Polymeric microneedles, microneedle patches and delivery systems containing the same, methods of manufacture, uses

Abstract

The application discloses a polymer microneedle, a microneedle sheet and a delivery system containing the same, a preparation method and application. The polymer microneedle comprises a drug and a polymer skeleton, and the drug is loaded in the polymer skeleton; wherein the drug is a GLP-1 receptor agonist or a composition containing the GLP-1 receptor agonist; the polymer skeleton is insoluble in water; the polymer skeleton is in the shape of a microneedle; preferably, the polymer skeleton further contains an effervescent component. The microneedle sheet contains a plurality of polymer microneedles and a plate on which the polymer microneedles are arranged. The microneedle sheet can be used immediately, can intelligently reduce the blood sugar level of a type 2 diabetes patient and maintain the blood sugar balance, is easy to operate, has low cost, can be removed without damage after the release is completed, can further load a medicinal effervescent component in the microneedle and can realize rapid release of the GLP-1 receptor agonist or the composition.

Description

[0001] This application claims priority to Chinese Patent Application No. CN202210038385.5, filed on January 13, 2022. This application incorporates the entirety of the aforementioned Chinese Patent Application. TECHNICAL FIELD

[0002] The present application relates to the field of drug delivery and microneedle patches, in particular to a polymer microneedle, a microneedle patch and a delivery system containing the same, a preparation method and applications. BACKGROUND

[0003] Type 2 diabetes is a chronic disease with an unclear cause, and the number of patients accounts for about 90%-95% of the total number of diabetes patients, which seriously endangers people's health and quality of life. In recent decades, the results of multiple epidemiological investigations in China show that the incidence of type 2 diabetes is increasing rapidly, and the incidence is becoming younger and more regional.

[0004] At present, GLP-1 (glucagon-like peptide-1, GLP-1) receptor agonists or compositions containing the same are considered to be relatively successful first-line drugs in clinical practice, which can effectively control the blood glucose level of type 2 diabetes patients and have a weight loss effect. At present, the administration of GLP-1 receptor agonists is mainly by subcutaneous injection and oral administration. Although these preparations play an efficient role in controlling blood glucose levels, as a long-term use of the preparation form, they still face some insurmountable barriers in actual use.

[0005] Specifically, subcutaneous injection preparations often bring patients a lot of injection pain, and liquid preparations often need to be stored at low temperature, which is not convenient for daily carrying and use in actual situations such as travel. Oral preparations have good patient compliance, are easy to use and carry, but their drug utilization rate is very low, resulting in a large amount of drug waste and seriously limiting the therapeutic effect.

[0006] Therefore, in order to alleviate the pain of long-term injection of patients and improve drug utilization, the development of microneedle patches (such as microneedle patches) as a preparation form has shown great market potential. Considering that GLP-1 receptor agonists are a self-body response drug that can intelligently respond to blood glucose levels in the body, they are a blood glucose regulation drug in the body that has more clinical use value than insulin or glucagon. Therefore, it is of great market value to develop a microneedle patch (such as a microneedle patch) that can be used to release GLP-1 receptor agonists or compositions containing the same as a substitute for the above two existing preparations. SUMMARY

[0007] The technical problem to be solved by the present application is to overcome the defects of inconvenient use or low drug utilization rate of the dosage form of the GLP-1 receptor agonist or the composition containing the same in the prior art, and to provide a polymer microneedle, a microneedle patch and a delivery system containing the same, a preparation method and application. The microneedle patch (for example, a microneedle patch) provided by the present application for transdermal delivery of the GLP-1 receptor agonist or the composition containing the same can be plug-and-play, and can be removed without damage after transdermal administration. The microneedle patch can be used for treating type 2 diabetes or obesity, has good compliance for patients, is convenient to use and carry, has high drug utilization rate, and can achieve rapid release of the GLP-1 receptor agonist or the composition containing the same.

[0008] The GLP-1 analogue is a kind of drug for intelligent regulation of blood glucose in vivo, which will not cause change of blood glucose level even if a large amount of accumulation in vivo for a short time (in contrast, drugs such as insulin can induce fatal hypoglycemia if the content is too high), based on this property of the drug, realizing the rapid release of GLP-1, accumulating in vivo, regulating the content of blood glucose for a long time is one of the technical problems to be solved in the art. More importantly, the rapid release of the GLP-1 analogue (such as within a few minutes to tens of minutes) can quickly remove the microneedle from the body, avoid the residual of the needle body material in the body, and there is no need to attach the microneedle to the skin for a long time, improve the patient's comfort, and reduce the risk of inflammation induced by long-term attachment.

[0009] In order to achieve rapid release of the drug, the existing patents generally use dissolvable high molecular microneedles to achieve release of the protein drug by dissolving the microneedles, but this release mode will leave the microneedle body in the patient's body, which is easy to induce inflammation and the like. The microneedle in the present application uses a cross-linking technical means, and creatively combines the effervescent component and the microneedle, without dissolving the high molecular microneedle, which realizes rapid release of the drug and can pull out the microneedle from the body after the drug is released, and takes into account the safety and efficacy of the microneedle.

[0010] The inventors also want to emphasize that the microneedle of the present application has a cross-linking structure, which generally limits the release of the protein drug and is easy to achieve sustained release. Creatively, the effervescent component is combined with the microneedle skeleton in the present application, which realizes rapid release of the drug loaded in the cross-linked microneedle. Moreover, the effervescent agent is a conventional pharmaceutical ingredient with high biological safety.

[0011] The purpose of the present application is achieved by the following technical scheme:

[0012] A polymer microneedle comprising a drug and a polymer skeleton, wherein the drug is loaded in the polymer skeleton; and wherein:

[0013] The drug is a GLP-1 receptor agonist or a composition containing a GLP-1 receptor agonist;

[0014] The polymer skeleton is insoluble in water;

[0015] The polymer skeleton is microneedle-shaped.

[0016] Preferably, the polymer skeleton further carries an effervescent component.

[0017] In the present application, the GLP-1 receptor agonist can be a conventional GLP-1 receptor agonist in the art, such as one or more of Exenatide, Liraglutide, Lixisenatide, Lixliraglutide, Dulaglutide, Taspoglutide, Albiglutide, Bezlutamide, Loixiraglutide, Soladexiraglutide, and Dulaglutide, such as Exenatide, Exenatide microspheres, Liraglutide, Lixisenatide, Lixliraglutide, Dulaglutide, Taspoglutide, Albiglutide, Bezlutamide, Loixiraglutide, Soladexiraglutide, or Dulaglutide, such as Lixliraglutide or Dulaglutide.

[0018] In the present application, the GLP-1 receptor agonist-containing composition refers to a pharmaceutical composition comprising a GLP-1 receptor agonist, which can be a pharmaceutical composition having synergistic therapeutic efficacy.

[0019] The GLP-1 receptor agonist can be as described above.

[0020] The GLP-1 receptor agonist-containing composition can further comprise one or more of an insulin receptor agonist, a glucagon receptor agonist, and a GIP (glucose-dependent insulinotropic polypeptide, GIP) receptor agonist, such as an insulin receptor agonist or a glucagon receptor agonist, such as at least two of an insulin receptor agonist, a glucagon receptor agonist, and a GIP receptor agonist.

[0021] The insulin receptor agonist can be a non-peptide or polypeptide small molecule compound, such as L-783,281 and / or insulin aspart.

[0022] The glucagon receptor agonist can be a glucagon peptide.

[0023] The GIP receptor agonist can be one or more of Lilly XW003 drug, Tirzepatide, Tirzepatide, “Exendin-4 and derivatives thereof”, and SCO-094, such as Lilly XW003 drug, Tirzepatide, Tirzepatide, “Exendin-4 and derivatives thereof”, or SCO-094.

[0024] The composition containing the GLP-1 receptor agonist can include a GLP-1 / GIP dual receptor agonist, a GLP-1 / insulin dual receptor agonist, a GLP-1 / glucagon dual receptor agonist, a GLP-1 / GIP / insulin triple receptor agonist, a GLP-1 / GIP / glucagon triple receptor agonist, a GLP-1 / glucagon / insulin triple receptor agonist, or a GLP-1 / GIP / glucagon / insulin quadruple receptor agonist. Here, " / " represents the relationship of "and", that is, the GLP-1 / GIP dual receptor agonist refers to an agonist containing both a GLP-1 receptor agonist and a GIP receptor agonist, or an agonist capable of simultaneously agonizing GLP-1 receptor and GIP receptor.

[0025] In the present application, preferably, the drug is liraglutide, "liraglutide, insulin aspart, tirzepatide and Tirzepatide", or "dulaglutide, insulin aspart, tirzepatide and Tirzepatide".

[0026] In the present application, the polymer skeleton can be a microneedle-shaped polymer skeleton obtained by physical crosslinking or chemical crosslinking.

[0027] The physical crosslinking can be crosslinking generated by physical interaction of hydrogen bonds and / or ionic bonds.

[0028] The chemical crosslinking can be chemical crosslinking generated by covalent bonds.

[0029] In the present application, the polymer skeleton can improve the mechanical stability of the microneedle, so that it can be removed without damage after being inserted into the skin, and no microneedle body is left in the body. As long as the microneedle patch can be pulled out without damage after being inserted into the skin, it is within the scope of the polymer skeleton mentioned in the present application.

[0030] In the present application, the polymer skeleton is generally prepared from a crosslinkable polymerizable system, which can be one or more of a system containing cellulose, a system containing chitosan, a system containing chitin, a system containing polyvinyl alcohol, a system containing DNA, a system containing silk fibroin, and a system containing a polymer based on a double bond-containing monomer, such as a system containing polyvinyl alcohol, a polymerizable system containing a double bond-containing monomer, a system containing chitosan, or a system containing DNA.

[0031] The crosslinkable polymerizable system can be a system that is hydrophilic or water-soluble under certain conditions, but forms a water-insoluble crosslinked structure after physical or chemical crosslinking treatment.

