efficacy of which can last for a long time after a single dose): 5-fluorouracil, oxaliplatin, folinic acid, and irinotecan, all purchased from MCE.

[0049] ② Molding material: the same as the sustained-release needle body molding material.

[0050] The preparation method of the drug-releasing microneedle in this embodiment is as follows:

[0051] Step S1, preparing the solution:

[0052] ①Sustained-release needle solution:

[0053] A. Preparation of molding material solution:

[0054] In this embodiment, the molding material solution used for the sustained-release needle body is an 18wt% polyvinyl alcohol aqueous solution: weigh 9g of polyvinyl alcohol powder, add 41g of deionized water, heat and stir in a water bath to obtain a clear, transparent, uniform polyvinyl alcohol aqueous solution with a concentration of 18wt%, and place it in a 45°C oven for storage.

[0055] B. Preparation of sustained-release needle solution:

[0056] Take a sustained-release drug, in this embodiment, the sustained-release drug is surufatinib. Dissolve surufatinib in DMSO, then add it to the above-mentioned molding material solution, and mix well to obtain a sustained-release needle solution (surufatinib concentration 80 mg to 90 mg / g).

[0057] ②Instantaneous drug layer solution:

[0058] The transient drug layer solution of this embodiment is prepared by dissolving the transient drug in the molding material solution, wherein the transient drug is 5-fluorouracil, folinic acid, irinotecan and oxaliplatin preformulations, and the molding material solution is a 18 wt % polyvinyl alcohol solution.

[0059] During the preparation process, the oxaliplatin preformulation is first suspended in the molding material solution, and then folinic acid, irinotecan, and 5-fluorouracil are added and stirred evenly, and then a vacuum degassing mixer is used to stir evenly and degas to prepare a bubble-free, stratified, uniform and stable instantaneous drug layer solution (5-fluorouracil concentration 5.6 mg to 5.8 mg / g, oxaliplatin concentration 0.5 mg to 0.6 mg / g, irinotecan concentration 5.6 mg to 5.8 mg / g, folinic acid concentration 6.8 mg to 7 mg / g).

[0060] As can be seen from the above, oxaliplatin needs to be prepared into a preformulation during the preparation process. The reason is that many drugs are difficult to dissolve in water and need to be dissolved in DMSO, and oxaliplatin is easily inactivated in DMSO, so oxaliplatin needs to be protected and prepared into an oxaliplatin preformulation. The specific method is as follows.

[0061] Weigh 75KD dextran (DEX) to prepare a DEX 75KD solution with a concentration of 8%; then weigh polyethylene glycol (PEG 8000) to prepare a PEG 8000 solution with a concentration of 8%;

[0062] Take oxaliplatin and add it to 8% DEX 75KD solution and mix well; then add PEG 8000 solution with 5 times volume of DEX75KD solution and shake gently to mix well;

[0063] After the solution is mixed, it is immediately transferred to a -40°C refrigerator for freezing for more than 4 hours and placed in a freeze dryer for 24 hours; then the powder is collected, washed with dichloromethane and centrifuged to collect the particles.

[0064] ③Backing layer solution:

[0065] In this embodiment, the backing layer solution is a 20wt% polyvinyl alcohol aqueous solution: weigh 10g of polyvinyl alcohol powder, add 40g of deionized water, heat and stir in a water bath to obtain a clear, transparent, uniform polyvinyl alcohol aqueous solution with a concentration of 20wt%, and place it in a 50°C oven for later use.

[0066] It can be seen from the above preparation method that the sustained-release needle body and the backing layer of this embodiment both contain polyvinyl alcohol, and the concentration of polyvinyl alcohol in the backing layer is greater than that in the sustained-release needle body. The reason is:

[0067] First, polyvinyl alcohol has high biosafety and biocompatibility and is a good biomedical material. Polyvinyl alcohol will cross-link with each other during the freeze-thaw process. The present invention adds polyvinyl alcohol to both the backing layer and the sustained-release needle body, so that the polyvinyl alcohol at the contact surface of the backing layer and the sustained-release needle body can cross-link with each other during the freeze-thaw process of preparing the microneedle, thereby cross-linking the backing layer and the sustained-release needle body. Therefore, the present invention can cross-link the backing layer and the sustained-release needle body into a whole by simply adding polyvinyl alcohol to the backing layer and the sustained-release needle body, without adding additional viscous materials and initiator materials.

[0068] Second, when the microneedle penetrates the tumor tissue, force needs to be applied to the backing layer to push the needle body into the tissue. Therefore, between the backing layer and the sustained-release needle body, the backing layer needs to have the greatest hardness and the strongest mechanical strength to have a better force-bearing capacity. The higher the concentration of polyvinyl alcohol, the higher the hardness after freeze-drying. The present invention makes the concentration of polyvinyl alcohol in the backing layer greater than the concentration of polyvinyl alcohol in the sustained-release needle body, so that the backing layer in the microneedle has the greatest hardness and the strongest mechanical strength, which facilitates the smooth penetration of the microneedle into the tissue.

