CN116421544A

CN116421544A - Polymer microneedle, microneedle sheet, delivery system containing polymer microneedle sheet, preparation method and application of polymer microneedle sheet

Info

Publication number: CN116421544A
Application number: CN202211486244.6A
Authority: CN
Inventors: 顾臻; 张宇琪; 俞计成; 韩金鹏; 游嘉欢
Original assignee: Zhejiang University ZJU
Current assignee: Zhejiang University ZJU
Priority date: 2022-01-13
Filing date: 2022-11-24
Publication date: 2023-07-14

Abstract

The invention discloses a polymer microneedle, a microneedle sheet, a delivery system containing the polymer microneedle and the microneedle sheet, a preparation method and application. The polymer microneedle comprises a drug and a polymer skeleton, wherein the drug is loaded in the polymer skeleton; wherein: the medicament is a GLP-1 receptor agonist or a composition containing the GLP-1 receptor agonist; the polymer backbone is insoluble in water; the polymer skeleton is micro needle; preferably, the polymer matrix also has an effervescent component supported therein. The microneedle patch comprises a plurality of polymeric microneedles and a plate on which the polymeric microneedles stand and are disposed. The micro-needle can be inserted and used at once, so that the blood sugar level of a type 2 diabetic patient can be intelligently reduced, and the blood sugar balance is maintained; the method has the advantages of simple operation and low cost, and the macromolecule crosslinked microneedle patch can be removed nondestructively after release is finished, and can further load medicinal effervescent components in the microneedle, so that the rapid release of GLP-1 receptor agonists or compositions can be realized.

Description

Polymer microneedle, microneedle sheet, delivery system containing polymer microneedle sheet, preparation method and application of polymer microneedle sheet

The present application claims priority from chinese patent application CN202210038385.5 on application day 2022, month 01, and day 13. The present application refers to the entirety of the above-mentioned chinese patent application.

Technical Field

The invention relates to the field of drug delivery and microneedle sheets, in particular to a polymer microneedle, a microneedle sheet, a delivery system containing the polymer microneedle and the microneedle sheet, a preparation method and application.

Background

Type 2 diabetes is a chronic disease with unknown etiology, the number of patients accounts for 90% -95% of the total number of diabetics, and the physical health and the quality of life of people are seriously endangered. In recent decades, the incidence of type 2 diabetes mellitus is rapidly increased through multiple investigation results of epidemiology in China, and the incidence of the type 2 diabetes mellitus is reduced and divided into multiple areas.

Currently, GLP-1 (glucagon-like peptide-1, GLP-1) receptor agonists or compositions containing them are considered to be more successful clinical first-line drugs, capable of effectively controlling blood glucose levels in type 2 diabetics and exerting a weight-reducing effect. The GLP-1 receptor agonist administration mode is mainly subcutaneous injection and oral administration, and although the preparations play a high-efficiency role in controlling blood sugar level, the preparation is still faced with a plurality of barriers which are difficult to overcome in practical use as a preparation form for long-term use.

In particular, subcutaneous formulations tend to give patients a greater pain on injection, while liquid formulations tend to require lower temperature storage and are inconvenient to carry and use daily in actual situations such as travel. Although the oral preparation has better compliance of patients and is convenient to use and carry, the utilization rate of the medicine is extremely low, so that a great deal of medicine is wasted, and the curative effect is severely limited.

Thus, the development of a microneedle (e.g., microneedle patch) formulation has shown great market potential for alleviating the pain of patients for long-term injection and improving the drug availability. Considering that the GLP-1 receptor agonist is an autonomous in vivo response drug, can intelligently respond to the in vivo blood sugar level, and is an in vivo response blood sugar regulating drug with clinical use value more than insulin or glucagon. For this reason, it would be of great market value to develop a microneedle patch (e.g., microneedle patch) that can be used to release GLP-1 receptor agonists or compositions containing them as a surrogate for both of the above existing formulations.

Disclosure of Invention

The invention aims to overcome the defects that a GLP-1 receptor agonist or a composition containing the GLP-1 receptor agonist is inconvenient to use or low in drug utilization rate in the prior art, and provides a polymer microneedle, a microneedle sheet, a delivery system containing the polymer microneedle and a preparation method and application of the polymer microneedle. The microneedle patch (e.g., microneedle patch) for transdermal delivery of GLP-1 receptor agonists or compositions containing the same provided by the invention can be plug and play, and can be removed intact after transdermal administration. The microneedle patch can be used for treating type 2 diabetes or obesity, has good compliance to patients, is convenient to use and carry, and has high drug utilization rate; rapid release of GLP-1 receptor agonists or compositions containing them may also be achieved.

GLP-1 analogues are a type of in vivo intelligent blood sugar regulating medicament, which can not cause blood sugar level change even if accumulated in a large amount in vivo for a short time (compared with medicines such as insulin and the like which can induce fatal hypoglycemia if the content is too high), based on the characteristics of the medicines, rapid release of GLP-1 is realized, and the GLP-1 is accumulated in vivo, so that the blood sugar content is regulated for a long time, so that the GLP-1 analogues are one of the technical problems to be solved in the field. More importantly, the rapid release of the GLP-1 analog (e.g., in minutes to tens of minutes) allows the microneedle to be removed from the body quickly, avoiding the needle material remaining in the body, and eliminating the need for long-term application of the microneedle to the skin, improving patient comfort and reducing the risk of inflammation induced by long-term application.

In the prior art, in order to realize quick release of the drug, a soluble polymer microneedle is generally adopted, and release of the protein drug is realized through dissolution of the microneedle, but the release mode can leave the microneedle body in a patient body, and inflammation and the like are easy to induce. The micro-needle adopts the cross-linking technical means to creatively combine the effervescent agent component with the micro-needle without dissolving the polymer micro-needle, thereby realizing quick release of the medicine, and also being capable of pulling out the micro-needle from the body after the medicine is released, and taking the safety and the medicine effect of the micro-needle into consideration.

The inventors also want to emphasize that the release of protein drugs is generally limited and slow release is easily achieved due to the cross-linked structure in the microneedles of the present invention. The invention creatively combines the effervescent agent component and the microneedle skeleton, thereby realizing the rapid release of the drug loaded in the crosslinked microneedle. Moreover, the effervescent agent is a conventional medicinal ingredient and has high biological safety.

The invention aims at realizing the following technical scheme:

a polymeric microneedle comprising a drug and a polymeric backbone, the drug being supported in the polymeric backbone; wherein:

the medicament is a GLP-1 receptor agonist or a composition containing the GLP-1 receptor agonist;

the polymer backbone is insoluble in water;

the polymer skeleton is micro needle-shaped;

preferably, the polymer matrix also has an effervescent component supported therein.

In the present invention, the GLP-1 receptor agonist may be a GLP-1 receptor agonist conventional in the art, such as one or more of exenatide, risperidin, liraglutide, abiratide, dulraglutide, tasraglutide, benraglutide, loxenaide, cable Ma Lutai and dulragide, and further such as exenatide, exenatide microsphere, risraglutide, liraglutide, abiraglutide, dulragide, tasragide, benraglutide, loxenade, cable Ma Lutai or dulragide, and further such as liraglutide or dulragide.

In the present invention, the GLP-1 receptor agonist-containing composition refers to a pharmaceutical composition including a GLP-1 receptor agonist, which may be a pharmaceutical composition having a synergistic therapeutic effect.

Wherein the GLP-1 receptor agonist may be as described previously.

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

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

The glucagon receptor agonist may be a glucagon peptide.

The GIP receptor agonist may be one or more of gili XW003 drug, telipopeptide, tirzepatide, "exendin-4 and derivatives thereof," and SCO-094, such as gili XW003 drug, telipopeptide, tirzepatide, "exendin-4 and derivatives thereof," or SCO-094.

Wherein the GLP-1 receptor agonist-containing composition may comprise 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 tri-receptor agonist, a GLP-1/GIP/glucagon tri-receptor agonist, a GLP-1/glucagon/insulin tri-receptor agonist, or a GLP-1/GIP/glucagon/insulin tetra-receptor agonist. Here, "/" means the relationship of "and", i.e., GLP-1/GIP dual receptor agonists refer to agonists that contain both GLP-1 receptor agonists and GIP receptor agonists, or agonists that are capable of agonizing both GLP-1 receptor and GIP receptor.

In the present invention, preferably, the drug is liraglutide, "liraglutide, insulin aspart, telipopeptide and Tirzepatide," or "liraglutide, insulin aspart, telipopeptide and Tirzepatide.

In the present invention, the polymer skeleton may be a microneedle-shaped polymer skeleton obtained by physical crosslinking or chemical crosslinking.

Wherein the physical cross-links may be cross-links produced by physical interactions of hydrogen bonds and/or ionic bonds.

Wherein the chemical crosslinking may be chemical crosslinking by covalent bonds.

According to the invention, the polymer skeleton can improve the mechanical stability of the microneedle, so that the microneedle can be removed without damage after being inserted into skin, and the microneedle body is not remained in the body. The polymer skeleton is the category of the invention as long as the microneedle patch can be pulled out without damage after being attached to the skin.