[0032] The polyvinyl alcohol in the system containing polyvinyl alcohol can be a conventional polyvinyl alcohol in the art, for example, polyvinyl alcohol with a weight average molecular weight of 50000-200000 g / mol, for another example, polyvinyl alcohol with a weight average molecular weight of 100000 g / mol.

[0033] The system containing polyvinyl alcohol can be an aqueous solution of polyvinyl alcohol. The mass concentration of the polyvinyl alcohol in the aqueous solution of polyvinyl alcohol can be 10-30 w / v%, for example, 20 w / v%.

[0034] In the mass concentration, 1 w / v% means that 1 gram of polyvinyl alcohol is contained in 100 milliliters of water.

[0035] The polymer backbone can be prepared from a polymerizable system containing a double bond-containing monomer. The double bond-containing monomer can be one or more of vinyl pyrrolidone, acrylamide, acrylic acid, dimethylaminoethyl acrylate, m-amino phenyl boronic acid, ethylene glycol dimethacrylate, dimethylaminoethyl methacrylate, methacrylic acid, glycidyl acrylate and polyethylene glycol diacrylate, for example, vinyl pyrrolidone.

[0036] When the polymer backbone is prepared from a polymerizable system containing a double bond-containing monomer, the polymerizable system containing a double bond-containing monomer can further comprise a crosslinking agent and / or an initiator.

[0037] The crosslinking agent can be a conventional crosslinking agent in the art, for example, when the double bond-containing monomer is vinyl pyrrolidone, the crosslinking agent can be ethylene glycol dimethacrylate.

[0038] The mass ratio of the double bond-containing monomer to the crosslinking agent can be (95-105):1.5, for example, 97:1.5.

[0039] The initiator can be a conventional initiator in the art, for example, when the double bond-containing monomer is vinyl pyrrolidone, the initiator can be a photoinitiator. The photoinitiator can be 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone (I2959).

[0040] The mass ratio of the double bond-containing monomer to the initiator can be (95-105):1.5, for example, 97:1.5.

[0041] The mass ratio of the double bond-containing monomer, the crosslinking agent and the initiator can be 97:1.5:1.5.

[0042] The chitosan in the system containing chitosan can be a conventional chitosan in the art, for example, chitosan with a weight average molecular weight of 200000-600000 g / mol, for another example, chitosan with a weight average molecular weight of 400000 g / mol.

[0043] The chitosan-containing system may be an aqueous solution of chitosan, wherein the mass concentration of chitosan in the aqueous solution of chitosan may be 1-10 w / v%, such as 5 w / v%.

[0044] In the mass concentration, 1 w / v% means that 1 gram of chitosan is contained in 100 ml of water.

[0045] In the system comprising DNA, the DNA can be conventional DNA in the art, such as natural DNA extracted from salmon sperm. The weight-average molecular weight of the DNA can be 800,000-1.5 million g / mol, such as 1.2 million g / mol or 1.5 million g / mol.

[0046] The system containing DNA may be an aqueous solution of DNA, and the mass concentration of the DNA in the aqueous solution may be 1-20 w / v%, such as 5 w / v% or 10 w / v%.

[0047] In the mass concentration, 1 w / v% means that 100 ml of water contains 1 gram of DNA.

[0048] When the polymer backbone is prepared from a system comprising DNA, the system comprising DNA may further comprise a cross-linking agent and / or an initiator. The cross-linking agent may be a conventional cross-linking agent in the art, for example, polyethylene glycol (glycol) diacrylate (PEGDA).

[0049] The mass ratio of the DNA to the cross-linking agent may be (1-100):1, for example, 10:1 or 20:1.

[0050] The cross-linking polymerization system can determine its cross-linking mode according to the types of polymers or monomers contained therein, and the cross-linking mode can be physical cross-linking or chemical cross-linking.

[0051] The physical crosslinking may be crosslinking through physical interactions such as hydrogen bonds and ionic bonds.

[0052] When the system capable of undergoing cross-linking polymerization is a system comprising polyvinyl alcohol and / or a system comprising chitosan, the cross-linking method may be physical cross-linking.

[0053] The chemical crosslinking is generally crosslinking by forming covalent bonds through copolymerization.

[0054] When the crosslinking method is chemical crosslinking, the crosslinking agent and / or initiator can be selected according to the types of polymers or monomers involved.

[0055] The cross-linking agent can be a cross-linking agent conventional in the art, for example, when the cross-linkable polymerizable system is a polymerizable system comprising a double-bond-containing monomer (for example, comprising vinylpyrrolidone), the cross-linking agent can be ethylene glycol dimethacrylate. For another example, when the cross-linkable polymerizable system is a system comprising DNA, the cross-linking agent can be polyethylene glycol (diol) diacrylate (PEGDA).

[0056] The initiator can be an initiator conventional in the art, for example, when the cross-linkable polymerizable system is a polymerizable system comprising a double-bond-containing monomer (for example, comprising vinylpyrrolidone), the cross-linking agent can be a photoinitiator, for another example, 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone (I2959).

[0057] For example, when the cross-linkable polymerizable system is a polymerizable system comprising a double-bond-containing monomer, the cross-linkable polymerizable system further comprises a cross-linking agent and / or an initiator.

[0058] The mass ratio of the double-bond-containing monomer and the cross-linking agent can be (95-105):1.5, for example, 97:1.5.

[0059] The mass ratio of the double-bond-containing monomer and the initiator can be (95-105):1.5, for example, 97:1.5.

[0060] The mass ratio of the double-bond-containing monomer, the cross-linking agent and the initiator can be 97:1.5:1.5.

[0061] For example, when the cross-linkable polymerizable system is a system comprising DNA, the cross-linkable polymerizable system further comprises a cross-linking agent polyethylene glycol (diol) diacrylate (PEGDA).

[0062] The mass ratio of the DNA and the cross-linking agent can be (1-100):1, for example, 10:1 or 20:1.

[0063] The polymer skeleton can be prepared by the following method: in a microneedle mold, the cross-linkable polymerizable system is subjected to a cross-linking reaction, and the polymer skeleton is obtained.

[0064] The cross-linking reaction can be a physical cross-linking reaction or a chemical cross-linking reaction.

[0065] When the cross-linking reaction is a physical cross-linking reaction, the time of the cross-linking reaction can be 12-24h.

[0066] When the cross-linking reaction is a chemical cross-linking reaction, and the cross-linking reaction is initiated by a photoinitiator, the conditions of the cross-linking reaction can be under ultraviolet light with an intensity of 50-150mW / cm 2(e.g. 120-140 mW / cm 2 , for example 130 mW / cm 2 ) for 5-30 min (e.g. 10 min).

[0067] wherein, before irradiation under the condition of ultraviolet intensity of 50-150 mW / cm 2 (e.g. 120-140 mW / cm 2 , for example 130 mW / cm 2 ) for 5-30 min (e.g. 10 min), the cross-linkable polymerizable system in the microneedle mold can be pre-cross-linked, for example, irradiation under the condition of ultraviolet intensity of 10-150 mW / cm 2 (e.g. 10-20 mW / cm 2 , for example 15 mW / cm 2 ) for 5-120 s (e.g. 1-30 s, for example 120 s).

[0068] After the pre-cross-linking treatment, an optical adhesive, for example NOA 86H liquid, can be added to the surface of the pre-cross-linked polymer microneedle.

[0069] In the present application, the drug loaded in the polymer framework generally refers to the dispersion of the drug in the polymer framework, which is uniformly or non-uniformly distributed on the surface and / or inside of the polymer framework.

[0070] In the present application, the mass ratio of the drug to the polymer microneedle can be (0.0001-0.1):1, for example 0.0001:1, 0.001:1, 0.01:1 or 0.1:1.

[0071] In the present application, the microneedle generally refers to a three-dimensional needle-like structure, for example a cone, a quadrangular pyramid or a cuboid.

[0072] wherein, the height of the microneedle in the microneedle can be a conventional height in the art, for example 500-2000 microns, for example 500 microns, 1200 microns or 1500 microns.

[0073] wherein, when the microneedle is a plurality of microneedles, the tip-to-tip distance of the microneedle in the microneedle can be a conventional tip-to-tip distance of the microneedle in the art, for example 100-1000 microns, for example 200 microns, 700 microns or 800 microns.

[0074] wherein, when the microneedle is a cone, the base diameter of the microneedle in the microneedle can be 200-800 microns, for example 500 microns.

[0075] When the microneedle is a tetrapod, the base side length of the microneedle can be 200-800 microns, for example 500 microns.

[0076] In the present application, the effervescent component can be a conventional effervescent component in the art, for example a mixture comprising an acid source and a base source.

[0077] Preferably, the effervescent component is in the form of particles, and the particle diameter of the effervescent component is 30-50 microns (this diameter corresponds to the D50 particle size of the effervescent particles), for example 40 microns. The effervescent component can be ground to obtain a diameter of 30-50 microns.

[0078] The acid source can be a conventional acid source in the art, for example one or more of citric acid, malic acid, boric acid, tartaric acid, fumaric acid and hydrochloric acid, for example one or more of citric acid, tartaric acid and malic acid, for example citric acid, tartaric acid or malic acid.

[0079] The base source can be a conventional base source in the art, for example sodium bicarbonate, sodium carbonate or a mixture of the two, for example sodium bicarbonate or sodium carbonate.

[0080] The mass ratio of the acid source to the base source can be (0.1-3):1, for example 1.76:1, 2:1, 0.5:1 or 1:1.3.

[0081] The effervescent component can be tartaric acid and sodium bicarbonate, citric acid and sodium bicarbonate, or malic acid and sodium carbonate.

[0082] When the effervescent component is tartaric acid and sodium bicarbonate, the mass ratio of the acid source to the base source can be (1.5-3):1, for example 2:1.

[0083] When the effervescent component is citric acid and sodium bicarbonate, the mass ratio of the acid source to the base source can be (0.5-3):1, for example 1.76:1, 2:1 or 1:1.3.

[0084] When the effervescent component is malic acid and sodium carbonate, the mass ratio of the acid source to the base source can be (0.1-1.0):1, for example 0.5:1.

