Phenylboronic acid compound, polymer, insulin sustained release preparation and application

Abstract

The invention discloses a phenylboronic acid compound which contains a phenylboronic acid group and a carbon-carbon double bond group, and the phenylboronic acid group can be combined with glucose. The invention also discloses a polymer which is obtained by carrying out free radical copolymerization reaction on the phenylboronic acid compound, a monomer containing A and an initiator in a solvent. The invention also discloses an insulin sustained-release preparation containing the polymer, and the preparation has different insulin release rates under different glucose concentrations, and accelerates the release of insulin in a hyperglycemia environment to reduce blood sugar. The invention also discloses a preparation method of the insulin sustained-release preparation. The insulin sustained-release preparation is prepared by self-assembling negatively charged insulin and positively charged bisphenylboronic acid modified polymer through electrostatic interaction, and the insulin sustained-release preparation has the characteristic of high load rate. The prepared insulin sustained-release preparation can release insulin, and the blood glucose level can be reduced after the released insulin is combined with an insulin receptor in a body.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a phenylboronic acid compound, a polymer, an insulin sustained-release preparation and applications. Background Art

[0002] Diabetes is a metabolic disease characterized by prolonged high blood sugar levels, affecting more than 1 in 10 adults worldwide. Due to rapid urbanization, unhealthy eating habits and increasingly sedentary lifestyles, global obesity has become a prominent problem in recent years, leading to a rapid increase in the incidence of diabetes. Continuous high blood sugar levels can cause diabetes-related complications, threatening the life and health of patients. Currently, the most mainstream treatment for diabetes is the use of exogenous insulin to maintain normal blood sugar levels. However, the temperature and enzyme instability of insulin molecules, the risk of hypoglycemia caused by insulin injections, and poor compliance caused by frequent insulin injections have limited its widespread application. Therefore, we need to design a new insulin delivery system to reduce the frequency of injections while improving the ability of insulin to regulate blood sugar.

[0003] There are currently three main glucose response mechanisms, including phenylboronic acid derivatives, glucose binding molecules, and glucose oxidase. Phenylboronic acid (PBA)-based glucose-responsive insulin has been verified to have rapid and powerful in vitro and in vivo glucose-responsive insulin release performance, which is closer to clinical application. However, it is still difficult for glucose-responsive insulin to control blood sugar within a normal range for a long period of time after a single injection. PBA and its derivatives are hydrophobic monomers, which become hydrophilic after forming a complex with glucose. This transformation can cause a change in the swelling degree of the polymer system. This type of substance exists in two forms in aqueous solution, one is a hydrophilic negatively charged dissociated state, and the other is a hydrophobic uncharged undissociated state. There is a dissociation equilibrium between the two states. The dissociated PBA in these two forms is more likely to bind glucose through covalent bonds to form a more hydrophilic structure. Therefore, this glucose responsiveness of PBA can be used to design a self-regulating insulin release system for blood sugar detection and control.

[0004] Publication No. CN118255997A discloses a polymer, an insulin composition containing the polymer and its application. The polymer is composed of three different structural units, wherein structural unit III contains a phenylboronic acid structure. The insulin composition prepared with the polymer as a drug carrier has the advantages of good stability, easy control of injection dosage, high drug loading, long insulin retention time in the body, and easy metabolism and clearance of the carrier from the body.

[0005] Publication No. CN117771387A discloses a sugar-responsive complex and its preparation method and application. The sugar-responsive complex comprises mutually complexed phenylboronic acid-based polylysine and insulin having a diol structure, wherein the complexing force comprises: (1) dynamic electrostatic attraction, and (2) covalent interaction between the phenylboronic acid structure of the phenylboronic acid-based polylysine and the diol structure of the insulin having a diol structure. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a phenylboronic acid compound, which contains a phenylboronic acid group and a carbon-carbon double bond group. The phenylboronic acid group can be combined with glucose and can be used for glucose response.

[0007] A phenylboronic acid compound, the structure of which is shown in formula (1),

[0008]

[0009] R1 is selected from a hydrogen atom, a C1-C6 alkyl group, and a halogen; R2 and R3 are each independently selected from a C1-C6 alkyl group.

[0010] Phenylboronic acid has Lewis acid properties and can reversibly form ester substances with compounds having cis-1,2 or cis-1,3 diol structures such as glucose. In aqueous media, phenylboronic acid exists in equilibrium with an uncharged trihedral structure and a negatively charged tetrahedral borate structure, both of which can reversibly bind to glucose and form a cyclic phenylboronic acid complex. In the present invention, a compound containing a phenylboronic acid group is designed and synthesized, which can bind to glucose and can be used to design a glucose-responsive insulin sustained-release preparation.

[0011] The present invention also provides a method for preparing the phenylboronic acid compound. The method is simple and can prepare the phenylboronic acid compound in just one step.

[0012] A preparation method of a phenylboronic acid compound comprises the following steps: N-(3-aminopropyl)acrylamide substituted with dialkyl on the terminal amino group and 4-bromomethylphenylboronic acid substituted on the benzene ring are reacted in N,N-dimethylformamide in one step to obtain the compound.

[0013] The specific synthetic route is as follows:

[0014]

[0015] The nitrogen atom of the tertiary amine has a lone pair of electrons, which can attack the carbon atom connected to the bromine, and the bromide ion leaves and pairs with the formed quaternary ammonium salt cation. In the present invention, the N-(3-aminopropyl)acrylamide substituted with dialkyl on the terminal amino group and the 4-bromomethylphenylboronic acid substituted on the benzene ring can be purchased, and only the raw materials with different substitutions of R1, R2, and R3 need to be replaced to react and obtain different substituted phenylboronic acid compounds.

[0016] The present invention also provides a polymer, which contains phenylboronic acid groups and can be combined with glucose.