In the present invention, the polymer backbone is generally made from a cross-polymerizable system, which may be one or more of a cellulose-containing system, a chitosan-containing system, a chitin-containing system, a polyvinyl alcohol-containing system, a DNA-containing system, a fibroin-containing system, and a polymer-containing system based on double bond-containing monomers, such as a polyvinyl alcohol-containing system, a polymerizable system containing double bond-containing monomers, a chitosan-containing system, or a DNA-containing system.

Wherein, the system capable of cross-linking polymerization can be hydrophilic or water-soluble under certain conditions, but forms a water-insoluble cross-linked structure after physical or chemical cross-linking treatment.

Wherein, in the system comprising the polyvinyl alcohol, the polyvinyl alcohol may be a polyvinyl alcohol conventional in the art, for example, a polyvinyl alcohol having a weight average molecular weight of 50000 to 200000g/mol, and further for example, a polyvinyl alcohol having a weight average molecular weight of 100000 g/mol.

Wherein the system comprising polyvinyl alcohol may be an aqueous solution of polyvinyl alcohol. The mass concentration of the polyvinyl alcohol in the aqueous solution of the polyvinyl alcohol may be 10 to 30w/v%, for example 20w/v%.

In the mass concentration, 1w/v% means that 100 ml of water contains 1 g of polyvinyl alcohol.

Wherein, in the polymerizable system containing the double bond-containing monomer, the double bond-containing monomer can be one or more of vinyl pyrrolidone, acrylamide, acrylic acid, dimethylaminoethyl acrylate, m-aminophenylboric acid, ethylene glycol dimethacrylate, dimethylaminoethyl methacrylate, methacrylic acid, glycidyl acrylate and polyethylene glycol diacrylate, such as vinyl pyrrolidone.

When the polymer backbone is made from a polymerizable system of double bond containing monomers, a crosslinking agent and/or an initiator may also be included in the polymerizable system of double bond containing monomers.

The crosslinking agent may be a crosslinking agent conventional in the art, for example, when the double bond-containing monomer is vinylpyrrolidone, the crosslinking agent may be ethylene glycol dimethacrylate.

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

The initiator may be a conventional initiator in the art, for example, when the double bond containing monomer is vinylpyrrolidone, the initiator may be a photoinitiator. The photoinitiator may be 2-hydroxy-4- (2-hydroxyethoxy) -2-methylpropionyl ketone (I2959).

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

The mass ratio of the double bond containing monomer, the crosslinking agent and the initiator may be 97:1.5:1.5.

Wherein, in the system comprising chitosan, the chitosan can be chitosan conventional in the art, such as chitosan with weight average molecular weight of 200000-600000g/mol, and further such as chitosan with weight average molecular weight of 400000 g/mol.

Wherein the chitosan-containing system may be an aqueous solution of chitosan. The mass concentration of the chitosan in the aqueous solution of chitosan may be 1-10w/v%, for example 5w/v%.

In the mass concentration, 1w/v% means that 100 ml of water contains 1 g of chitosan.

Wherein, in the system comprising DNA, the DNA may be DNA conventional in the art, such as natural DNA extracted from salmon sperm. The weight average molecular weight of the DNA may be 80 to 150 thousand g/mol, for example 120 or 150 thousand g/mol.

Wherein the system comprising DNA may be an aqueous solution of DNA. The mass concentration of the DNA in the aqueous solution of the DNA may be 1 to 20w/v%, for example 5w/v% or 10w/v%.

In the above mass concentration, 1w/v% means that 100 ml of water contains 1 g of DNA.

When the polymer scaffold is made from a DNA-containing system, a cross-linking agent and/or initiator may also be included in the DNA-containing system. The crosslinking agent may be a crosslinking agent conventional in the art, for example, the crosslinking agent may be polyethylene glycol (diol) diacrylate (PEGDA).

The mass ratio of the DNA to the crosslinking agent may be (1-100): 1, for example 10:1 or 20:1.

Wherein the system capable of undergoing cross-linking polymerization can determine the 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.

The physical cross-links may be cross-links that occur through physical interactions such as hydrogen bonding, ionic bonding, and the like.

When the system in which cross-linking polymerization can occur is a system comprising polyvinyl alcohol and/or a system comprising chitosan, the cross-linking means may be physical cross-linking.

The chemical cross-links are generally cross-links that form covalent bonds by copolymerization.

When the crosslinking means is chemical crosslinking, the crosslinking agent and/or initiator may be selected according to the kind of polymer or monomer contained.

The crosslinking agent may be a crosslinking agent conventional in the art, for example, when the crosslinkable polymeric system is a polymerizable system comprising a double bond-containing monomer (e.g., comprising vinylpyrrolidone), the crosslinking agent may be ethylene glycol dimethacrylate. For another example, when the cross-linkable polymeric system is a system comprising DNA, the cross-linking agent may be polyethylene glycol (diol) diacrylate (PEGDA).

The initiator may be conventional in the art, for example, when the cross-linkable polymerization system is a polymerizable system comprising a double bond containing monomer (e.g., comprising vinylpyrrolidone), the cross-linking agent may be a photoinitiator, for example, 2-hydroxy-4- (2-hydroxyethoxy) -2-methylpropenode (I2959).

For example, when the crosslinkable system is a polymerizable system comprising a monomer having a double bond, a crosslinking agent and/or an initiator is further included in the crosslinkable system.

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

Wherein, the polymer skeleton can be prepared by the following method: and (3) in the microneedle mould, the system capable of undergoing cross-linking polymerization is subjected to cross-linking reaction, and the preparation is obtained.

The crosslinking reaction may be a physical crosslinking reaction or a chemical crosslinking reaction.

When the crosslinking reaction is a physical crosslinking reaction, the time of the crosslinking reaction may be 12 to 24 hours.

When the crosslinking reaction is a chemical crosslinking reaction and the crosslinking reaction is initiated by a photoinitiator, the conditions of the crosslinking reaction may be such that the ultraviolet intensity is 50 to 150mW/cm ² (e.g. 120-140mW/cm ² Also for example 130mW/cm ² ) Is irradiated for 5 to 30 minutes (e.g., 10 minutes).

Wherein the ultraviolet intensity is 50-150mW/cm ² (e.g. 120-140mW/cm ² Also for example 130mW/cm ² ) Before irradiation for 5-30min (e.g. 10 min), the crosslinkable system may also be pre-crosslinked in the microneedle mould, e.g. at an ultraviolet intensity of 10-150mW/cm ² (e.g., 10-20 mW/cm) ² Also for example 15mW/cm ² ) For 5-120s (e.g., 1-30s, also e.g., 120 s).

After the pre-crosslinking treatment, an optical adhesive, such as a NOA 86H liquid, may be added to the pre-crosslinked polymeric microneedle skin layer.

In the present invention, the drug being supported in the polymer skeleton generally means that the drug is dispersed in the polymer skeleton and uniformly or unevenly distributed on the surface and/or inside of the polymer skeleton.

In the present invention, the mass ratio of the drug to the polymeric microneedle may be (0.0001-0.1): 1, for example, 0.0001:1, 0.001:1, 0.01:1, or 0.1:1.

In the present invention, the micropin generally refers to a three-dimensional needle-like structure such as a cone, a quadrangular pyramid, or a rectangular parallelepiped.

Wherein the height of the microneedles in the microneedles may be of a height conventional in the art, such as 500-2000 microns, further such as 500 microns, 1200 microns or 1500 microns.

Wherein, when the microneedle structure is a plurality, the microneedle tip pitch in the microneedle may be a conventional microneedle tip pitch in the art, such as 100-1000 microns, further such as 200 microns, 700 microns, or 800 microns.

Wherein, when the microneedle is a cone, the diameter of the bottom surface of the microneedle in the microneedle may be 200-800 micrometers, for example, 500 micrometers.

Wherein, when the microneedle is a quadrangular pyramid, the side length of the bottom surface of the microneedle in the microneedle may be 200-800 micrometers, for example, 500 micrometers.

In the present invention, the effervescent ingredients may be effervescent ingredients conventional in the art, for example, comprising a mixture of an acid source and an alkali source.

Wherein, preferably, the effervescent ingredient is in the form of granules, the granules of the effervescent ingredient having a diameter of 30-50 microns (which diameter corresponds to the D50 particle size of the effervescent granule), for example 40 microns. The effervescent ingredients may be ground and sieved to obtain a diameter of 30-50 microns.

Wherein the acid source may be a source of acids conventional in the art, such as one or more of citric acid, malic acid, boric acid, tartaric acid, fumaric acid, and hydrochloric acid, further such as one or more of citric acid, tartaric acid, and malic acid, further such as citric acid, tartaric acid, or malic acid.

Wherein the alkali source may be an alkali source conventional in the art, such as sodium bicarbonate, sodium carbonate or a mixture of both, for example sodium bicarbonate or sodium carbonate.

Wherein the mass ratio of the acid source and the alkali source may be (0.1-3): 1, such as 1.76:1, 2:1, 0.5:1 or 1:1.3.

Wherein the effervescent ingredients may be tartaric acid and sodium bicarbonate, citric acid and sodium bicarbonate, or malic acid and sodium carbonate.

When the effervescent ingredients are tartaric acid and sodium bicarbonate, the mass ratio of the acid source to the base source may be (1.5-3): 1, for example 2:1.