[0085] The mass ratio of the drug to the effervescent component can be 1:(1-20), for example 1:1.0, 1:1.5, 1:2.0, 1:3.0, 1:5, 1:10 or 1:20.

[0086] The mass ratio of the effervescent component to the polymer microneedle can be (0.001-0.1):1, such as 0.002:1, 0.005:1, 0.01:1, 0.015:1, 0.02:1, 0.03:1 or 0.1:1.

[0087] In the present application, the loading of the effervescent component in the polymer matrix generally means that the effervescent component is dispersed in the polymer matrix and uniformly or non-uniformly distributed on the surface and / or inside of the polymer matrix.

[0088] In the present application, preferably, the effervescent component is distributed in the tip portion of the polymer microneedle.

[0089] In the present application, when the polymer matrix further comprises an effervescent component, the microneedle sheet (such as a microneedle patch) can achieve rapid release. Specifically, the GLP-1 receptor agonist or the composition containing the GLP-1 receptor agonist can be released within 1-60 minutes, and the amount of the GLP-1 receptor agonist or the composition containing the GLP-1 receptor agonist released reaches 20%-100%.

[0090] The present application also provides a raw material composition comprising the following components: a drug and a cross-linking polymerizable system, wherein the drug is a GLP-1 receptor agonist or a composition containing a GLP-1 receptor agonist.

[0091] Preferably, the raw material composition further comprises an effervescent component.

[0092] Optionally, the cross-linking polymerizable system further comprises a cross-linking agent and / or an initiator.

[0093] The GLP-1 receptor agonist can be as described above.

[0094] The composition containing the GLP-1 receptor agonist can be as described above.

[0095] The cross-linking polymerizable system can be as described above.

[0096] The particle size, type, amount, etc. of the effervescent component can be as described above.

[0097] Preferably, the diameter of the effervescent component is 30-50 microns, such as 40 microns. The effervescent component can be ground and sieved to obtain a diameter of 30-50 microns.

[0098] The type and amount of the cross-linking agent can be as described above.

[0099] The type and amount of the initiator can be as described above.

[0100] The application also provides a preparation method of the polymer microneedle, comprising the following steps:

[0101] 1) mixing the drug, the cross-linking polymerization system to obtain a mixture C, and filling the mixture C into a microneedle mold;

[0102] When the raw material composition of the microneedle preparation further comprises an effervescent component, the drug, the cross-linking polymerization system and the effervescent component are mixed to obtain a mixture C, and the mixture C is filled into a microneedle mold;

[0103] 2) in the microneedle mold, the cross-linking polymerization system is cross-linked to fix the drug or the drug and the effervescent component in the microneedle chamber, and a solidified microneedle is formed;

[0104] The polymer skeleton formed after the cross-linking reaction of the cross-linking polymerization system is insoluble in water.

[0105] In step 1), when the raw material composition of the microneedle preparation further comprises an effervescent component, and the cross-linking polymerization system further comprises a cross-linking agent and / or an initiator, the mixture C can be prepared by the following method:

[0106] Mixing the components in the cross-linking polymerization system to obtain a mixture A;

[0107] Mixing the drug and the effervescent component to obtain a mixture B;

[0108] Mixing the mixture A and the mixture B to obtain a mixture C.

[0109] The mixture B can be added to the mixture A to obtain the mixture C.

[0110] In step 1), when the raw material composition of the microneedle preparation further comprises an effervescent component, the mixture C can be subjected to a centrifugal concentration treatment before the cross-linking reaction after being filled into the microneedle mold.

[0111] The centrifugal concentration treatment can be centrifugation at 4000 rpm for 2 minutes.

[0112] In step 1), the mixture C can fill the microneedle mold.

[0113] The filling method can be micro-injection, vacuum degassing or centrifugation.

[0114] The vacuum degassing time can be 1 min-1 h, for example, 2 min, and further for example, 20 min or 30 min.

[0115] The centrifugation conditions can be conventional centrifugation conditions in the art, for example, 2000-5000 rpm, centrifugation for 1-20 min, for another example, 4000 rpm, centrifugation for 10 min or 20 min.

[0116] After the filling, the mixture C can be further subjected to a pre-centrifugation treatment.

[0117] The pre-centrifugation conditions can be 3000-5000 rpm, centrifugation for 1-5 min, for example, 4000 rpm, centrifugation for 2 min.

[0118] In step 2), the cross-linking reaction can be a physical cross-linking reaction or a chemical cross-linking reaction.

[0119] When the cross-linking reaction is a physical cross-linking reaction, the time of the cross-linking reaction can be 12-24 h.

[0120] When the cross-linking reaction is a chemical cross-linking reaction, and the cross-linking reaction is initiated by a photo initiator, the conditions of the cross-linking reaction can be irradiation for 5-30 min (for example, 10 min) under the condition that the ultraviolet intensity is 50-150 mW / cm 2 (for example, 120-140 mW / cm 2 , for another example, 130 mW / cm 2 ).

[0121] Wherein, before irradiation for 5-30 min (for example, 10 min) under the condition that the ultraviolet intensity is 50-150 mW / cm 2 (for example, 120-140 mW / cm 2 , for another example, 130 mW / cm 2 ), the cross-linkable polymerizable system in the microneedle mold can be further subjected to a pre-cross-linking treatment, for example, irradiation for 5-120 s (for example, 1-30 s, for another example, 5 s) under the condition that the ultraviolet intensity is 10-150 mW / cm 2 (for example, 10-20 mW / cm 2 , for another example, 15 mW / cm 2 ).

[0122] After the pre-cross-linking treatment, an adhesive, for example, an optical adhesive, for another example, NOA 86H liquid, can be added to the surface layer of the pre-cross-linked polymer microneedle. The adhesive can connect the individual microneedles to each other to form a complete microneedle sheet.

[0123] The application further provides a polymer microneedle prepared by the above preparation method.

[0124] The application further provides a microneedle sheet comprising a plurality of polymer microneedles and a plate on which the polymer microneedles stand and are arranged.

[0125] The polymer material of the polymer microneedle and the polymer material of the plate can be the same or different.

[0126] The polymer material of the plate can be hydrophilic or water-soluble under certain conditions, but forms a water-insoluble cross-linked structure after physical or chemical cross-linking treatment.

[0127] The microneedle tip spacing in the microneedle sheet can be a conventional microneedle tip spacing in the art, for example, 100-1000 microns, for example, 200 microns, 700 microns, or 800 microns.

[0128] The application also provides a preparation method of a microneedle sheet, which is prepared by the following method I or method II:

[0129] Method I:

[0130] The plurality of polymer microneedles are connected into a plate by rigid or flexible material, and the preparation is completed.

[0131] Method II:

[0132] S1: mixing the drug, the cross-linking polymerizable system to obtain a mixture C, and filling the mixture C into a microneedle mold;

[0133] When the raw material composition of the microneedle preparation further comprises an effervescent component, the drug, the cross-linking polymerizable system and the effervescent component are mixed to obtain a mixture C, and the mixture C is filled into a microneedle mold;

[0134] S2: an adhesive is added to the surface of the microneedle mold; in the microneedle mold, the cross-linking polymerizable system undergoes a cross-linking reaction, and the drug or the "drug and effervescent component" is fixed in the microneedle chamber to form a solidified microneedle, and the preparation is completed.

[0135] The polymer skeleton formed after the cross-linking reaction of the cross-linking polymerizable system is insoluble in water.

[0136] In step S1, the preparation method of the mixture C can be as described above.

[0137] In step S1, the method of filling the mixture C into the microneedle mold can be as described above.

[0138] In step S2, the cross-linking reaction can be as described above.

[0139] In step S2, the type of the adhesive can be a conventional type in the art, for example, an optical adhesive, for example, NOA 86H liquid. The adhesive can connect the individual microneedles to each other to form a complete microneedle sheet.

[0140] The application also provides a microneedle sheet prepared by the above method.

[0141] The application also provides a polymer material comprising a drug and a polymer framework, wherein the drug is loaded in the polymer framework; and wherein:

[0142] The drug is a GLP-1 receptor agonist or a composition comprising a GLP-1 receptor agonist.

[0143] The polymer framework is insoluble in water.

[0144] Preferably, the polymer framework further comprises an effervescent component.

[0145] The GLP-1 receptor agonist can be as described above.

[0146] The composition comprising a GLP-1 receptor agonist can be as described above.

[0147] The mass ratio of the drug to the polymer material can be (0.0001-0.1):1, such as 0.0001:1, 0.001:1, 0.01:1 or 0.1:1.

[0148] The polymer framework can be as described above.

[0149] The particle size, type and amount of the effervescent component can be as described above.

[0150] The application also provides a preparation method of the polymer material, comprising the following steps:

[0151] Mixing the raw material composition and cross-linking to form the polymer material insoluble in water.

[0152] The application also provides a GLP-1 receptor agonist delivery system comprising the polymer microneedle, the microneedle sheet or the polymer material as described above.

[0153] The GLP-1 receptor agonist delivery system can be in the form of a sheet or a roller.

[0154] The application also provides use of the polymer microneedle, the microneedle sheet, the polymer material and the GLP-1 receptor agonist delivery system in the preparation of a drug for treating diabetes.

[0155] The application also provides a method for treating diabetes, comprising administering the polymer microneedle, the microneedle sheet, the polymer material or the GLP-1 receptor agonist delivery system to a subject.

[0156] The above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present application.

[0157] The reagents and raw materials used in the present application are commercially available.

[0158] The positive progress effect of the present application is that:

[0159] 1. The present application provides a plug-and-play micro-needle patch that can also administer drugs quickly, without leaving any residual components other than drugs, and the GLP-1 receptor agonist or composition released can quickly and intelligently reduce the blood glucose level of patients with type 2 diabetes and maintain blood glucose balance. The micro-needle patch does not dissolve when in use, can be removed intact after use, does not leave micro-needle material in the body, and greatly ensures the safety of patients using the patch.