[0069] Step S2, preparing drug-releasing microneedle precursors:

[0070] Figure 1 FIG. 4 is a flow chart of the preparation of the drug-releasing microneedle of the present invention. Figure 1 As shown, an existing polytetrafluoroethylene microneedle mold (structure as shown in Figure 2 As shown in the figure, the microneedle mold includes a needle body cavity 11 distributed in an array and a backing cavity 12 connected to the open end of the needle body cavity 11. The needle body cavity 11 is a cone with a length of 600 μm to 800 μm, and the surface diameter of the open end of the needle body cavity 11 is 200 μm to 400 μm.

[0071] First, add the sustained-release needle solution prepared in step S1 to the microneedle mold, and evenly apply it with a scraper, then move the microneedle mold to the vacuum aspirator, turn on the vacuum pump, and suck the sustained-release needle solution into the needle cavity 11, and scrape off the excess sustained-release needle solution with a scraper. Then pour the backing layer solution into the backing cavity 12 to obtain a drug-releasing microneedle precursor.

[0072] Step S3, preparing drug-releasing microneedles:

[0073] The drug-releasing microneedle precursor was placed in a -80°C ultra-low temperature freezer for more than 6 hours, and then thawed at -4°C for 4 hours, and the freezing and thawing cycle was repeated three times, so that the sustained-release needle body solution formed a sustained-release needle body, and the backing layer solution formed a backing layer, and the end surface of the sustained-release needle body and the backing layer were cross-linked and bonded. Then demolding, and then pouring an instantaneous drug layer solution on the surface of the sustained-release needle body, and cross-linking at -18°C to -22°C to obtain the drug-releasing microneedle for pancreatic cancer treatment in this embodiment.

[0074] As can be seen from the above, the number of freeze-thaw cycles of the sustained-release needle body in this embodiment (3 freeze-thaw cycles in this embodiment) is greater than the number of freeze-thaw cycles of the instantaneous drug layer (1 freeze cycle in this embodiment). This arrangement makes the porosity of the sustained-release needle body (loaded with sustained-release drugs) lower than the porosity of the instantaneous drug layer (loaded with instantaneous drugs), so that the release rate of the sustained-release drugs is lower than the release rate of the instantaneous drugs. The specific principles are as follows:

[0075] During the freeze-thaw process, the polyvinyl alcohol solution will form multiple microcrystalline areas in the frozen state. These microcrystalline areas will serve as physical cross-linking points when thawed, and cross-link to form a three-dimensional network structure. As the number of freeze-thaw cycles increases, the number of microcrystalline areas formed in the sustained-release needle will gradually increase, making the three-dimensional network structure formed in the sustained-release needle more compact and the overall porosity of the sustained-release needle lower, making it difficult to release the sustained-release drug in the sustained-release needle, slowing down the release rate of the sustained-release drug.

[0076] Step S5, drying of microneedles: After the microneedles are frozen and thawed, they are transferred to a stainless steel fixture and placed in a vacuum desiccator filled with silica gel desiccant to dry and shrink for standby use.

[0077] Next, the anti-cancer effect of the microneedles used for pancreatic cancer treatment in this example was tested through experiments.

[0078] The experimental steps are as follows:

[0079] The mice were randomly divided into: saline group, blank microneedle group, conventional drug group, and microneedle drug group, with 6 mice in each group. The mice in each group were modeled to simulate pancreatic cancer in mice. The modeling method was: 5-week-old C57BL / 6J mice were anesthetized, and panc02 cell suspension in the logarithmic growth phase was added, about 1×10 7 All animal experiments were conducted in strict accordance with the animal protection procedures and methods approved by the Animal Management Committee of Shanghai First People's Hospital.

[0080] Microneedle administration group: The microneedles of Example 1 were administered to model mice.

[0081] Blank microneedle group: blank microneedles were administered to the modeled mice. The blank microneedles were substantially the same as the microneedles in Example 1, except that the blank microneedles did not contain drugs.

[0082] Conventional drug administration group: The modeled mice were intraperitoneally injected with a total dose of drugs that was twice that of the microneedle administration group. 5-fluorouracil, oxaliplatin, folinic acid, and irinotecan were injected on the first day of the experiment, and sorafenib was administered by oral gavage every day.

[0083] Normal saline group: Normal saline was injected intraperitoneally into the model mice from day 1 to day 7 of the experiment.

[0084] The changes in the tumor volume of the mice were recorded after 7 days of drug administration. On the 8th day, the mice in each group were killed and the tumors were removed and weighed to verify the killing effect of the microneedles of Example 1 on tumors in animals.