When the effervescent ingredients are citric acid and sodium bicarbonate, the mass ratio of the acid source to the base source may be (0.5-3): 1, such as 1.76:1, 2:1 or 1:1.3.

When the effervescent ingredients are malic acid and sodium carbonate, the mass ratio of the acid source to the base source may be (0.1-1.0): 1, for example 0.5:1.

Wherein the mass ratio of the drug to the effervescent ingredient may 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.

Wherein the ratio of the mass of the effervescent ingredient to the mass of the polymeric microneedle may be (0.001-0.1): 1, for example 0.002:1, 0.005:1, 0.01:1, 0.015:1, 0.02:1, 0.03:1 or 0.1:1.

In the present invention, the effervescent ingredient is supported in the polymer skeleton generally means that the effervescent ingredient is dispersed in the polymer skeleton and uniformly or unevenly distributed on the surface and/or inside of the polymer skeleton.

In the present invention, preferably, the effervescent ingredient is distributed at the tip portion of the polymer microneedle.

In the present invention, the microneedle patch (e.g., microneedle patch) can achieve rapid release when an effervescent component is also included in the polymer matrix. In particular, the GLP-1 receptor agonist or the composition containing the GLP-1 receptor agonist can be released within 1-60 minutes, and the release amount of the GLP-1 receptor agonist or the composition containing the GLP-1 receptor agonist reaches 20% -100%.

The invention also provides a raw material composition, which comprises the following components: a drug and a cross-linkable polymeric system, the drug being a GLP-1 receptor agonist or a composition comprising a GLP-1 receptor agonist;

preferably, the raw material composition further comprises an effervescent ingredient;

optionally, a crosslinking agent and/or an initiator are also included in the system in which crosslinking polymerization can occur.

Wherein the GLP-1 receptor agonist may be as described previously.

Wherein the GLP-1 receptor agonist-containing composition may be as described previously.

Wherein the cross-linkable polymeric system may be as described previously.

Wherein the particle size, type, amount, etc. of the effervescent ingredients may be as described above.

Wherein, preferably, the effervescent ingredient has a diameter of 30-50 microns, for example 40 microns. The effervescent ingredients may be ground and sieved to obtain a diameter of 30-50 microns.

Wherein, the type and the amount of the cross-linking agent can be as described above.

Wherein, the type and the amount of the initiator can be as described above.

The invention also provides a preparation method of the polymer microneedle, which comprises the following steps:

1) Mixing the medicine and the system capable of undergoing cross-linking polymerization to obtain a mixture C, and filling the mixture C into a microneedle mould;

when the raw material composition of the microneedle preparation further comprises an effervescent agent component, mixing the drug, the cross-linking polymerizable system and the effervescent agent component to obtain a mixture C, and filling the mixture C into a microneedle mould;

2) In the microneedle mould, the system capable of undergoing cross-linking polymerization undergoes cross-linking reaction, and the medicine or the medicine and the effervescing agent component are fixed in a microneedle cavity to form a solidified microneedle;

the polymer skeleton formed by the cross-linking reaction of the cross-linking polymerizable system is insoluble in water.

In step 1), when the starting composition of the microneedle preparation further includes an effervescent ingredient and the crosslinkable system further includes a crosslinking agent and/or an initiator, the mixture C may be prepared by the following method:

Mixing the components in the system capable of undergoing cross-linking polymerization to obtain a mixture A;

mixing the medicine and the effervescent agent to obtain a mixture B;

and mixing the mixture A and the mixture B to obtain a mixture C.

Wherein the mixture B can be added into the mixture A to be mixed to obtain a mixture C.

In step 1), when the raw material composition of the microneedle preparation further comprises an effervescent agent component, after the mixture C is filled into the microneedle mould, the mixture C may be further subjected to centrifugal concentration before the crosslinking reaction.

Wherein the conditions for the centrifugal concentration treatment may be centrifugation at 4000rpm for 2 minutes.

In step 1), the mixture C may fill the microneedle mould.

Wherein the filling method can be microinjection, vacuum degassing or centrifugation.

The vacuum degassing time may be 1min-1h, for example 2min, for example 20min or 30min.

The centrifugation conditions may be centrifugation conditions conventional in the art, for example, 2000-5000rpm, centrifugation for 1-20min, and further, for example, 4000rpm, centrifugation for 10min or 20min.

Wherein, after the filling, the mixture C may also be subjected to a pre-centrifugation treatment.

The conditions for the pre-centrifugation may be 3000-5000rpm, centrifugation for 1-5min, e.g. 4000rpm, centrifugation for 2min.

In step 2), the crosslinking reaction may be a physical crosslinking reaction or a chemical crosslinking reaction.

Wherein the ultraviolet intensity is 50-150mW/cm ² (e.g. 120-140mW/cm ² Also for example 130mW/cm ² ) Before irradiation for 5-30min (e.g. 10 min), the crosslinkable system may also be pre-crosslinked in the microneedle mould, e.g. at an ultraviolet intensity of 10-150mW/cm ² (e.g., 10-20 mW/cm) ² Also for example 15mW/cm ² ) Under conditions of 5-120s (e.g. 1-30s, also exemplified)Such as 5 s).

After the pre-crosslinking treatment, the pre-crosslinked polymeric microneedle surface layer may be added with an adhesive, such as an optical adhesive, and also such as a NOA 86H liquid. The adhesive may interconnect individual microneedles to form a complete microneedle patch.

The invention also provides a polymer microneedle which is prepared by the preparation method.

The present invention also provides a microneedle sheet comprising a plurality of the polymeric microneedles and a plate on which the polymeric microneedles stand and are arranged.

Wherein the polymeric material of the polymeric microneedles and the plates may be the same or different.

The polymeric material of the sheet may be hydrophilic or water-soluble under certain conditions, but is subjected to a physical or chemical crosslinking treatment to form a water-insoluble crosslinked structure.

Wherein, in the microneedle patch, the microneedle tip pitch may be a microneedle tip pitch conventional in the art, for example, 100-1000 microns, further for example, 200 microns, 700 microns, or 800 microns.

The invention also provides a preparation method of the micro-needle slice, which is prepared by the following method one or the method two:

the method comprises the following steps:

connecting a plurality of polymer microneedles into a plate through a rigid or flexible material;

the second method is as follows:

s1: mixing the medicine and the system capable of undergoing cross-linking polymerization to obtain a mixture C, and filling the mixture C into a microneedle mould;

S2: adding an adhesive on the surface of the microneedle mould; in the microneedle mould, the system capable of undergoing cross-linking polymerization undergoes cross-linking reaction, and the medicine or the medicine and the effervescing agent component are fixed in a microneedle cavity to form a solidified microneedle;

In step S1, the preparation method of the mixture C may be as described above.

In step S1, the method of filling the microneedle mould with the mixture C may be as described above.

In step S2, the crosslinking reaction may be as described above.

In step S2, the adhesive may be of a type conventional in the art, such as an optical adhesive, and further such as NOA 86H liquid. The adhesive may interconnect individual microneedles to form a complete microneedle patch.

The invention also provides a microneedle sheet prepared by the preparation method.

The present invention also provides a polymeric material comprising a drug and a polymeric backbone, the drug being supported in the polymeric backbone; wherein:

The polymer backbone is insoluble in water;

Wherein the GLP-1 receptor agonist may be as described previously.

Wherein the mass ratio of the drug to the polymeric material may be (0.0001-0.1): 1, for example 0.0001:1, 0.001:1, 0.01:1 or 0.1:1

Wherein the polymer backbone may be as described previously.

Wherein the particle size, type and amount of the effervescent ingredients may be as described above.

The invention also provides a preparation method of the polymer material, which comprises the following steps:

mixing the raw material composition, and forming the water-insoluble polymer material through crosslinking.

The invention also provides a delivery system for a GLP-1 receptor agonist comprising a polymeric microneedle, microneedle sheet or polymeric material as described above.

The GLP-1 receptor agonist delivery system can be in the form of a tablet or a roller.

The invention also provides application of the polymer microneedle, the microneedle sheet, the polymer material and the GLP-1 receptor agonist delivery system in preparation of drugs for treating diabetes.

The invention also provides a method of treating diabetes comprising administering to a subject the polymeric microneedle, the microneedle patch, the polymeric material, or the delivery system of a GLP-1 receptor agonist.

On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that:

1. the invention provides a microneedle patch which can be used by plug and play, can be rapidly administered, has no other components except medicines, and can rapidly and intelligently reduce the blood sugar level of a type 2 diabetes patient and maintain blood sugar balance by released GLP-1 receptor agonist or composition. The microneedle patch is insoluble in use, can be removed intact after use, does not leave microneedle material in vivo, and greatly ensures the safety of using the patch for patients.

2. The microneedle patch is used for loading GLP-1 receptor agonists or compositions, and can further load medicinal effervescent components in the microneedles to realize rapid release of the GLP-1 receptor agonists or compositions, rapidly and stably reduce blood sugar level in vivo, maintain blood sugar balance and treat type 2 diabetes or obesity.

3. The administration mode of the microneedle patch (such as the microneedle patch) can obviously relieve the administration pain of patients, and simultaneously ensures higher drug availability, thereby being an administration mode which has both patient compliance and drug availability.