[0160] 2. The micro-needle patch in the present application is used to load GLP-1 receptor agonists or compositions, and can further load pharmaceutical effervescent components inside the micro-needle to achieve rapid release of GLP-1 receptor agonists or compositions, can quickly and stably reduce blood glucose levels in the body, maintain blood glucose balance, and be used for treating type 2 diabetes or obesity.

[0161] 3. The administration mode of the micro-needle patch (such as a micro-needle patch) can significantly reduce the pain of patients taking drugs, while ensuring a high drug utilization rate, and is an administration mode that takes into account patient compliance and drug utilization.

[0162] 4. The micro-needle patch in the present application has a simple preparation method, low cost, and is easy to carry. The prepared micro-needle patch has good biocompatibility, can quickly release GLP-1 receptor agonists or compositions through transdermal administration, and the high-molecular-weight cross-linked micro-needle patch can be removed intact after release, is an administration system that is convenient to use, has high comfort, and has great potential for clinical transformation. Moreover, the drug is used in the form of a micro-needle patch, which can significantly prolong the storage time of the drug at room temperature. BRIEF DESCRIPTION OF DRAWINGS

[0163] Figure 1 It is an optical microscope picture of the conical micro-needle patch prepared in Example 1.

[0164] Figure 2 It is an optical microscope picture of the four-prism micro-needle patch prepared in Example 2.

[0165] Figure 3 It is a scanning electron microscope picture of the micro-needle patch containing liraglutide and effervescent agent prepared in Example 3.

[0166] Figure 4 It is the drug in vitro release curve of the micro-needle patches A, B, and C prepared in Example 6.

[0167] Figure 5 The in vitro drug release curves of the microneedle patches with different effervescent content prepared in Example 7.

[0168] Figure 6 The in vitro drug release curves of the microneedle patches prepared using different preparation processes in Example 7.

[0169] Figure 7 These are fluorescence microscopy photos of in vitro release of microneedle patches obtained with different preparation processes in Example 7.

[0170] Figure 8 The mechanical properties of the microneedle patches with different effervescent agent contents prepared in Example 7.

[0171] Figure 9 These are the results of an in vitro transdermal test of the centrifuged microneedle sheet containing 1.5% effervescent agent prepared in Example 7.

[0172] Figure 10 The surface morphologies of the microneedle patches with different effervescent agent contents prepared in Example 7 before use, after release, and after use.

[0173] Figure 11 Circular dichroism spectra of liraglutide and native liraglutide released from the microneedle sheet containing 1.5% effervescent agent prepared in Example 7 and subjected to centrifugation.

[0174] Figure 12 The blood sugar lowering effects of liraglutide and original liraglutide released from the microneedle tablet containing 1.5% effervescent prepared in Example 7 and subjected to centrifugation in type 2 diabetic mice.

[0175] Figure 13 The blood sugar lowering effects of the centrifuged microneedle sheet containing 1.5% effervescent agent and the uncentrifuged microneedle sheet without effervescent agent prepared in Example 7 in type 2 diabetic mice.

[0176] Figure 14 Pharmacokinetic curves of the centrifuged microneedle tablet containing 1.5% effervescent agent and the uncentrifuged microneedle tablet containing no effervescent agent prepared in Example 7 in type 2 diabetic mice. DETAILED DESCRIPTION

[0177] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0178] In the following examples and comparative examples:

[0179] The microneedle mold preparation method is as follows:

[0180] The polydimethylsiloxane prepolymer and the curing agent (silane crosslinking agent) are mixed at a mass ratio (1:10-10:1) (for example, 1:1) at room temperature, and the mixture is filled into a microneedle mold. The specific shape and size of the microneedle can be selected according to the actual situation, for example, a four-pyramidal or conical microneedle positive mold, and for example, a conical microneedle positive mold (500 microns (bottom diameter) * 800 microns (microneedle tip spacing) * 1500 microns (microneedle height)). The mixture is degassed under vacuum for 20 min-2 hours (for example, 30 min), and then placed in an oven at 50-100 degrees Celsius (for example, 70 degrees Celsius) for crosslinking and curing for 0.5-24 hours to form a polydimethylsiloxane microneedle mold.

[0181] Chemical polymer crosslinking microneedle preparation:

[0182] An appropriate amount of a drug (GLP-1 receptor agonist or a composition containing the same) and an effervescent agent component (for example, a pharmaceutical effervescent agent component) are pre-mixed to obtain a mixture A, the mixture A is added to a bio-based polymer system mixture B (the bio-based polymer system contains a polymerizable system, and optionally, a crosslinking agent and / or an initiator), and vortexed to obtain a mixture C. The mixture C is added to a pre-prepared microneedle mold, and the bio-based polymer system containing the drug is filled into the microneedle mold by vacuum degassing or centrifugation. Then, the bio-based polymer system in the microneedle mold undergoes a crosslinking reaction (for example, physical crosslinking or chemical crosslinking), the “GLP-1 receptor agonist or a composition containing the same” and the pharmaceutical effervescent agent component are fixed in the microneedle chamber, a solidified microneedle is formed, and the microneedle is removed from the microneedle mold.

[0183] All the polymer crosslinking systems in the present application can be prepared by the above method to obtain a non-invasive microneedle patch capable of rapidly releasing a GLP-1 receptor agonist or a composition containing the same.

[0184] In the following examples and comparative examples:

[0185] GLP-1 receptor agonist: Liraglutide, CAS No. 204656-20-2; Dulaglutide, purchased from Novo Nordisk, Denmark;

[0186] Insulin receptor agonist: non-peptide or polypeptide small molecule compound, for example, L-783,281 or insulin aspart;

[0187] Glucagon receptor agonist: glucagon peptide;

[0188] GIP receptor agonist: Lilly XW003 drug, Tirzepatide, SCO-094;

[0189] GIP receptor agonists and glucagon dual receptor agonists: Tirzepatide, Exendin-4 and derivatives thereof;

[0190] GLP-1 and GIP receptor agonists: SCO-094, Tirzepatide;

[0191] GLP-1 and glucagon receptor agonists: SAR425899.

[0192] The application will be further described in conjunction with specific embodiments and the accompanying drawings.

[0193] Example 1

[0194] A non-invasively removable polyvinyl alcohol cross-linked microneedle patch, the preparation method comprising the following steps.

[0195] Microneedle mold fine processing: polydimethylsiloxane prepolymer and curing agent (silane crosslinking agent) are fully stirred and mixed at room temperature in a mass ratio of 1:1, the mixture is filled into a conical microneedle male mold (500 microns (bottom diameter) * 800 microns (microneedle tip spacing) * 1500 microns (microneedle height)), and is degassed under vacuum conditions for 30 minutes, so that the mixture fills the microneedle male mold, and then it is placed in a 70 degree Celsius oven for cross-linking and curing for 6 hours to form a polydimethylsiloxane microneedle mold.

[0196] Chemical polymer cross-linked microneedle preparation:

[0197] A mixture A of a uniformly mixed polyvinyl alcohol polymer cross-linking system (20w / v%, the weight (g) to volume (mL) ratio of the polyvinyl alcohol polymer in the mixture A, for example, 100 milliliters of water dissolving 20 grams of polyvinyl alcohol) is prepared, and the weight (g) to volume (mL) ratio of the polyvinyl alcohol polymer in the mixture A is 20w / v%.

[0198] The mixture A is added to the previously prepared microneedle mold, and centrifuged at a speed of 4000 rpm for 10 minutes, so that the polyvinyl alcohol polymer cross-linking system fills the microneedle mold. Then, it is placed in a room temperature ventilated place and dried overnight to form a cured microneedle, and the cured microneedle patch is taken out of the mold.

[0199] Figure 1 An optical microscope picture of the microneedle prepared for this example.

[0200] Example 2

[0201] A non-invasively removable polyvinyl pyrrolidone cross-linked microneedle patch, the preparation method comprising the following steps.

[0202] Fine processing of microneedle mold: the polydimethylsiloxane prepolymer and the curing agent (silane crosslinking agent) are mixed uniformly at room temperature in a mass ratio of 1:1, the mixture is filled into a four-pyramid-shaped microneedle male mold (500 microns (bottom side length) * 700 microns (microneedle tip spacing) * 1200 microns (microneedle height)), and the mixture is filled into the microneedle male mold under vacuum for 20 minutes. Then, the mixture is placed in a 70-degree Celsius oven for cross-linking and curing for 2 hours to form a polydimethylsiloxane microneedle mold.

[0203] Preparation of chemical polymer cross-linked microneedles:

[0204] (1) The vinyl pyrrolidone monomer (97 w / w%), cross-linking agent ethylene glycol dimethacrylate (1.5 w / w%), and photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5 w / w%) are mixed uniformly by vortex to obtain a mixture A; wherein the proportions of the vinyl pyrrolidone monomer, the initiator, and the cross-linking agent refer to the mass percentages in the total mass of the monomer, the initiator, and the cross-linking agent (i.e., the total mass of the mixture A).

[0205] (2) The polymer cross-linking system (mixture A) is added to the previously prepared microneedle mold, and the polyvinyl alcohol polymer cross-linking system is filled into the microneedle mold by vacuum degassing for 30 minutes. The excess polymer cross-linking system on the surface of the mold is removed, and pre-cross-linking is performed under ultraviolet conditions (ultraviolet intensity is 15 mW / cm 2 ) for 5 seconds.

[0206] (3) A small amount of NOA 86H liquid (“NOA 86H liquid” refers to Norlan optical adhesive, purchased from Norlan, model NOA 86H) is added to the surface of the microneedle, uniformly spread on the surface of the microneedle, and cross-linking is performed under ultraviolet conditions (ultraviolet intensity is 130 mW / cm 2 ) for 10 minutes. After the reaction is completed, the microneedle can be taken out of the mold.

[0207] Figure 2 The optical microscope picture of the microneedle prepared in this embodiment.

[0208] Example 3

[0209] A non-destructive removable polyvinyl pyrrolidone cross-linked microneedle patch for rapid release of liraglutide, the preparation method comprising the following steps.