[0085] like Figure 3 and Figure 4 As shown, compared with the conventional administration group, the microneedle administration group with only 1 / 2 of the administration dose has a better tumor inhibition effect, indicating that the drug-releasing microneedles of this example have excellent anti-tumor ability.

[0086] In actual application, the microneedle of this embodiment can be inserted into the pancreatic tumor site through laparoscopy under the guidance of laparoscopic ultrasound minimally invasive technique.

[0087] Example 2 Preparation of drug-releasing microneedles for the treatment of pancreatic cancer

[0088] This embodiment provides another drug-releasing microneedle, which is different from the embodiment 1 in that the components of the drug-releasing microneedle in this embodiment are as follows:

[0089] Backing layer

[0090] Polyvinylpyrrolidone: molecular weight 360kDa, product number: PVP360, manufacturer: Sigma-Aldrich (Shanghai) Trading Co., Ltd.

[0091] Polyvinyl alcohol: alcoholysis degree 86.5-89%, item number: P139538, manufacturer: Aladdin.

[0092] Compared with Example 1, polyvinyl pyrrolidone is added as a component of the backing layer in this embodiment. The reason is that the function of the backing layer of the present invention is to improve the mechanical strength of the microneedle as a whole, so that the microneedle can easily penetrate the tumor tissue. After the microneedle penetrates the tumor tissue during surgery, the backing layer has completed its function and can be separated from the microneedle. The backing layer can be taken out during surgery, so that the backing layer does not need to be degraded in the body, reducing the metabolic burden of the patient. Polyvinyl pyrrolidone has high biocompatibility and high water solubility. Its water solubility is greater than that of polyvinyl alcohol. When it is used as a component of the backing layer, after the microneedle penetrates the tumor tissue, under the action of physiological saline or body fluid, the polyvinyl pyrrolidone in the contact part of the backing layer with the sustained-release needle body will be rapidly degraded, reducing the connection stability between the backing layer and the sustained-release needle body, making the backing layer easy to separate from the sustained-release needle body.

[0093] Sustained release needle

[0094] ①Sustained-release drugs:

[0095] PD-1 antibody drugs: at least one of nivolumab, pembrolizumab and tislelizumab.

[0096] PD-L1 antibody drugs: at least one of atezolizumab, durvalumab and avelumab.

[0097] ②Molding materials:

[0098] Polyvinyl alcohol: alcoholysis degree 98-98.8%, item number: 30153084, manufacturer: Sinopharm Chemical Reagent Co., Ltd.

[0099] ③ Polysaccharide: at least one of hyaluronic acid, carboxymethyl cellulose, dextran and chitosan.

[0100] The reason why polysaccharides are added to the components of the sustained-release needle body in this embodiment is that the sustained-release drugs PD-1 antibody drugs and PD-L1 antibody drugs used in this embodiment are macromolecular drugs, and the porosity of the sustained-release needle body after manufacture is low, which makes it difficult for the PD-1 antibody drugs and PD-L1 antibody drugs to be released through the pores inside the sustained-release needle body. In this embodiment, polysaccharides are added to the sustained-release needle body. Due to the good water solubility of polysaccharides, the polysaccharides are first dissolved and released after the sustained-release needle body meets water, forming holes at the position where they were originally loaded, increasing the pores inside the sustained-release needle body, so that the PD-1 antibody drugs and PD-L1 antibody drugs can be released through the pores inside the sustained-release needle body.

[0101] The method for preparing the solution of the drug-releasing microneedle in this embodiment is as follows:

[0102] ①Sustained-release needle solution:

[0103] A. Preparation of molding material solution: same as Example 1.

[0104] B. Preparation of sustained-release needle solution:

[0105] Take the sustained-release drug. In this embodiment, the sustained-release drug is a PD-1 antibody drug and a PD-L1 antibody drug. The PD-1 antibody drug and the PD-L1 antibody drug are dissolved with Invivo PD-1 Recombinant Mouse mAb (Article No.: S0B0594-50 mg, purchased from STARTER), and then added to the above-mentioned molding material solution, and then hyaluronic acid is added, and the sustained-release needle solution is obtained after mixing.

[0106] ② Preparation of instant drug layer solution: same as in Example 1.

[0107] ③ Preparation of backing layer solution:

[0108] In this embodiment, the backing layer solution is 15wt% polyvinyl pyrrolidone and 20wt% polyvinyl alcohol: weigh 10g polyvinyl pyrrolidone and 7.5g polyvinyl alcohol powder, add 32.5g deionized water, use a vacuum degassing mixer at 2000rmp speed for 5min, and set aside.