4. The microneedle patch provided by the invention has the advantages of simple preparation mode, low cost, portability, good biocompatibility, and capability of rapidly releasing GLP-1 receptor agonist or composition in a transdermal administration mode, and can be removed without damage after release, thus being an administration system with convenient use, high comfort and great clinical transformation potential. In addition, the medicine is used in the form of a microneedle patch, so that the storage time of the medicine under the room temperature condition can be remarkably prolonged.

Drawings

Fig. 1 is an optical microscope photograph of the conical microneedle patch prepared in example 1.

Fig. 2 is an optical microscope photograph of the quadrangular pyramid-shaped microneedle patch prepared in example 2.

Fig. 3 is a scanning electron microscope picture of the microneedle patch containing liraglutide and effervescent agent prepared in example 3.

Fig. 4 is an in vitro drug release profile of the microneedle patch A, B, C prepared in example 6.

Fig. 5 is an in vitro drug release profile of microneedle patches of varying effervescent content prepared in example 7.

Fig. 6 is an in vitro drug release profile of microneedle patches obtained by different preparation procedures in example 7.

FIG. 7 is an in vitro release fluorescence micrograph of a microneedle patch obtained from the different preparation procedures of example 7.

Fig. 8 is a graph showing the mechanical properties of the microneedle patches of varying effervescent content prepared in example 7.

FIG. 9 is a chart showing the results of an in vitro transdermal test of a centrifuged microneedle patch containing 1.5% effervescent agent prepared in example 7.

Fig. 10 shows the surface morphology of the microneedle patches of different effervescent content prepared in example 7 before, after and after use.

FIG. 11 is a circular dichroism spectrum of liraglutide released from 1.5% effervescent tablet containing 1.5% effervescent agent by centrifugation and crude liraglutide prepared in example 7.

FIG. 12 shows the hypoglycemic effect of 1.5% effervescent preparation in the case of example 7 in mice with type II diabetes, by releasing liraglutide from the micro-needle tablet by centrifugation.

FIG. 13 is a graph showing the hypoglycemic effect of 1.5% effervescent centrifuged and non-effervescent centrifuged microneedles prepared in example 7 in type II diabetic mice.

FIG. 14 is a graph showing the in vivo pharmacokinetic profile of 1.5% effervescent centrifuged and non-effervescent centrifuged microneedles prepared in example 7 in type II diabetic mice.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

In the following examples and comparative examples:

the preparation method of the microneedle mould comprises the following steps:

the preparation method comprises the steps of fully stirring and uniformly mixing a polydimethylsiloxane prepolymer and a curing agent (silane crosslinking agent) according to a mass ratio of (1:10-10:1) (for example, 1:1) at room temperature, filling the mixture into a microneedle mould, wherein the specific shape and size of a microneedle can be selected according to practical situations, for example, a quadrangular pyramid-shaped or conical microneedle male mould, for example, a conical microneedle male mould (500 micrometers (bottom surface diameter) 800 micrometers (microneedle tip distance) 1500 micrometers (microneedle height)), degassing under vacuum for 20min-2 hours (for example, 30 min), filling the mixture into the microneedle male mould, and then placing the microneedle male mould in an oven at 50-100 ℃ for crosslinking and curing for 0.5-24 hours to form the polydimethylsiloxane microneedle mould.

Preparing a chemical macromolecule crosslinking microneedle:

mixing proper amount of medicine (GLP-1 receptor agonist or composition containing the same) and effervescent agent component (such as medicinal effervescent component) in advance to obtain mixture A, adding the mixture A into bio-based polymer system mixture B (the bio-based polymer system contains a polymerizable system, optionally a cross-linking agent and/or initiator), vortex mixing to uniformly distribute the mixture C, adding the mixture C into a pre-prepared microneedle mould, and filling the microneedle mould with the bio-based polymer system containing the medicine by adopting a vacuum degassing or centrifuging method. Thereafter, a crosslinking reaction (e.g., physical crosslinking or chemical crosslinking) of the bio-based polymer system within the microneedle mould secures the "GLP-1 receptor agonist or composition comprising the same" and the pharmaceutical effervescent ingredient within the microneedle cavity to form a cured microneedle, and removing it from the microneedle mould.

All the polymer crosslinking systems in the invention can be prepared into the nondestructive removable microneedle patch capable of rapidly releasing GLP-1 receptor agonist or composition containing the GLP-1 receptor agonist by adopting the method.

In the following examples and comparative examples:

GLP-1 receptor agonists: liraglutide, CAS number 204656-20-2; dolapride, available from danish and nod corporation;

Insulin receptor agonists: non-peptide or polypeptide small molecule compounds such as L-783,281 or insulin aspart;

glucagon receptor agonists: glucagon peptides;

GIP receptor agonists: gift XW003 drug, telipopeptide, tirzepatide, exendin-4 and its derivative, SCO-094;

GIP receptor agonists and glucagon dual receptor agonists: telipopeptide, exendin-4 and derivatives thereof;

GLP-1 and GIP receptor agonists: SCO-094, tirzepatide;

GLP-1 and glucagon receptor agonists: SAR425899.

The invention will be further described with reference to specific examples and figures.

Example 1

A method for preparing a non-destructive removable polyvinyl alcohol microneedle patch comprises the following steps.

Fine processing of a microneedle mould: the preparation method comprises the following steps of (1) mixing a polydimethylsiloxane prepolymer with a curing agent (silane cross-linking agent) according to a mass ratio of 1:1, fully stirring and uniformly mixing at room temperature, filling the mixture into a conical microneedle male mold (500 micrometers (bottom diameter) ×800 micrometers (microneedle tip distance) ×1500 micrometers (microneedle height)), degassing under vacuum for 30 minutes, filling the mixture into the microneedle male mold, and then placing the mixture into a 70 ℃ oven for crosslinking and curing for 6 hours to form the polydimethylsiloxane microneedle mold.

Preparing a chemical macromolecule crosslinking microneedle:

a uniformly mixed polyvinyl alcohol polymer crosslinking system (20 w/v%, weight average molecular weight: 100000 g/mol) is prepared to obtain a mixture A, wherein 20w/v% refers to the weight (g) to volume (mL) ratio of polyvinyl alcohol polymer in the mixture A, for example, 100 mL of water is used to dissolve 20 g of polyvinyl alcohol.

The mixture A is added into a pre-prepared microneedle mould, and the mixture A is centrifuged for 10 minutes at a rotation speed of 4000rpm, so that the microneedle mould is filled with the polyvinyl alcohol polymer crosslinking system. Thereafter, it was left at room temperature in a vented place, dried overnight to form cured microneedles, and the cured microneedle patches were removed from the mold.

Fig. 1 is an optical microscope photograph of the microneedle prepared in this example.

Example 2

A method for preparing a non-destructive polyvinylpyrrolidone-crosslinked microneedle patch comprises the following steps.

Fine processing of a microneedle mould: the preparation method comprises the following steps of (1) mixing a polydimethylsiloxane prepolymer with a curing agent (silane cross-linking agent) according to a mass ratio of 1:1, fully stirring and uniformly mixing at room temperature, filling the mixture into a quadrangular microneedle male die (500 micrometers (side length of bottom surface) 700 micrometers (distance between microneedle tips) 1200 micrometers (height of microneedles)), degassing under vacuum for 20 minutes, filling the mixture into the microneedle male die, and then placing the mixture into a 70 ℃ oven for crosslinking and curing for 2 hours to form the polydimethylsiloxane microneedle mould.

Preparing a chemical macromolecule crosslinking microneedle:

(1) Uniformly mixing a vinyl pyrrolidone monomer (97 w/w%), a crosslinking agent ethylene glycol dimethacrylate (1.5 w/w%) and a photoinitiator I2959 (2-hydroxy-4- (2-hydroxyethoxy) -2-methyl propiophenone) (1.5 w/w%) in a vortex manner to obtain a mixture A; wherein the proportion of the vinyl pyrrolidone monomer, the initiator and the crosslinking agent refers to the mass percent of the vinyl pyrrolidone monomer, the initiator and the crosslinking agent in the total mass of the monomer, the initiator and the crosslinking agent (namely, the total mass of the mixture A).

(2) Adding the polymer crosslinking system (mixture A) into a pre-prepared microneedle mould, filling the microneedle mould with the polyvinyl alcohol polymer crosslinking system by adopting a vacuum degassing method, and carrying out vacuum degassing for 30 minutes. Removing excessive polymer crosslinking system on the surface layer of the mold under ultraviolet (ultraviolet intensity of 15 mW/cm) ² ) The pre-crosslinking was performed by irradiation for 5 seconds.

(3) Adding a small amount of NOA 86H liquid (NOA 86H liquid is Nolan optical adhesive, available from Nolan Norlan, model NOA 86H) onto the microneedle surface layer, uniformly spreading the microneedle surface layer, and applying ultraviolet light (with ultraviolet intensity of 130 mW/cm) ² ) The crosslinking was carried out by irradiation for 10 minutes. After the reaction is completed, the microneedle can be removed from the mold.

Fig. 2 is an optical microscope image of the microneedle prepared in this example.