[0210] Fine processing of microneedle mold: The polydimethylsiloxane prepolymer and the curing agent (silane crosslinking agent) were mixed uniformly at room temperature in a mass ratio of 1:1, the mixture was filled into a four-prism-shaped microneedle male mold (500 microns (bottom side length) * 700 microns (microneedle tip spacing) * 1200 microns (microneedle height)), and the mixture was filled into the microneedle male mold under vacuum for 30 minutes. Then the mixture was placed in a 70-degree Celsius oven for 3 hours for cross-linking and curing to form a polydimethylsiloxane microneedle mold.

[0211] Preparation of chemical polymer cross-linked microneedles:

[0212] (1) The mixture A was obtained by mixing the vinyl pyrrolidone monomer (97 w / w%), the cross-linking agent ethylene glycol dimethacrylate (1.5 w / w%), and the photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5 w / w%) uniformly by vortexing, wherein the proportions of the vinyl pyrrolidone monomer, the initiator, and the cross-linking agent refer to the mass percentages in the total mass of the monomer, the initiator, and the cross-linking agent (i.e., the total mass of the mixture A).

[0213] (2) The mixture B was obtained by uniformly mixing the liraglutide and the pharmaceutical effervescent agent ingredients (citric acid + sodium bicarbonate) (the mass ratio of the acid source to the base source in the effervescent agent ingredients was 1.76:1; the mass ratio of the effervescent agent ingredients to the drug was 5:1). The specific mixing method is as follows:

[0214] The effervescent agent ingredients were ground and sieved to obtain an effervescent agent with a diameter of 40 microns (the diameter refers to the D50 diameter of the effervescent agent powder particles obtained by sieving), and the effervescent agent and the liraglutide were mixed uniformly to obtain the mixture B.

[0215] (3) The mixture B was added to the uniformly mixed polymer cross-linking system (mixture A) to obtain the mixture C, wherein the proportion of the drug in the mixture C was 0.1% (mass ratio), the proportion of the effervescent agent was 0.5% (mass ratio), and the proportion of the polymer cross-linking system (mixture A) was 99.4% (mass ratio). The mixture C was mixed uniformly by vortexing. The obtained mixture C was added to the previously prepared microneedle mold, and the microneedle mold was filled with the mixture C by vacuum degassing (vacuum degassing for 20 minutes), and then pre-centrifuged at 4000 rpm for 2 minutes.

[0216] (4) The excess polymer mixed cross-linking system (mixture C) on the surface of the mold was removed, and pre-cross-linking was performed under ultraviolet conditions (ultraviolet intensity was 15 mW / cm 2 ) for 5 seconds. Then a small amount of NOA 86H liquid was added to the surface of the microneedles and evenly spread on the surface of the microneedles, and cross-linking was performed under ultraviolet conditions (ultraviolet intensity was 130 mW / cm 2 ) for 10 minutes. After the reaction was completed, the microneedles could be taken out of the mold.

[0217] Figure 3 Scanning electron microscope picture of the microneedle patch containing liraglutide and effervescent agent prepared for this example.

[0218] Example 4

[0219] A non-destructive removable chitosan cross-linked microneedle patch for fast release of liraglutide / insulin dual-target agonist, the preparation method comprising the following steps.

[0220] Micro-needle mold fine processing: polydimethylsiloxane prepolymer and curing agent (silane crosslinking agent) are mixed uniformly at room temperature with a mass ratio of 1:1, the mixture is filled into a four-prism-shaped micro-needle male mold (500 microns (bottom side length) * 700 microns (micro-needle tip spacing) * 1200 microns (micro-needle height)), and is degassed under vacuum conditions for 40 minutes, so that the mixture fills the micro-needle male mold, and then it is placed in a 70 degree Celsius oven for cross-linking and curing for 4 hours to form a polydimethylsiloxane micro-needle mold.

[0221] Chemical high molecular cross-linked micro-needle preparation:

[0222] (1) Prepare a uniform chitosan high molecular cross-linking system (5w / v% chitosan, the weight average molecular weight of chitosan is 400000g / mol) to obtain mixture A, 5w / v% refers to the weight (g) of chitosan high molecular in mixture A volume (mL) ratio, for example, 100 milliliters of water dissolves 5 grams of chitosan, and mixture A is prepared at this concentration.

[0223] (2) Mix liraglutide and insulin dual receptor agonists (specific drug types: liraglutide, insulin aspart, tirzepatide and Tirzepatide) and pharmaceutical effervescent agent ingredients (tartaric acid + sodium bicarbonate) (the mass ratio of acid source and alkali source in the effervescent agent ingredient is 2:1; the mass ratio of effervescent agent ingredient and drug is 10:1) uniformly in advance to obtain mixture B. The specific mixing method is as follows:

[0224] Grind the effervescent agent ingredient, sieve, and obtain 40 micron diameter (diameter refers to the D50 diameter of the effervescent agent powder particles obtained by sieving) effervescent agent, mix the effervescent agent, liraglutide and insulin receptor agonist uniformly to obtain mixture B.

[0225] (3) The mixture B is added to the above mixed polymer crosslinking system (mixture A) to obtain mixture C, wherein the drug accounts for 1% (mass ratio), the effervescent agent accounts for 10% (mass ratio), and the polymer crosslinking system (mixture A) accounts for 89% (mass ratio). The mixture C is fully mixed by vortex. The obtained mixture C is added to the previously prepared microneedle mold, and centrifuged at 4000 rpm for 2 minutes in advance, and then centrifuged at 4000 rpm for 10 minutes, so that the chitosan polymer crosslinking system fills the microneedle mold. Then, it is placed in a room temperature ventilated place and dried overnight to form solidified microneedles, and the solidified microneedle patch is taken out of the mold.

[0226] Example 5

[0227] A non-destructive removable DNA crosslinking microneedle patch of a rapid release degree of liraglutide / GIP / glucagon / insulin four-target agonist, the preparation method comprising the following steps.

[0228] Fine processing of the microneedle mold: the polydimethylsiloxane prepolymer and the curing agent (silane crosslinking agent) are fully stirred and mixed at room temperature at a mass ratio of 1:1, the mixture is filled into the microneedle male mold of the cone (500 microns (bottom diameter)*800 microns (microneedle tip spacing)*1500 microns (microneedle height)), and is degassed under vacuum conditions for 30 minutes to fill the mixture into the microneedle male mold. Then, it is placed in a 70 degree Celsius oven for crosslinking and curing for 1 hour to form a polydimethylsiloxane microneedle mold.

[0229] Chemical polymer crosslinking microneedle preparation:

[0230] (1) The DNA solution (deoxyribonucleic acid, natural DNA extracted from salmon sperm (the extraction method of DNA is a conventional method in the art), containing 20,000 base pairs, and the molecular weight is about 1.2 million g / mol) and the crosslinking agent PEGDA (polyethylene glycol (diol) diacrylate, molecular weight 550 g / mol) are mixed to obtain mixture A. The content of DNA in the mixture A can be 5 w / v% or 10 w / v%, for example, 10 w / v% means that the weight volume ratio of DNA in the mixture A is, for example, 100 milliliters of water dissolves 10 grams of DNA polymer crosslinking system, and the content of the crosslinking agent in the mixture A is 0.5 w / v% (weight (g) volume (mL) ratio).

[0231] (2) The liraglutide / GIP / glucagon / insulin four-receptor agonist (specific drug types: liraglutide, insulin aspart, tirzepatide and Tirzepatide) and the pharmaceutical effervescent agent component (malic acid + sodium carbonate) (the mass ratio of the acid source and the base source in the effervescent agent component is 1:2; the mass ratio of the effervescent agent component and the drug is 5:1) are previously mixed uniformly to obtain mixture B. The specific mixing method is as follows:

[0232] The effervescent ingredient was ground and sieved to obtain an effervescent agent having a diameter of 40 microns (the diameter refers to the D50 diameter of the effervescent agent powder particles obtained by sieving), and the effervescent agent, dulaglutide, a GIP receptor agonist, a glucagon receptor agonist, and an insulin receptor agonist were mixed to obtain a mixture B.

[0233] (3) The mixture B was added to the mixed polymer crosslinking system (mixture A) to obtain a mixture C, in which the drug accounted for 0.1% (mass ratio), the effervescent agent accounted for 0.5% (mass ratio), and the polymer crosslinking system (mixture A) accounted for 99.4% (mass ratio). The mixture C was mixed well by vortex. The obtained mixture C was added to the previously prepared microneedle mold, and centrifuged at 4000 rpm for 2 minutes in advance, and then centrifuged at 4000 rpm for 20 minutes, so that the DNA polymer crosslinking system filled the microneedle mold. Then, it was placed in a room temperature ventilated place and dried overnight to form a solidified microneedle, and the solidified microneedle patch was taken out of the mold.

[0234] Example 6

[0235] Fine processing of the microneedle mold: The polydimethylsiloxane prepolymer and the curing agent (silane crosslinking agent) were mixed well at room temperature in a mass ratio of 1:1, and the mixture was filled into a four-prism-shaped microneedle male mold (500 microns (bottom side length) * 700 microns (microneedle tip spacing) * 1200 microns (microneedle height)), and the mixture was degassed under vacuum for 30 minutes to fill the microneedle male mold. Then, it was placed in a 70-degree Celsius oven for crosslinking and curing for 3 hours to form a polydimethylsiloxane microneedle mold.

[0236] (1) Preparation method of microneedle A:

[0237] The ethylene pyrrolidone monomer (97 w / w%), the crosslinking agent ethylene glycol dimethacrylate (1.5 w / w%), and the photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5 w / w%) were mixed well by vortex to obtain a mixture A. The drug (0.01 w / w%) was added to the mixture. After being mixed well by vortex, it was added to the previously prepared microneedle mold, and the microneedle mold was filled by vacuum degassing for 10 minutes. Then, it was pre-centrifuged at 4000 rpm for 2 minutes.