[0109] The above are the differences between the method for preparing drug-releasing microneedles of this embodiment and that of Example 1. The remaining steps of the method for preparing microneedles of this embodiment are the same as those of Example 1.

[0110] In summary, the present invention provides a controlled-release drug-releasing microneedle with good biocompatibility and a preparation method thereof. The controlled-release drug-releasing microneedle can flexibly load different drugs according to the clinical flexible medication needs, and release the drugs in different orders and rates, thereby solving the technical problem of the single drug delivery method of existing microneedles.

[0111] Although the content of the present invention has been described in detail through the above preferred embodiments, it should be appreciated that the above description should not be considered as a limitation of the present invention. After reading the above content, it will be apparent to those skilled in the art that various modifications and substitutions of the present invention will occur. Therefore, the protection scope of the present invention should be limited by the appended claims.

Claims

1. A method for preparing a controlled-release drug-releasing microneedle with good biocompatibility, characterized in that: The following steps are involved: Step S1, preparing the solution: dissolving the sustained-release drug in the molding material solution to obtain a sustained-release needle solution; dissolving a transient drug in a molding material solution to obtain a transient drug layer solution; The molding material solution includes: 16wt%-19wt% polyvinyl alcohol solution; Step S2, preparing drug-releasing microneedle precursors: Providing a microneedle mold, the microneedle mold comprising array-distributed needle body cavities and a backing cavity connected to an open end of the needle body cavity; Adding the sustained-release needle solution into the needle cavity to fill the needle cavity with the sustained-release needle solution, and then adding a backing layer solution into the backing cavity to obtain a drug-releasing microneedle precursor; the backing layer solution comprises: 20wt%-22wt% polyvinyl alcohol solution; Step S3, preparing controlled-release drug-releasing microneedles with good biocompatibility: Repeatedly freeze-thaw the drug-releasing microneedle precursor m times, where m>1, so that the sustained-release needle body solution forms a sustained-release needle body, the backing layer solution forms a backing layer, and the sustained-release needle body and the backing layer are cross-linked and bonded; The microneedle mold is removed, and the instantaneous drug layer solution is applied to the surface of the sustained-release needle body, followed by freeze cross-linking to obtain the controlled-release drug-releasing microneedle with good biocompatibility.

2. The method for preparing the controlled-release drug-releasing microneedle with good biocompatibility as claimed in claim 1, characterized in that: The sustained-release drug includes at least one of sorafenib, PD-1 antibody drug, PD-L1 antibody drug, albumin paclitaxel, and gemcitabine; the transient drug includes at least one of 5-fluorouracil, oxaliplatin, folinic acid, and irinotecan.

3. The method for preparing the controlled-release drug-releasing microneedle with good biocompatibility as claimed in claim 1, characterized in that: In step S3, repeatedly freezing and thawing the drug-releasing microneedle precursor m times means: freezing and cross-linking the drug-releasing microneedle precursor for 6 to 8 hours, and then thawing for 1 to 4 hours, and repeating this process m times.

4. The method for preparing the controlled-release drug-releasing microneedle with good biocompatibility as claimed in claim 3, characterized in that: m is 2 or 3.

5. The method for preparing the controlled-release drug-releasing microneedle with good biocompatibility as claimed in claim 3, characterized in that: During the repeated freezing and thawing process of the drug-releasing microneedle precursor, the freezing cross-linking temperature is -20°C to -80°C, and the thawing temperature is -2°C to -6°C.

6. The method for preparing a controlled-release drug-releasing microneedle with good biocompatibility as claimed in claim 1, characterized in that: The backing layer solution further comprises: 14 wt % to 16 wt % of polyvinyl pyrrolidone.

7. A controlled drug-releasing microneedle with good biocompatibility, characterized in that: Prepared according to the preparation method according to any one of claims 1 to 6.

8. The controlled drug-releasing microneedle with good biocompatibility as claimed in claim 7, characterized in that: The controlled-release drug-releasing microneedle comprises: a backing layer and a plurality of sustained-release needle bodies distributed in an array; The sustained-release needle body is fixed to one side of the backing layer, the interior of the sustained-release needle body is loaded with sustained-release drugs, and the exterior of the sustained-release needle body is coated with a transient drug layer; the interior of the transient drug layer is loaded with transient drugs; the release rate of the transient drugs is greater than the release rate of the sustained-release drugs.

9. The controlled drug-releasing microneedle with good biocompatibility as claimed in claim 8, characterized in that: The porosity of the sustained-release needle body is smaller than the porosity of the transient drug layer.

10. The controlled drug-releasing microneedle with good biocompatibility as claimed in claim 8, characterized in that: The sustained-release needle body is a cone, the length of the sustained-release needle body is 600 μm to 800 μm, and the diameter of the end surface of the sustained-release needle body is 200 μm to 400 μm.

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