Example 3

A method for preparing a non-destructive polyvinylpyrrolidone crosslinked microneedle patch capable of rapidly releasing liraglutide comprises the following steps.

Fine processing of a microneedle mould: the preparation method comprises the following steps of (1) mixing a polydimethylsiloxane prepolymer with a curing agent (silane cross-linking agent) according to a mass ratio of 1:1, fully stirring and uniformly mixing at room temperature, filling the mixture into a quadrangular micro-needle male die (500 micrometers (side length of bottom surface) 700 micrometers (distance between micro-needle tips) 1200 micrometers (height of micro-needle)), degassing under vacuum for 30 minutes, filling the mixture into the micro-needle male die, and then placing the mixture into a 70 ℃ oven for crosslinking and curing for 3 hours to form the polydimethylsiloxane micro-needle die.

Preparing a chemical macromolecule crosslinking microneedle:

(1) Uniformly mixing vinyl pyrrolidone monomer (97 w/w%), crosslinking agent ethylene glycol dimethacrylate (1.5 w/w%) and photoinitiator I2959 (2-hydroxy-4- (2-hydroxyethoxy) -2-methyl propiophenone) (1.5 w/w%) in a vortex manner to obtain a mixture A, wherein the proportion of the vinyl pyrrolidone monomer, the initiator and the crosslinking agent refers to the mass percentage of the vinyl pyrrolidone monomer, the initiator and the crosslinking agent in the total mass of the monomer, the initiator and the crosslinking agent (namely, the total mass of the mixture A).

(2) The liraglutide and medicinal effervescent ingredients (citric acid and sodium bicarbonate) (the mass ratio of acid source and alkali source in the effervescent ingredients is 1.76:1, and the mass ratio of effervescent ingredients and medicines is 5:1) are mixed uniformly in advance to obtain a mixture B. The specific mixing method is as follows:

grinding and sieving effervescent components to obtain effervescent agent with diameter of 40 μm (diameter refers to D50 diameter of effervescent powder granule obtained by sieving), and mixing effervescent agent and liraglutide uniformly to obtain mixture B.

(3) Adding the mixture B into the uniformly mixed polymer crosslinking system (mixture A) to obtain a mixture C, wherein the mixture C is prepared by the following steps: the medicine accounts for 0.1 percent (mass ratio), the effervescent agent accounts for 0.5 percent (mass ratio), and the polymer crosslinking system (mixture A) accounts for 99.4 percent (mass ratio). Thoroughly mixed by vortex. The resulting mixture C was added to a microneedle mould prepared in advance, and was filled in the microneedle mould by vacuum degassing (vacuum degassing for 20 minutes), followed by centrifugation at 4000rpm for 2 minutes.

(4) Removing excessive polymer mixed crosslinking system (mixture C) on the surface layer of the mold, and removing the polymer mixed crosslinking system under ultraviolet (with ultraviolet intensity of 15 mW/cm) ² ) The pre-crosslinking was performed by irradiation for 5 seconds. Adding a little NOA 86H liquid into the surface layer of the micro-needle, spreading the surface layer of the micro-needle uniformly, and applying the solution under ultraviolet condition (ultraviolet intensity is 130 mW/cm) ² ) The crosslinking was carried out by irradiation for 10 minutes. After the reaction is completed, the microneedle can be removed from the mold.

Fig. 3 is a scanning electron microscope image of a microneedle patch containing liraglutide and effervescent agent prepared in this example.

Example 4

A non-destructive chitosan crosslinked microneedle patch capable of rapidly releasing liraglutide/insulin dual-target agonist, and its preparation method comprises the following steps.

Fine processing of a microneedle mould: the preparation method comprises the following steps of (1) mixing a polydimethylsiloxane prepolymer with a curing agent (silane cross-linking agent) according to a mass ratio of 1:1, fully stirring and uniformly mixing at room temperature, filling the mixture into a quadrangular microneedle male die (500 micrometers (side length of bottom surface) 700 micrometers (distance between microneedle tips) 1200 micrometers (height of microneedles)), degassing under vacuum for 40 minutes, filling the mixture into the microneedle male die, and then placing the mixture into a 70 ℃ oven for crosslinking and curing for 4 hours to form the polydimethylsiloxane microneedle mould.

Preparing a chemical macromolecule crosslinking microneedle:

(1) A uniform chitosan polymer crosslinking system (5 w/v% chitosan, weight average molecular weight of chitosan is 400000 g/mol) is prepared to obtain a mixture A,5w/v% refers to the weight (g) to volume (mL) ratio of chitosan polymer in the mixture A, for example, 100 milliliters of water is used for dissolving 5 grams of chitosan, and the mixture A is prepared at the concentration.

(2) The liraglutide and the insulin dual receptor agonist (specific medicine types are liraglutide, insulin aspart, telpoAN and Tirzepatide) are pre-mixed uniformly to obtain a mixture B, wherein the medicinal effervescent component (tartaric acid and sodium bicarbonate) comprises an acid source and an alkali source in the effervescent component in a mass ratio of 2:1, and the effervescent component and the medicine in a mass ratio of 10:1. The specific mixing method is as follows:

grinding and sieving effervescent components to obtain effervescent agent with diameter of 40 μm (diameter refers to D50 diameter of effervescent powder granule obtained by sieving), and mixing effervescent agent, liraglutide and insulin receptor agonist uniformly to obtain mixture B.

(3) Adding the mixture B into the uniformly mixed polymer crosslinking system (mixture A) to obtain a mixture C, wherein the mixture C is prepared by the following steps: the medicine accounts for 1 percent (mass ratio), the effervescent agent accounts for 10 percent (mass ratio), and the high molecular crosslinking system (mixture A) accounts for 89 percent (mass ratio). Thoroughly mixed by vortex. The resulting mixture C was added to a pre-prepared microneedle mould, pre-centrifuged at 4000rpm for 2 minutes, and then centrifuged at 4000rpm for 10 minutes to fill the microneedle mould with the chitosan polymer crosslinking system. Thereafter, it was left at room temperature in a vented place, dried overnight to form cured microneedles, and the cured microneedle patches were removed from the mold.

Example 5

A DNA cross-linked microneedle patch capable of rapidly releasing dolapride/GIP/glucagon/insulin four-target agonist without damage is prepared by the following steps.

Fine processing of a microneedle mould: the preparation method comprises the following steps of (1) mixing a polydimethylsiloxane prepolymer with a curing agent (silane cross-linking agent) according to a mass ratio of 1:1, fully stirring and uniformly mixing at room temperature, filling the mixture into a conical microneedle male die (500 micrometers (bottom diameter) ×800 micrometers (microneedle tip distance) ×1500 micrometers (microneedle height)), degassing under vacuum for 30 minutes, filling the mixture into the microneedle male die, and then placing the mixture into a 70 ℃ oven for crosslinking and curing for 1 hour to form the polydimethylsiloxane microneedle mould.

Preparing a chemical macromolecule crosslinking microneedle:

(1) The DNA solution (deoxyribonucleic acid, natural DNA extracted from salmon sperm (DNA extraction method is conventional in the art), contains 20000 base pairs, and has a molecular weight of about 120 ten thousand g/mol), and a crosslinking agent PEGDA (polyethylene glycol) diacrylate, and has a molecular weight of 550 g/mol) is mixed to obtain a mixture A. Wherein the content of DNA in the mixture A may be 5w/v% or 10w/v%, for example 10w/v%, means the weight-to-volume ratio of DNA in the mixture A, for example 100 mL of water to dissolve 10 g of the DNA polymer crosslinking system, and the content of the crosslinking agent in the mixture A is 0.5w/v% (weight (g) to volume (mL).

(2) The dolapride/GIP/glucagon/insulin four receptor agonist (specific medicine types are dolapride, insulin aspart, telipopeptide and Tirzepatide) and medicinal effervescent agent component (malic acid and sodium carbonate) (the mass ratio of acid source and alkali source in the effervescent agent component is 1:2, and the mass ratio of the effervescent agent component and medicine is 5:1) are pre-mixed uniformly to obtain a mixture B. The specific mixing method is as follows:

grinding and sieving effervescent components to obtain effervescent agent with diameter of 40 μm (diameter refers to D50 diameter of effervescent powder granule obtained by sieving), and mixing effervescent agent, dolapride, GIP receptor agonist, glucagon receptor agonist and insulin receptor agonist uniformly to obtain mixture B.

(3) Adding the mixture B into the uniformly mixed polymer crosslinking system (mixture A) to obtain a mixture C, wherein the mixture C is prepared by the following steps: the medicine accounts for 0.1 percent (mass ratio), the effervescent agent accounts for 0.5 percent (mass ratio), and the polymer crosslinking system (mixture A) accounts for 99.4 percent (mass ratio). Thoroughly mixed by vortex. The resulting mixture C was added to a previously prepared microneedle mould, centrifuged at 4000rpm for 2 minutes, and then centrifuged at 4000rpm for 20 minutes, so that the microneedle mould was filled with the DNA polymer crosslinking system. Thereafter, it was left at room temperature in a vented place, dried overnight to form cured microneedles, and the cured microneedle patches were removed from the mold.