[0238] The excess polymer mixed crosslinking system on the surface of the mold was removed, and pre-crosslinking was performed under ultraviolet conditions (ultraviolet intensity was 15 mW / cm 2 ) for 5 seconds. Then, a small amount of NOA 86H liquid was added to the surface of the microneedle to evenly cover the surface of the microneedle, and the microneedle was irradiated under ultraviolet conditions (ultraviolet intensity was 130 mW / cm2 ) irradiation for 10 minutes for crosslinking. After the reaction is completed, the microneedle can be taken out of the mold.

[0239] (2) Preparation method of microneedle B:

[0240] The ethylene pyrrolidone monomer (97% w / w%), crosslinking agent ethylene glycol dimethacrylate (1.5% w / w%) and photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5% w / w%) were mixed uniformly by vortex to obtain mixture A.

[0241] Liraglutide and pharmaceutical effervescent ingredient (citric acid + sodium bicarbonate) (the mass ratio of acid source and alkali source in the effervescent ingredient is 1:1.3; the mass ratio of effervescent ingredient and drug is 20:1) were mixed uniformly in advance to obtain mixture B. The effervescent ingredient was mixed with liraglutide and then directly added to mixture A. The effervescent ingredient was not subjected to a grinding process.

[0242] The remaining steps are the same as the preparation method of the chemical polymer crosslinked microneedle containing effervescent agent in (1).

[0243] (3) Microneedle C

[0244] The ethylene pyrrolidone monomer (97% w / w%), crosslinking agent ethylene glycol dimethacrylate (1.5% w / w%) and photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5% w / w%) were mixed uniformly by vortex to obtain mixture A.

[0245] The effervescent ingredient (citric acid + sodium bicarbonate) (the mass ratio of acid source and alkali source in the effervescent ingredient is 1:1.3) was ground and sieved to obtain an effervescent agent with a diameter of 40 microns (the diameter refers to the D50 diameter of the effervescent agent powder particles obtained by sieving). The effervescent agent was mixed with liraglutide (the mass ratio of effervescent ingredient and drug is 20:1) to obtain mixture B. Then, mixture B was mixed with mixture A, and the mixture was uniformly mixed by ultrasonic for 10 minutes to obtain mixture C. Mixture C was added to the microneedle mold prepared in advance, and centrifuged at 4000 rpm for 2 minutes in advance. In mixture C, the proportion of drug is 0.01% (w / w%), and the proportion of effervescent agent is 0.2% (w / w%).

[0246] The remaining steps are the same as the preparation method of the chemical polymer crosslinked microneedle containing effervescent agent in (1).

[0247] (4) The prepared microneedle A, microneedle B and microneedle C were immersed in a PBS buffer solution with the needle tip facing down to simulate their release in vitro. The release amount of liraglutide was detected by a BCA protein detection kit.

[0248] Figure 4 The in vitro release curves of the microneedles A, B, and C prepared in this example were obtained. From Figure 4 It can be seen from the above table that the processing method of introducing the effervescent agent into the microneedle is crucial to its in vitro release effect. The microneedle A is a microneedle patch without effervescent agent, the microneedle B is a microneedle patch containing effervescent agent (the microneedle B simply adds the effervescent agent to the microneedle mixture system), and the microneedle C is a microneedle patch containing effervescent agent (the effervescent agent in the microneedle C is ground before being added to the microneedle system, and the ground effervescent agent is sieved to obtain effervescent agent with a diameter of 40 microns).

[0249] The experimental results show that directly introducing the effervescent agent into the microneedle patch cannot significantly promote the release of the drug. The effervescent agent powder needs to be ground, evenly dispersed, and then concentrated by centrifugation (concentration refers to pre-centrifuging the mixture C at 4000 rpm for 2 minutes, and the effervescent agent component and the drug are centrifuged to the tip of the microneedle by centrifugation to make them concentrated) to achieve excellent rapid release effect. For specific data, see Figure 4 , Table 1.

[0250] Table 1

[0251]

[0252] The above experiments prove that the microneedle patch prepared by one of Examples 3-5 has similar drug release effect as the microneedle C of Example 6.

[0253] Example 7

[0254] A non-destructive removable polyvinylpyrrolidone cross-linked microneedle patch for rapid release of liraglutide has the following in vitro release, in vivo administration process, and efficacy in a type 2 diabetes mouse model.

[0255] 1) Preparation of microneedles containing effervescent agent concentrated by centrifugation: ethylene pyrrolidone monomer (97 w / w%), crosslinking agent ethylene glycol dimethacrylate (1.5 w / w%), and photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5 w / w%) were mixed uniformly by vortex to obtain mixture A.

[0256] Liraglutide and pharmaceutical effervescent agent components (citric acid + sodium bicarbonate) (the mass ratio of acid source to base source in the effervescent agent component is 1:1.3) were pre-mixed uniformly to obtain mixture B. The mass ratio of the effervescent agent component to the drug in mixture B was 1.0:1, 1.5:1, 2.0:1, and 3.0:1, respectively. The specific mixing method is as follows:

[0257] The effervescent ingredient was ground and sieved to obtain an effervescent with a diameter of 40 microns (diameter refers to the D50 diameter of the effervescent powder particles obtained by sieving), and the effervescent and liraglutide were mixed to obtain mixture B.

[0258] Mixture B was added to the mixed polymer crosslinking system (mixture A) to obtain mixture C, and microneedle patches containing different proportions of effervescent were prepared, wherein the drug accounted for 1% (w / w%), the effervescent accounted for 1.0%, 1.5%, 2.0% and 3.0% (w / w%) respectively, and the rest was the polymer crosslinking system (mixture A). The mixture was mixed by vortex. The obtained mixture was added to the pre-prepared microneedle mold, and the microneedle mold was filled by vacuum degassing (vacuum degassing time 2 min), and then the effervescent and drug filled in the microneedle were aggregated at the tip of the needle by pre-centrifugation at 4000 rpm for 2 min.

[0259] The excess polymer mixed crosslinking system (mixture C) on the surface of the mold was removed, and pre-crosslinking was performed under ultraviolet conditions (ultraviolet intensity 120 mW / cm 2 ) for 120 s. Then a small amount of NOA 86H liquid was added to the surface of the microneedle, and the microneedle surface was evenly spread, and crosslinking was performed under ultraviolet conditions (ultraviolet intensity 120 mW / cm 2 ) for 10 min. After the reaction was completed, the microneedle could be taken out of the mold.

[0260] 2) Preparation of chemical polymer crosslinked microneedles containing effervescent without centrifugal concentration: The remaining steps are the same as those of "1) Preparation of microneedles containing effervescent with centrifugal concentration". The specific different steps are as follows:

[0261] Mixture B was added to the mixed polymer crosslinking system (mixture A, same as 1) to prepare microneedle patches without effervescent, wherein the drug accounted for 1% (w / w%), and the effervescent accounted for 1.5% (w / w%). The mixture was mixed by vortex. The obtained mixture was added to the pre-prepared microneedle mold, and there was no centrifugation operation. The vacuum degassing, centrifugation and ultraviolet crosslinking curing methods were the same as those in 1).

[0262] 3) Preparation of chemical polymer crosslinked microneedles without effervescent without centrifugal concentration: The remaining steps are the same as those of "1) Preparation of microneedles containing effervescent with centrifugal concentration". The specific different steps are as follows:

[0263] Mixing mixture B into the mixed polymer cross-linking system (mixture A, same as 1) to prepare the micro-needle patch without effervescent agent, with the drug accounting for 1% (w / w%). Mix well by vortex. Add the resulting mixture into the pre-prepared micro-needle mold, without centrifugation, vacuum degassing and UV cross-linking curing, same as 1).

[0264] 4) Preparation of chemical polymer cross-linking micro-needle without effervescent agent by centrifugal concentration: the remaining steps are the same as "1) Preparation of micro-needle with effervescent agent by centrifugal concentration". The specific different steps are as follows:

[0265] Mixing mixture B into the mixed polymer cross-linking system (mixture A, same as 1) to prepare the micro-needle patch without effervescent agent, with the drug accounting for 1% (w / w%). Mix well by vortex. Add the resulting mixture into the pre-prepared micro-needle mold, without centrifugation, vacuum degassing and UV cross-linking curing, same as 1).

[0266] 5) Respectively, immerse the micro-needle patches prepared in 1), 2), 3) and 4) into PBS buffer solution to simulate their in vitro release, and detect the release amount of liraglutide by Coomassie brilliant blue. See Table 2, Table 3 for specific data. Figure 5 、 Figure 6 、Table 2, Table 3.

[0267] From Figure 5 , Table 2, it can be seen that the micro-needle containing 1.5 (w / w%) effervescent agent is the minimum effervescent agent dose under the fastest release rate, and from Figure 6 , Table 3, it can be seen that the micro-needle prepared by centrifugal concentration after sufficient dispersion of the effervescent agent (concentration refers to pre-centrifugation of mixture C at 4000 rpm for 2 minutes, and centrifugation of the effervescent agent component and the drug to the micro-needle tip by centrifugation to concentrate) can significantly improve the drug release rate.

[0268] Table 2

[0269]

[0270] Table 3

[0271]

[0272]

[0273] 6) In vitro release results observation: To observe the release rate difference of four groups of microneedles, including 1.5% effervescent agent centrifuged microneedles, 1.5% effervescent agent non-centrifuged microneedles, no effervescent agent centrifuged microneedles and no effervescent agent non-centrifuged microneedles, FITC-labeled liraglutide was used instead of ordinary liraglutide to add to the microneedles, and the fluorescence signal change of the microneedles in the phosphate buffer was observed by fluorescence microscope. For specific data, see Figure 7 .

[0274] As can be seen from Figure 7 , compared with the other three groups, the release rate of liraglutide in the microneedles containing 1.5% effervescent agent centrifuged was significantly faster.

[0275] 7) Mechanical strength test of microneedle patch: The microneedle patches containing different proportions of effervescent agent prepared in 1) were cut into 2x2 microneedle arrays, respectively, and fixed on the sample stage of the electric tensile testing machine, and the compression speed was set to 1.2 mm·min -1 . The force-displacement curve of the microneedles was recorded, and the results are shown in Figure 8 .