Example 6

(1) The preparation method of the microneedle A comprises the following steps:

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-methyl propiophenone) (1.5 w/w%) were mixed uniformly by vortex to obtain mixture A. Drug (0.01 w/w%) was added to the mixture. Mixing thoroughly by vortex, adding into a pre-prepared microneedle mould, filling the microneedle mould by vacuum degassing method, vacuum degassing for 10 min, and pre-centrifuging at 4000rpm for 2 min.

Removing excessive polymer mixed crosslinking system on the surface layer of the mold, and removing the polymer mixed crosslinking system under ultraviolet condition (ultraviolet intensity is 15mW/cm ² ) The pre-crosslinking was performed by irradiation for 5 seconds. Adding a little NOA 86H liquid into the surface layer of the micro-needle, spreading the surface layer of the micro-needle uniformly, and applying the solution under ultraviolet condition (ultraviolet intensity is 130 mW/cm) ² ) The crosslinking was carried out by irradiation for 10 minutes. After the reaction is completed, the microneedle can be removed from the mold.

(2) The preparation method of the microneedle B comprises the following steps:

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-methyl propiophenone) (1.5 w/w%) were mixed uniformly by vortex to obtain mixture A.

The method comprises the steps of pre-mixing liraglutide and a medicinal effervescent ingredient (citric acid and sodium bicarbonate) (the mass ratio of an acid source to an alkali source in the effervescent ingredient is 1:1.3, and the mass ratio of the effervescent ingredient to a medicine is 20:1) uniformly to obtain a mixture B, mixing the effervescent ingredient and the liraglutide, directly adding the mixture A, and carrying out no grinding process on the effervescent.

The rest steps are the same as the preparation method of the chemical polymer crosslinking microneedle containing the effervescent agent in the step (1).

(3) Microneedle C

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-methyl propiophenone) (1.5 w/w%) were mixed uniformly by vortex to obtain mixture A.

Grinding effervescent agent component (citric acid and sodium bicarbonate) (the mass ratio of acid source and alkali source in the effervescent agent component is 1:1.3), sieving to obtain effervescent agent with diameter of 40 μm (diameter refers to D50 diameter of effervescent agent powder granule obtained by sieving), mixing effervescent agent and liraglutide (the mass ratio of effervescent agent component and medicine is 20:1) uniformly to obtain mixture B, mixing mixture B with mixture A, ultrasonic mixing for 10 min to obtain mixture C, adding mixture C into pre-prepared microneedle mould, and pre-centrifuging at 4000rpm for 2 min. In mixture C: the medicine accounts for 0.01% (w/w%), and the effervescent agent accounts for 0.2% (w/w%).

(4) And immersing the prepared micro needle A, micro needle B and micro needle C with the needle tip downwards into PBS buffer solution to simulate the release condition of the micro needle A, micro needle B and micro needle C in vitro, and detecting the release amount of the liraglutide by using the BCA protein detection kit.

Fig. 4 shows in vitro release curves of the drugs of the microneedles a, B, and C prepared in this example. As can be seen from fig. 4, the manner of processing the effervescent agent into the microneedle is critical to the in vitro release effect, and the microneedle a is a microneedle patch without effervescent agent, and the microneedle B is a microneedle patch with effervescent agent (the microneedle B simply adds the effervescent agent into the microneedle mixing system), and the microneedle C is a microneedle patch with effervescent agent (the effervescent agent in the microneedle C is ground before being added into the microneedle system, and the grinding and sieving are performed to obtain an effervescent agent with a D50 of 40 μm diameter).

Experimental results indicate that the direct introduction of the effervescent agent into the microneedle patch does not significantly promote drug release. The effervescent powder is required to be ground, fully dispersed and uniformly concentrated by centrifugation (concentration means that the mixture C is centrifuged at 4000rpm for 2 minutes in advance, and the effervescent component and the drug are centrifuged to the tip of the microneedle by centrifugation, so that the effervescent component and the drug are concentrated) to achieve an excellent rapid release effect. See fig. 4, table 1 for specific data.

TABLE 1

The above experiments demonstrate that the microneedle patch prepared in one of examples 3 to 5 has a similar drug release effect as the microneedle C of example 6.

Example 7

A non-destructive polyvinylpyrrolidone crosslinked microneedle patch for rapidly releasing liraglutide has the following in-vitro release condition, in-vivo administration process and drug effect in a type II diabetes mouse model.

1) Preparation of microneedles containing effervescent agents concentrated by centrifugation: 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-methyl propiophenone) (1.5 w/w%) were mixed uniformly by vortex to obtain mixture A.

The liraglutide and the medicinal effervescent ingredient (citric acid and sodium bicarbonate) (the mass ratio of acid source and alkali source in the effervescent ingredient is 1:1.3) are pre-mixed uniformly to obtain a mixture B, and the mass ratio of the effervescent ingredient to the medicine in the mixture B is 1.0:1, 1.5:1, 2.0:1 and 3.0:1 respectively. The specific mixing method is as follows:

Adding the mixture B into the uniformly mixed polymer crosslinking system (mixture A) to obtain a mixture C, and preparing micro-needle tablets containing different effervescent agent proportions, wherein: the medicine accounts for 1% (w/w%), the effervescent agent accounts for 1.0%, 1.5%, 2.0% and 3.0% (w/w), respectively, and the balance is the polymer crosslinking system (mixture A). Thoroughly mixed by vortex. The resulting mixtures were respectively added to a microneedle mould prepared in advance, and the microneedle mould was filled with the mixture by vacuum degassing (vacuum degassing time 2 min), and then the mixture was centrifuged at 4000rpm for 2min in advance to cause the effervescent agent and the drug filled with the microneedles to be accumulated at the tip portion.

Removing excessive polymer mixed crosslinking system (mixture C) on the surface layer of the mold, and removing the polymer mixed crosslinking system under ultraviolet (ultraviolet intensity of 120 mW/cm) ² ) The pre-crosslinking was performed by irradiation for 120 s. Adding a little NOA 86H liquid into the surface layer of the micro-needle, spreading the surface layer of the micro-needle uniformly, and applying ultraviolet light (with ultraviolet intensity of 120 mW/cm) ² ) The crosslinking was carried out by irradiation for 10 minutes. After the reaction is completed, the microneedle can be removed from the mold.

2) The chemical polymer crosslinking microneedle containing the effervescent agent and not subjected to centrifugal concentration is prepared by the following steps: the steps are the same as "1) preparation of the concentrated effervescent-agent-containing microneedle by centrifugation" except for the following steps. The specific and different steps are as follows:

the mixture B was added to a well-mixed polymer crosslinking system (mixture A, same as in 1) to prepare a microneedle tablet without effervescent agent, wherein the drug was 1% (w/w%) and the effervescent agent was 1.5% (w/w%). Thoroughly mixed by vortex. The resulting mixture was added to a microneedle mould prepared in advance, without centrifugation, vacuum degassing, centrifugation and uv cross-linking solidification in the same manner as in 1).

3) The preparation method of the chemical polymer crosslinking microneedle without effervescent agent and centrifugal concentration comprises the following steps: the steps are the same as "1) preparation of the concentrated effervescent-agent-containing microneedle by centrifugation" except for the following steps. The specific and different steps are as follows:

the mixture B was added to a well-mixed polymer crosslinking system (mixture A, same as in 1) to prepare a microneedle patch without effervescent agent, wherein the drug content was 1% (w/w%). Thoroughly mixed by vortex. The resulting mixtures were separately added to a microneedle mould prepared in advance, without centrifugation, and vacuum degassing and uv crosslinking curing were carried out in the same manner as in 1).

4) The preparation method comprises the following steps of (1) preparing a chemical polymer crosslinking microneedle without effervescent agent through centrifugal concentration: the steps are the same as "1) preparation of the concentrated effervescent-agent-containing microneedle by centrifugation" except for the following steps. The specific and different steps are as follows:

the mixture B was added to the above-mentioned well-mixed polymer crosslinking system (mixture A, same as 1) to prepare a microneedle sheet containing no effervescent agent, wherein the drug content was 1% (mass ratio). Thoroughly mixed by vortex. The resulting mixture was added to a microneedle mould prepared in advance, and vacuum deaeration, centrifugation and uv cross-linking curing were carried out in the same manner as in 1).

5) The microneedle patches prepared in 1), 2), 3) and 4) were immersed in PBS buffer solution with the tip facing downwards to simulate the release conditions in vitro, and the release amount of liraglutide was detected by coomassie brilliant blue, and specific data are shown in fig. 5, 6, table 2 and table 3.

From fig. 5 and table 2, it can be seen that the micro-needle contains 1.5 (w/w%) of effervescent agent, which is the minimum effervescent agent dosage at the fastest release rate, and from fig. 6 and table 3, it can be seen that the micro-needle prepared by dispersing the effervescent agent sufficiently and uniformly, and then centrifuging and concentrating (concentrating means that the mixture C is centrifuged at 4000rpm for 2 minutes in advance, and the effervescent agent component and the drug are centrifuged to the tip of the micro-needle by centrifugation, so that the drug release rate can be significantly improved).

TABLE 2

TABLE 3 Table 3

6) In vitro release results observations: to observe the difference in drug release rates of the microneedle containing 1.5% effervescent agent and concentrated by centrifugation, the microneedle containing 1.5% effervescent agent and not concentrated by centrifugation, the microneedle containing no effervescent agent and not concentrated by centrifugation, the group 4 microneedles were added with FITC-labeled liraglutide instead of ordinary liraglutide, and their changes in fluorescence signals in phosphate buffer were observed with a fluorescence microscope, see fig. 7 for specific data.

As can be seen from fig. 7, the release rate of liraglutide in the centrifuged microneedles containing 1.5% effervescent agent was significantly faster than the other three groups.

7) Mechanical strength test of microneedle patch: taking the micro-needle sheets prepared in 1) and containing different effervescent agent proportions, respectively cutting into 2×2 micro-needle arrays, fixing on an objective table of an electric tension experiment machine, and setting the compression speed to be 1.2mm & min ^-1 The force-displacement curve of the microneedle was recorded and the results are shown in figure 8.

As can be seen from FIG. 8, as the effervescent ratio increases, the mechanical strength of the microneedle decreases, and therefore the formulation with the smallest effervescent ratio is selected with similar release rates, with a 1.5w/w% effervescent formulation being the preferred formulation.

8) To determine whether the 1.5% effervescent agent-containing centrifuged microneedle fabricated in 1) penetrated the skin, the skin of the isolated mice was obtained by pressing the microneedle sheet (the 1.5% effervescent agent-containing centrifugally concentrated chemically polymeric crosslinked microneedle sheet prepared in this example) with a finger to penetrate the skin for 5s, leaving for 1min, removing the microneedle, staining the puncture site with trypan blue, staining the skin sample after the puncture with trypan blue dye solution for 3min, rinsing with distilled water, and removing the surface flooding, and the results showed that the microneedle could penetrate substantially all the skin of the isolated mice, with reference to fig. 9.

9) Microneedle morphology observation: the micro-needle tablet containing different effervescent agent ratios prepared in 1) is released in PBS buffer solution according to the method described in 4), and the micro-needle tablet containing different effervescent agent ratios prepared in 1) is removed from the skin of a mouse after being operated according to the method of 7), and the surface morphology is respectively observed by a scanning electron microscope after drying, so that the micro-needle tip containing 1.5% of effervescent agent after in vitro release can form a small cavity after in vitro release, and the micro-needle structure after in vivo use is not damaged obviously, and the result is shown in figure 10.

10 Drug activity test): in order to determine whether the conformation of the drug is changed in the manufacturing process of the microneedle, so that the activity of the drug is reduced, circular dichroism spectrum data and hypoglycemic results of mice (db/db mice) with type II diabetes models are measured by taking the liraglutide with the same concentration and 1.5% of effervescent agent and the liraglutide solution released by centrifugally concentrated chemical macromolecule crosslinked microneedle, and the results show that the conformation of the liraglutide in the release liquid is not obviously changed and is consistent with the hypoglycemic effect of the original liraglutide, so that the crosslinking process of the microneedle is considered to not have obvious influence on the activity of the drug, and specific data are shown in fig. 11 and 12.

11 Efficacy experiment): male db/db mice were purchased from Hangzhou Susource laboratory animal technologies Inc., the backs of the mice were dehaired the day before the experiment, the day was divided into two groups of 5 mice, each group was anesthetized with isoflurane, the 1.5% effervescent agent, the centrifugally concentrated microneedles and the non-centrifugally concentrated microneedles without effervescent agent in this example were pressed into the back skin of the mice, and after 5 minutes were removed, the blood glucose values of the mice were measured at 0, 1, 2, 4, 6, 12, 24 hours, respectively, and the structure showed that the blood glucose lowering effect of the groups of microneedles with 1.5% effervescent agent and centrifugally concentrated was clearly better than that of the groups of microneedles without effervescent agent without centrifugally concentration, see FIG. 13, table 4 for specific data.

TABLE 4 Table 4

Note that: in table 4, "" means the difference in blood glucose concentration between the microneedles with 1.5% effervescent and those without effervescent without centrifugal concentration at the same time point, P <0.001, P <0.0001, by the saliency test method non-paired t test.

12 Pharmacokinetic experiment): male db/db mice were purchased from Hangzhou child source laboratory animal technologies Inc., the backs of the mice were dehaired the day before the experiment, the day was randomized into two groups of 5 mice, each group was anesthetized with isoflurane and the back skin of the mice was each pricked with 1.5% effervescent agent-containing and non-effervescent agent-containing microneedles pressed, removed after 5 minutes, and blood was collected from the orbital venous plexus of the mice at 0, 1, 3, 6, 12, 24h, and plasma was collected after centrifugation at 4000rpm for 15min for measuring blood concentration using the Liraglutide ELISA kit, and the results showed that the effervescent-containing microneedle groups delivered significantly higher amounts of Liraglutide than the conventional microneedles, see Table 5 in FIG. 14 (FIG. 14).

TABLE 5

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Note that: in table 5, "" means the difference in blood concentration between the microneedles with 1.5% effervescent and the microneedles without effervescent without centrifugal concentration at the same time point, P <0.001, P <0.0001, by the saliency test method non-paired t test.

While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.

Claims

1. A polymeric microneedle comprising a drug and a polymeric backbone, the drug being supported in the polymeric backbone; wherein:

the polymer backbone is insoluble in water;

the polymer skeleton is micro needle-shaped;

2. The polymeric microneedle of claim 1, wherein the polymeric microneedle meets one or more of the following conditions:

(1) The GLP-1 receptor agonist is one or more of exenatide, risinatide, risinaide, risinatide, abilurin, dulcamide, tasinamide, benalalutide, rosinatide and rope Ma Lutai, for example exenatide, exenatide microsphere, risinatide, risinamide, lixisenatide, liraglutide, abilurin, dulcamide, tasinalutide, benalalutide or dulcamide, and for example liraglutide or dulcamide;

(2) the mass ratio of the drug to the polymeric microneedle is (0.0001-0.1): 1, e.g., 0.0001:1, 0.001:1, 0.01:1, or 0.1:1;

(3) the GLP-1 receptor agonist-containing composition meets one or more of the following conditions:

i. the GLP-1 receptor agonist is one or more of exenatide, risinatide, risinaide, risinatide, abilurin, dulcamide, tasinamide, benalalutide, rosinatide and rope Ma Lutai, for example exenatide, exenatide microsphere, risinatide, risinamide, lixisenatide, liraglutide, abilurin, dulcamide, tasinalutide, benalalutide or dulcamide, and for example liraglutide or dulcamide; the GLP-1 receptor agonist-containing composition further comprises one or more of an insulin receptor agonist, a glucagon receptor agonist and a GIP receptor agonist, such as an insulin receptor agonist or a glucagon receptor agonist, and further such as at least two of an insulin receptor agonist, a glucagon receptor agonist and a GIP receptor agonist;

Preferably, the GLP-1 receptor agonist-containing composition comprises 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 tri-receptor agonist, a GLP-1/GIP/glucagon tri-receptor agonist, a GLP-1/glucagon/insulin tri-receptor agonist or a GLP-1/GIP/glucagon/insulin tetra-receptor agonist.

3. The polymeric microneedle of claim 1, wherein the polymeric backbone is made from a cross-linkable system that can be one or more of a cellulose-containing system, a chitosan-containing system, a chitin-containing system, a polyvinyl alcohol-containing system, a DNA-containing system, a fibroin-containing system, and a polymer-based system comprising monomers containing double bonds, such as a polyvinyl alcohol-containing system, a polymerizable system comprising monomers containing double bonds, a chitosan-containing system, or a DNA-containing system;

preferably, in the system comprising polyvinyl alcohol, the polyvinyl alcohol has a weight average molecular weight of 50000-200000g/mol, for example a weight average molecular weight of 100000 g/mol;

Preferably, the system comprising polyvinyl alcohol is an aqueous solution of polyvinyl alcohol; the mass concentration of the polyvinyl alcohol in the aqueous solution of the polyvinyl alcohol may be 10 to 30w/v%, for example 20w/v%;

preferably, in the polymerizable system comprising double bond monomers, the double bond containing monomers are one or more of vinyl pyrrolidone, acrylamide, acrylic acid, dimethylaminoethyl acrylate, m-aminophenylboronic acid, ethylene glycol dimethacrylate, dimethylaminoethyl methacrylate, methacrylic acid, glycidyl acrylate and polyethylene glycol diacrylate, for example vinyl pyrrolidone;

preferably, in the system comprising chitosan, the chitosan has a weight average molecular weight of 200000-600000g/mol, for example a weight average molecular weight of 400000 g/mol;

preferably, the chitosan-containing system is an aqueous solution of chitosan; the mass concentration of the chitosan in the aqueous solution of chitosan may be 1-10w/v%, for example 5w/v%;

preferably, in the system comprising DNA, the DNA is natural DNA extracted from salmon sperm;

preferably, the weight average molecular weight of the DNA is 80 to 150 thousand g/mol, for example 120 or 150 thousand g/mol;