[0276] As can be seen from Figure 8 , with the increase of the proportion of effervescent agent, the mechanical strength of the microneedles will decrease, so it is necessary to select the formulation with the smallest proportion of effervescent agent under the condition of similar release rate. The formulation containing 1.5 w / w% effervescent agent is the preferred formulation.

[0277] 8) To determine whether the microneedles containing 1.5% effervescent agent centrifuged prepared in 1) can penetrate the skin, the mouse skin was taken out and the microneedle patch (containing 1.5% effervescent agent, centrifuged and concentrated chemical polymer cross-linked microneedle patch prepared in this embodiment) was pressed into the skin with fingers for 5s. After 1min, the microneedles were removed, and the puncture site was stained with trypan blue. The skin sample after puncture was stained with trypan blue dye for 3min, and then washed with distilled water to remove the surface floating color. The results showed that the microneedles could basically penetrate the mouse skin, and the specific results are shown in Figure 9 .

[0278] 9) Morphology observation of microneedles: The microneedle patches containing different proportions of effervescent agent prepared in 1) were released in PBS buffer according to the method described in 4), and the microneedle patches containing different proportions of effervescent agent prepared in 1) were removed from the mouse skin after the administration method in 7) was operated. After drying, the surface morphology was observed by scanning electron microscope, respectively. The results showed that the tip of the microneedles containing 1.5% effervescent agent centrifuged could form small cavities after in vitro release, and the structure of the microneedles used in vivo was not significantly damaged. The results are shown in Figure 10 .

[0279] 10) Drug activity test: In order to determine whether the conformation of the drug changes during the preparation of the microneedle, resulting in a decrease in drug activity, the circular dichroism spectrum data of the liraglutide solution released by the 1.5% effervescent agent-containing, centrifugally concentrated chemical polymer cross-linked microneedle of the present embodiment and the liraglutide solution released by the same concentration liraglutide were determined, and the hypoglycemic results of the two solutions when injected subcutaneously into a type 2 diabetes model mouse (db / db mouse) were determined. The results showed that the conformation of liraglutide in the released solution did not change significantly, and the hypoglycemic effect was consistent with that of the original liraglutide. Therefore, it is believed that the cross-linking process of the microneedle does not significantly affect the drug activity. For specific data, see Figure 11 , Figure 12 .

[0280] 11) Drug efficacy experiment: Male db / db mice were purchased from Hangzhou Ziyuan Experimental Animal Technology Co., Ltd. The mice were shaved on the back the day before the experiment, and then randomly divided into two groups of 5 mice each on the same day. After isoflurane anesthesia, the 1.5% effervescent agent-containing, centrifugally concentrated microneedle of the present embodiment and the microneedle without effervescent agent and without centrifugal concentration were pressed and inserted into the skin of the mouse back, respectively. After 5 minutes, they were removed, and the blood glucose values of the mice were determined at 0, 1, 2, 4, 6, 12, and 24 h, respectively. The results showed that the hypoglycemic effect of the 1.5% effervescent agent-containing, centrifugally concentrated microneedle group was significantly better than that of the microneedle without effervescent agent and without centrifugal concentration. For specific data, see Figure 13 , Table 4.

[0281] Table 4

[0282]

[0283] Note: In Table 4, “***” and “****” refer to the difference in blood glucose concentration between the 1.5% effervescent agent-containing, centrifugally concentrated microneedle and the microneedle without effervescent agent and without centrifugal concentration at the same time point by the non-paired t-test method. ***P < 0.001, ****P < 0.0001.

[0284] 12) Pharmacokinetic experiment: Male db / db mice were purchased from Hangzhou Ziyuan Experimental Animal Technology Co., Ltd. The mice were shaved on the back the day before the experiment, and then randomly divided into two groups of 5 mice each on the same day. After isoflurane anesthesia, the 1.5% effervescent agent-containing, centrifugally concentrated microneedle and the microneedle without effervescent agent and without centrifugal concentration were pressed and inserted into the skin of the mouse back, respectively. After 5 minutes, they were removed, and the blood glucose values of the mice were determined at 0, 1, 2, 4, 6, 12, and 24 h, respectively. The results showed that the hypoglycemic effect of the 1.5% effervescent agent-containing, centrifugally concentrated microneedle group was significantly better than that of the microneedle without effervescent agent and without centrifugal concentration. For specific data, see Figure 14 ( Figure 14 ), Table 5.

[0285] Table 5

[0286]

[0287]

[0288] Note: *** and **** in Table 5 refer to the difference in blood concentration between the micro-needles containing 1.5% effervescent agent centrifuged and the micro-needles without effervescent agent not centrifuged at the same time point by the non-paired t-test method of significance test, *** P < 0.001, **** P < 0.0001.

[0289] Although the specific embodiments of the present application are described above, those skilled in the art should understand that these are only illustrative, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present application. Therefore, the scope of protection of the present application is defined by the appended claims.

Claims

1. A polymer microneedle, characterized in that: It comprises a drug and a polymer skeleton, wherein the drug is loaded in the polymer skeleton; wherein: The drug is a GLP-1 receptor agonist or a composition containing a GLP-1 receptor agonist; The GLP-1 receptor agonist is one or more of exenatide, lixisenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, taseroglutide, benaglutide, dulaglutide, loxenatide and semaglutide; The polymer skeleton is insoluble in water, and the polymer skeleton is prepared from a system capable of undergoing cross-linking polymerization, wherein the system capable of undergoing cross-linking polymerization is a polymerizable system comprising a double bond-containing monomer, wherein the double bond-containing monomer is vinylpyrrolidone, and the system capable of undergoing cross-linking polymerization further comprises a cross-linking agent and / or an initiator; The polymer skeleton is in the shape of microneedles; The polymer skeleton is also loaded with an effervescent ingredient, which is a mixture of an acid source and an alkali source; the acid source is one or more of citric acid, malic acid, tartaric acid and fumaric acid; the alkali source is sodium bicarbonate, sodium carbonate or a mixture of the two; the mass ratio of the acid source to the alkali source is (0.1-3):1; the effervescent ingredient is in granular form, and the particle diameter of the effervescent ingredient is 30-50 microns; the effervescent ingredient is distributed at the needle tip of the polymer microneedle, and the mass ratio of the effervescent ingredient to the polymer microneedle is (0.001-0.1):1; the mass ratio of the drug to the effervescent ingredient is 1:(1-20).

2. The polymer microneedle according to claim 1, wherein The polymer microneedles meet one or more of the following conditions: ① The mass ratio of the drug to the polymer microneedle is (0.0001-0.1):1; ② The composition containing the GLP-1 receptor agonist meets one or more of the following conditions: i. The GLP-1 receptor agonist is one or more of exenatide, lixisenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, taseroglutide, benaglutide, dulaglutide, loxenatide and semaglutide; ii. The composition containing the GLP-1 receptor agonist further comprises one or more of an insulin receptor agonist, a glucagon receptor agonist and a GIP receptor agonist.

3. The polymer microneedle according to claim 2, wherein The GLP-1 receptor agonist is exenatide, lixisenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, taseroglutide, benaglutide or dulaglutide.

4. The polymer microneedle according to claim 2, wherein The mass ratio of the drug to the polymer microneedle is 0.0001:1, 0.001:1, 0.01:1 or 0.1:

1.

5. The polymer microneedle according to claim 2, wherein The GLP-1 receptor agonist-containing composition further comprises an insulin receptor agonist or a glucagon receptor agonist, or at least two of an insulin receptor agonist, a glucagon receptor agonist and a GIP receptor agonist.

6. The polymer microneedle according to claim 1, wherein The composition containing the GLP-1 receptor agonist includes a GLP-1 / GIP dual receptor agonist, a GLP-1 / insulin dual receptor agonist, a GLP-1 / glucagon dual receptor agonist, a GLP-1 / GIP / insulin triple receptor agonist, a GLP-1 / GIP / glucagon triple receptor agonist, a GLP-1 / glucagon / insulin triple receptor agonist or a GLP-1 / GIP / glucagon / insulin quadruple receptor agonist.

7. The polymer microneedle according to claim 1, wherein The crosslinking agent is ethylene glycol dimethacrylate.

8. The polymer microneedle according to claim 1, wherein The mass ratio of the double bond-containing monomer to the cross-linking agent is (95-105):1.

5.

9. The polymer microneedle according to claim 8, wherein The mass ratio of the double bond-containing monomer to the cross-linking agent is 97:1.

5.

10. The polymer microneedle according to claim 1, wherein The initiator is a photoinitiator.

11. The polymer microneedle according to claim 10, wherein The photoinitiator is 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone.

12. The polymer microneedle according to claim 1, wherein The mass ratio of the double bond-containing monomer to the initiator is (95-105):1.

5.

13. The polymer microneedle according to claim 12, wherein The mass ratio of the double bond-containing monomer to the initiator is 97:1.

5.

14. The polymer microneedle according to claim 1, wherein The polymer skeleton is prepared by the following method: in a microneedle mold, the system capable of undergoing cross-linking polymerization undergoes a cross-linking reaction to obtain the polymer skeleton; The cross-linking reaction is a chemical cross-linking reaction.

15. The polymer microneedle according to claim 14, wherein The cross-linking reaction is initiated by a photoinitiator under the conditions of ultraviolet intensity of 50-150 mW / cm 2 Irradiate for 5-30 minutes under the conditions of 16. The polymer microneedle according to claim 15, wherein At UV intensity of 50-150 mW / cm 2 Before irradiation for 5-30 min under the conditions of 2 Irradiate for 5-120s under the conditions of 17. The polymer microneedle according to claim 1, wherein The microneedle is a three-dimensional needle-like structure.

18. The polymer microneedle according to claim 17, wherein The three-dimensional needle-like structure is a cone, a quadrangular pyramid or a cuboid.

19. The polymer microneedle according to claim 1, wherein The height of the microneedles in the microneedle shape is 500-2000 microns.

20. The polymer microneedle according to claim 1, wherein The height of the microneedles in the microneedle shape is 500 microns, 1200 microns or 1500 microns.

21. The polymer microneedle according to claim 1, wherein When there are multiple microneedle-shaped structures, the distance between the microneedle tips is 100-1000 microns.

22. The polymer microneedle according to claim 21, wherein The microneedle tip spacing in the microneedle shape is 200 microns, 700 microns or 800 microns.

23. The polymer microneedle according to claim 1, wherein The particle diameter of the effervescent ingredient is 40 microns.

24. The polymer microneedle according to claim 1, wherein The acid source is citric acid, tartaric acid or malic acid.

25. The polymer microneedle according to claim 1, wherein The mass ratio of the acid source to the alkali source is 1.76:1, 2:1, 0.5:1 or 1:1.

3.

26. The polymer microneedle according to claim 1, wherein The effervescent ingredients are tartaric acid and sodium bicarbonate, citric acid and sodium bicarbonate, or malic acid and sodium carbonate.

27. The polymer microneedle according to claim 26, wherein When the effervescent ingredients are tartaric acid and sodium bicarbonate, the mass ratio of the acid source to the alkali source is (1.5-3):

1.

28. The polymer microneedle according to claim 27, wherein When the effervescent ingredients are tartaric acid and sodium bicarbonate, the mass ratio of the acid source to the alkali source is 2:

1.

29. The polymer microneedle according to claim 26, wherein When the effervescent ingredients are citric acid and sodium bicarbonate, the mass ratio of the acid source to the alkali source is (0.5-3):

1.

30. The polymer microneedle according to claim 29, wherein When the effervescent ingredients are citric acid and sodium bicarbonate, the mass ratio of the acid source to the alkali source is 1.76:1, 2:1 or 1:1.

3.

31. The polymer microneedle according to claim 26, wherein When the effervescent ingredients are malic acid and sodium carbonate, the mass ratio of the acid source to the alkali source is (0.1-1.0):

1.

32. The polymer microneedle according to claim 31, wherein When the effervescent ingredients are malic acid and sodium carbonate, the mass ratio of the acid source to the alkali source is 0.5:

1.

33. The polymer microneedle according to claim 1, wherein The mass ratio of the drug to the effervescent component is 1:1.0, 1:1.5, 1:2.0, 1:3.0, 1:5, 1:10 or 1:

20.

34. The polymer microneedle according to claim 1, wherein The mass ratio of the effervescent ingredient to the polymer microneedles is 0.002:1, 0.005:1, 0.01:1, 0.015:1, 0.02:1, 0.03:1 or 0.1:

1.

35. The polymer microneedle according to claim 2, wherein The exenatide in the GLP-1 receptor agonist is exenatide microspheres.

36. A method for preparing a polymer microneedle, characterized in that: It includes the following steps: 1) Mixing the drug according to any one of claims 1 to 6, the cross-linkable system according to any one of claims 1 and 7 to 22, and the effervescent component according to any one of claims 1 and 23 to 32 to obtain a mixture C, and filling the mixture C into a microneedle mold; after filling the microneedle mold and before the cross-linking reaction occurs, the mixture C is further subjected to centrifugal concentration; 2) In the microneedle mold, the cross-linkable system undergoes a cross-linking reaction to fix the "drug and the effervescent component" within the microneedle cavity to form a solidified microneedle; The effervescent component is distributed on the tip of the polymer microneedle, and the mass ratio of the effervescent component to the polymer microneedle is (0.001-0.1):1; the mass ratio of the drug to the effervescent component is 1:(1-20); The polymer skeleton formed after the cross-linking reaction of the cross-linkable polymerization system is insoluble in water.

37. The method for preparing a polymer microneedle according to claim 36, wherein: The method for preparing the polymer microneedle satisfies one or more of the following conditions: ① In step 1), when the raw material composition of the microneedle preparation further includes an effervescent component, and the cross-linkable polymerization system further includes a cross-linking agent and / or an initiator, the mixture C is prepared by the following method: Mixing the components of the cross-linkable polymerization system to obtain a mixture A; Mixing the drug and the effervescent component to obtain a mixture B; Mixing the mixture A and the mixture B to obtain a mixture C; ② In step 1), the mixture C fills the microneedle mold; the filling method is microinjection, vacuum degassing or centrifugation; And ③ in step 2), the cross-linking reaction is a chemical cross-linking reaction.

38. The method for preparing a polymer microneedle according to claim 37, wherein: The mixture B was added to the mixture A and mixed to obtain a mixture C.

39. The method for preparing a polymer microneedle according to claim 36, wherein: The centrifugal concentration treatment was performed at 4000 rpm for 2 minutes.

40. The method for preparing a polymer microneedle according to claim 37, wherein: The vacuum degassing time is 1 min-1 h.

41. The method for preparing a polymer microneedle according to claim 37, wherein: The vacuum degassing time is 20-30 minutes.

42. The method for preparing a polymer microneedle according to claim 37, wherein: The centrifugal conditions are 1000-5000 rpm and 1-30 min.

43. The method for preparing a polymer microneedle according to claim 37, wherein: The centrifugal conditions are 4000 rpm and 10 min or 20 min.

44. The method for preparing a polymer microneedle according to claim 37, wherein: The centrifugal condition is that after the filling, the mixture C is also pre-centrifuged; The pre-centrifugation conditions are 3000-5000 rpm and centrifugation for 1-5 min.

45. The method for preparing a polymer microneedle according to claim 44, wherein: The pre-centrifugation conditions are 4000 rpm and centrifugation for 2 minutes.

46. ​​The method for preparing a polymer microneedle according to claim 37, wherein: The cross-linking reaction is initiated by a photoinitiator under the conditions of ultraviolet intensity of 50-150 mW / cm 2 Irradiate for 5-30 minutes under the conditions of 47. A polymer microneedle, characterized in that It is prepared by the preparation method described in any one of claims 36 to 46.

48. A microneedle sheet, characterized in that The method comprises a plurality of polymer microneedles according to any one of claims 1 to 34 and 47 and a plate on which the polymer microneedles stand and are arranged.

49. A method for preparing a microneedle sheet, characterized in that: It is prepared by the following method 1 or method 2: Method 1: The polymer microneedles according to any one of claims 1 to 34 and 47 are connected into a plate through a rigid or flexible material; Method 2: S1: mixing the drug according to any one of claims 1 to 6, the cross-linkable system according to any one of claims 1 and 7 to 22, and the effervescent component according to any one of claims 1 and 23 to 32 to obtain a mixture C, and filling the mixture C into a microneedle mold; after the mixture C is filled into the microneedle mold and before the cross-linking reaction occurs, the mixture C is further subjected to a centrifugal concentration treatment; S2: Adding an adhesive to the surface of the microneedle mold; in the microneedle mold, the cross-linkable system undergoes a cross-linking reaction, fixing the "drug and the effervescent component" in the microneedle cavity to form a solidified microneedle; The effervescent component is distributed on the tip of the polymer microneedle, and the mass ratio of the effervescent component to the polymer microneedle is (0.001-0.1):1; the mass ratio of the drug to the effervescent component is 1:(1-20); The polymer skeleton formed after the cross-linking reaction of the cross-linkable polymerization system is insoluble in water.

50. A microneedle sheet, characterized in that It is prepared by the preparation method as claimed in claim 49.

51. A polymer material, characterized in that The invention comprises a drug and a polymer skeleton, wherein the polymer skeleton is in the shape of microneedles and the drug is loaded in the polymer skeleton; wherein: The drug is a GLP-1 receptor agonist or a composition containing a GLP-1 receptor agonist; The GLP-1 receptor agonist is one or more of exenatide, lixisenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, taseroglutide, benaglutide, dulaglutide, loxenatide and semaglutide; The polymer skeleton is insoluble in water, and the polymer skeleton is prepared from a system capable of undergoing cross-linking polymerization, wherein the system capable of undergoing cross-linking polymerization is a polymerizable system comprising a double bond-containing monomer, wherein the double bond-containing monomer is vinylpyrrolidone, and the system capable of undergoing cross-linking polymerization further comprises a cross-linking agent and / or an initiator; The polymer skeleton is also loaded with an effervescent ingredient, which is a mixture of an acid source and an alkali source; the acid source is one or more of citric acid, malic acid, tartaric acid and fumaric acid; the alkali source is sodium bicarbonate, sodium carbonate or a mixture of the two; the mass ratio of the acid source to the alkali source is (0.1-3):1; the effervescent ingredient is in granular form, and the particle diameter of the effervescent ingredient is 30-50 microns; the effervescent ingredient is distributed at the needle tip of the polymer microneedle, and the mass ratio of the effervescent ingredient to the polymer microneedle is (0.001-0.1):1; the mass ratio of the drug to the effervescent ingredient is 1:(1-20).

52. The polymer material of claim 51, wherein The polymer material meets one or more of the following conditions: ① The GLP-1 receptor agonist is the GLP-1 receptor agonist according to any one of claims 2 to 6; ② The composition containing a GLP-1 receptor agonist is a composition containing a GLP-1 receptor agonist according to any one of claims 2 to 6; ③ The mass ratio of the drug to the polymer material is (0.0001-0.1):1; ④ The polymer backbone is a polymer backbone as described in any one of claims 7 to 22; and ⑤ the effervescent ingredient is the effervescent ingredient as described in claims 23-34.

53. The polymer material of claim 52, wherein The mass ratio of the drug to the polymer material is 0.0001:1, 0.001:1, 0.01:1 or 0.1:

1.

54. A delivery system for a GLP-1 receptor agonist, characterized in that: It comprises the polymer microneedle according to any one of claims 1 to 34 and 47, the microneedle sheet according to claim 48 or 50, or the polymer material according to claims 51 to 53.

55. Use of the polymer microneedle according to any one of claims 1-34 and 47, the microneedle sheet according to claim 48 or 50, the polymer material according to claims 51-53, and the delivery system of the GLP-1 receptor agonist according to claim 54 in preparing a drug for treating diabetes.

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