Preferably, the system comprising DNA is an aqueous solution of DNA; the mass concentration of the DNA in the aqueous solution of the DNA may be 1 to 20w/v%, for example 5w/v% or 10w/v%;

preferably, the system capable of undergoing cross-linking polymerization further comprises a cross-linking agent and/or an initiator;

preferably, when the cross-linkable polymerizable system is a polymerizable system comprising a double bond containing monomer, for example when the double bond containing monomer is vinylpyrrolidone:

the cross-linking agent is ethylene glycol dimethacrylate; the mass ratio of the double bond containing monomer to the crosslinking agent may be (95-105) 1.5, for example 97:1.5;

preferably, the initiator is a photoinitiator, which may be 2-hydroxy-4- (2-hydroxyethoxy) -2-methylpropionne; the mass ratio of the double bond containing monomer to the initiator may be (95-105): 1.5, for example 97:1.5;

preferably, when the system in which cross-linking polymerization can occur is a system comprising DNA, the cross-linking agent is polyethylene glycol (diol) diacrylate;

the mass ratio of the DNA to the crosslinking agent may be (1-100): 1, for example 10:1 or 20:1;

the polymer skeleton can be prepared by the following method: in the microneedle mould, the system capable of undergoing cross-linking polymerization is subjected to cross-linking reaction, and the preparation method is obtained;

The crosslinking reaction may be a physical crosslinking reaction or a chemical crosslinking reaction;

when the crosslinking reaction is a physical crosslinking reaction, the time of the crosslinking reaction may be 1 to 24 hours;

when the crosslinking reaction is a chemical crosslinking reaction and the crosslinking reaction is initiated by a photoinitiator, the conditions of the crosslinking reaction may be such that the ultraviolet intensity is 50 to 150mW/cm ² Irradiating for 5-30min;

wherein the ultraviolet intensity is 50-150mW/cm ² The crosslinkable system may also be pre-crosslinked in the microneedle mould before 5-30min of irradiation, for example at an ultraviolet intensity of 10-150mW/cm ² Is irradiated for 5 to 120 seconds;

preferably, the micropins are three-dimensional, stereoscopic needle-like structures, such as cones, pyramids or cuboids;

the microneedles in the microneedles may have a height of 500-2000 microns, for example 500 microns, 1200 microns or 1500 microns;

when the microneedle structure is a plurality, the microneedle tip pitch in the microneedle may be 100-1000 microns, such as 200 microns, 700 microns, or 800 microns.

4. A polymeric microneedle according to any one of claims 1 to 3 wherein the effervescent ingredient is a mixture comprising an acid source and an alkali source;

Preferably, the effervescent ingredient is in the form of granules, the granules of the effervescent ingredient having a diameter of 30-50 microns, for example 40 microns;

the acid source may be 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, further for example, citric acid, tartaric acid, or malic acid;

the alkali source may be sodium bicarbonate, sodium carbonate or a mixture of both, for example sodium bicarbonate or sodium carbonate;

the mass ratio of the acid source to the alkali source may be (0.1-3) 1, for example 1.76:1, 2:1, 0.5:1 or 1:1.3;

preferably, the effervescent ingredients may be tartaric acid and sodium bicarbonate, citric acid and sodium bicarbonate, or malic acid and sodium carbonate;

when the effervescent ingredients are tartaric acid and sodium bicarbonate, the mass ratio of the acid source to the base source may be (1.5-3): 1, e.g. 2:1;

when the effervescent ingredients are citric acid and sodium bicarbonate, the mass ratio of the acid source to the base source may be (0.5-3): 1, such as 1.76:1, 2:1 or 1:1.3;

when the effervescent ingredients are malic acid and sodium carbonate, the mass ratio of the acid source to the base source may be (0.1-1.0): 1, for example 0.5:1;

Preferably, the ratio of the mass of the drug to the mass of the effervescent ingredient is 1 (1-20), for example 1:1.0, 1:1.5, 1:2.0, 1:3.0, 1:5, 1:10 or 1:20;

preferably, the ratio of the mass of the effervescent ingredient to the mass of the polymeric microneedle is (0.001-0.1): 1, e.g., 0.002:1, 0.005:1, 0.01:1, 0.015:1, 0.02:1, 0.03:1, or 0.1:1;

preferably, the effervescent ingredient is distributed at the tip portion of the polymeric microneedle.

5. A raw material composition, characterized in that it comprises the following components: a drug and a cross-linkable polymeric system, the drug being a GLP-1 receptor agonist or a composition comprising a GLP-1 receptor agonist;

optionally, the system capable of undergoing cross-linking polymerization further comprises a cross-linking agent and/or an initiator;

preferably, the feedstock composition satisfies one or more of the following conditions:

(1) the GLP-1 receptor agonist is the GLP-1 receptor agonist of claim 2;

(2) the GLP-1 receptor agonist-containing composition of claim 2;

(3) the crosslinkable system according to claim 3;

(4) The effervescent ingredient is an effervescent ingredient according to claim 4;

(5) the crosslinking agent according to claim 3; and

(6) the initiator is an initiator as claimed in claim 3.

6. A method for preparing a polymer microneedle, which is characterized by comprising the following steps:

1) Mixing the drug according to claim 5 and the system capable of undergoing cross-linking polymerization to obtain a mixture C, and filling the mixture C into a microneedle mould;

when the starting composition of the microneedle preparation further comprises an effervescent ingredient as defined in claim 5, mixing the drug, the cross-linkable polymeric system, and the effervescent ingredient to obtain a mixture C, and filling the mixture C into a microneedle mould;

the polymer skeleton formed after the cross-linking reaction of the cross-linking polymerizable system is insoluble in water;

preferably, the preparation method of the polymer microneedle meets one or more of the following conditions:

(1) In step 1), when the raw material composition of the microneedle preparation further comprises an effervescent agent component and the crosslinkable polymerization system further comprises a crosslinking agent and/or an initiator, the mixture C is prepared by the following method:

mixing the medicine and the effervescent agent to obtain a mixture B;

mixing the mixture A and the mixture B to obtain a mixture C;

wherein, the mixture B can be added into the mixture A to be mixed to obtain a mixture C;

(2) in the step 1), when the raw material composition of the microneedle preparation further comprises an effervescent agent component, after the mixture C is filled into the microneedle mould, the mixture C is subjected to centrifugal concentration treatment before the crosslinking reaction;

wherein the conditions of the centrifugal concentration treatment may be centrifugation at 4000rpm for 2 minutes;

(3) in step 1), the mixture C fills the microneedle mould; the method of filling may be microinjection, vacuum degassing or centrifugation;

the vacuum degassing time may be 1min-1h, such as 20-30min, and further such as 20min or 30min; the centrifugation conditions may be, for example, 1000-5000rpm, centrifugation for 1-30min, for example 4000rpm, centrifugation for 10min or 20min;

After the filling, the mixture C may also be subjected to a pre-centrifugation treatment; the conditions of the pre-centrifugation may be 3000-5000rpm, centrifugation for 1-5min, such as 4000rpm, centrifugation for 2min;

and (4) in step 2), the crosslinking reaction is a physical crosslinking reaction or a chemical crosslinking reaction;

when the crosslinking reaction is a chemical crosslinking reaction and the crosslinking reaction is initiated by a photoinitiator, the conditions of the crosslinking reaction may be such that the ultraviolet intensity is 50 to 150mW/cm ² Is irradiated for 5-30min.

7. A polymeric microneedle produced by the method of claim 6.

8. A microneedle sheet comprising a plurality of polymeric microneedles according to any one of claims 1-4 and 7 and a plate on which the polymeric microneedles stand.

9. The preparation method of the micro-needle sheet is characterized by comprising the following steps:

the method comprises the following steps:

joining polymeric microneedles according to any one of claims 1-4 and 7 to a plate by means of a rigid or flexible material;

the second method is as follows:

S1: mixing the drug according to claim 5 and the system capable of undergoing cross-linking polymerization to obtain a mixture C, and filling the mixture C into a microneedle mould;

10. A microneedle sheet produced by the production method according to claim 9.

11. A polymeric material comprising a drug and a polymeric backbone, the drug being supported in the polymeric backbone; wherein:

The polymer backbone is insoluble in water;

preferably, the polymer matrix also has an effervescent component supported therein;

preferably, the polymeric material satisfies one or more of the following conditions:

(1) the GLP-1 receptor agonist is a GLP-1 receptor agonist as defined in claim 2;

(2) the GLP-1 receptor agonist-containing composition is a GLP-1 receptor agonist-containing composition as described in claim 2;

(3) the mass ratio of the drug to the polymeric material is (0.0001-0.1): 1, e.g. 0.0001:1, 0.001:1, 0.01:1 or 0.1:1;

(4) the polymer skeleton is the polymer skeleton as described in claim 3;

and (5) the effervescent ingredient is an effervescent ingredient as claimed in claim 4.

12. A delivery system for a GLP-1 receptor agonist, characterized in that it comprises a polymeric microneedle according to any one of claims 1-4 and 7, a microneedle sheet according to claim 8 or 10, or a polymeric material according to claim 11.

13. Use of a polymeric microneedle according to any one of claims 1-4 and 7, a microneedle sheet according to claim 8 or 10, a polymeric material according to claim 11 and a GLP-1 receptor agonist delivery system according to claim 12 for the manufacture of a medicament for the treatment of diabetes.