[0017] A polymer, wherein the polymer is obtained by free radical copolymerization of the above-mentioned phenylboronic acid compound, a monomer containing A and an initiator in a solvent, and the structure of the polymer is shown in formula (2),

[0018]

[0019] In formula (2), A is One of

[0020] n=5~1000,m=1~200, is the connection position, R1 is selected from a hydrogen atom, a C1-C6 alkyl group, and a halogen; R2 and R3 are each independently selected from a C1-C6 alkyl group.

[0021] Preferably, the structure of the polymer is as follows,

[0022]

[0023] Wherein, n=5~1000, m=1~200, For the connection location.

[0024] Preferably, the molar ratio of the phenylboronic acid compound to the monomer containing A is 1-2:3-19.

[0025] In the present invention, the polymer having a phenylboric acid content of 5% to 40% can be obtained by adjusting the molar ratio of the monomer containing A and the phenylboric acid compound.

[0026] Preferably, the initiator is an azo initiator or an inorganic peroxide initiator.

[0027] In the present invention, the azo initiator may be azobisisobutyronitrile (AIBN), azobisisoheptanenitrile (ABVN), etc., and the inorganic peroxide initiator may be hydrogen peroxide, ammonium persulfate, potassium persulfate, etc.

[0028] Preferably, the solvent is one or more of alcohol or water.

[0029] Preferably, the volume ratio of the total mass of the monomer containing A and the phenylboronic acid compound to the solvent is 100 to 400 mg / mL.

[0030] Preferably, the reaction temperature of the free radical copolymerization reaction is 35-75° C., and the reaction time is 3-10 h.

[0031] Preferably, the dialysis step is to dialyze the solution after the reaction using a 3500-15000 kDa dialysis membrane for at least 5 times, and each dialysis time is 6-8 hours.

[0032] The present invention also provides an insulin sustained-release preparation containing the polymer, which has different insulin release rates under different glucose concentrations and accelerates the release of insulin to lower blood sugar in a high blood sugar environment.

[0033] An insulin sustained-release preparation comprises the above polymer and insulin.

[0034] Compared with polymers with secondary amine structures at the benzyl position, polymers with positively charged quaternary ammonium salt structures can better adsorb negatively charged insulin and increase the insulin loading rate in insulin sustained-release preparations. Under normal blood sugar conditions, the combination of glucose and phenylboronic acid groups will reduce the positive charge density on the polymer chain, allowing a small amount of insulin to be released, thereby providing slow and continuous insulin and allowing high-dose injections. Under high blood sugar conditions, the combination of a large number of phenylboronic acid groups with glucose will accelerate the release of insulin and thus lower blood sugar.

[0035] Preferably, the insulin is porcine insulin, human insulin, recombinant human insulin or FITC-porcine insulin.

[0036] In the present invention, the FITC-insulin is obtained by labeling porcine insulin with fluorescein isothiocyanate.

[0037] Preferably, the mass ratio of the polymer to insulin is 1-4:1-4.

[0038] The present invention also provides a method for preparing the above-mentioned insulin sustained-release preparation, in which negatively charged insulin and positively charged phenylboronic acid-modified polymer are self-assembled into the insulin sustained-release preparation through electrostatic interaction, and the preparation has the characteristic of high loading rate.

[0039] A method for preparing an insulin sustained-release preparation comprises the following steps: dissolving the above-mentioned polymer and insulin in acidified water, adjusting the pH to neutral with alkaline solution to form an insulin complex, adding PBS solution to adjust the insulin concentration, and resuspending after centrifugation to obtain the insulin sustained-release preparation.

[0040] Preferably, the acidified water is a hydrochloric acid aqueous solution, and the concentration of the acidified water is 0.01-1M.

[0041] Preferably, the mass volume ratio of the total mass of the polymer and insulin to the acidified water is 5 to 20 mg / mL.

[0042] Preferably, the alkali solution is a sodium hydroxide aqueous solution, and the concentration of the alkali solution is 0.01-1M.

[0043] Preferably, the centrifugal speed is 10000-20000 rpm, and the centrifugal time is 5-10 min.

[0044] The present invention also provides the use of the above-mentioned insulin sustained-release preparation in the preparation of medicines for treating diabetes. The insulin sustained-release preparation can release insulin, and the released insulin can reduce blood sugar levels after binding to insulin receptors in the body.

[0045] In the present invention, the diabetes mellitus may refer to a disease with a blood sugar level greater than normal, specifically a fasting blood sugar ≥ 7.0 mmol / L or a 2-hour blood sugar ≥ 11.1 mmol / L or a glycosylated hemoglobin ≥ 6.5%.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] (1) The phenylboronic acid compound and the polymer prepared from the phenylboronic acid compound in the present invention both contain phenylboronic acid groups capable of binding to glucose, and can recognize and bind to glucose.

[0048] (2) The insulin sustained-release preparation of the present invention has different insulin release rates under different glucose concentrations, and accelerates the release of insulin to lower blood sugar in a hyperglycemic environment.

[0049] (3) The preparation method of the insulin sustained-release preparation of the present invention self-assembles negatively charged insulin and positively charged phenylboronic acid-modified polymer into an insulin sustained-release preparation through electrostatic interaction, and has the characteristic of high loading rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 The specific synthetic route of the phenylboronic acid compound (AAPBA) prepared in Example 1 is shown in FIG.

[0051] Figure 2 This is the H NMR spectrum of the phenylboronic acid compound (AAPBA) prepared in Example 1.

[0052] Figure 3 This is the carbon NMR spectrum of the phenylboronic acid compound (AAPBA) prepared in Example 1.

[0053] Figure 4 The following is the hydrogen nuclear magnetic resonance spectrum of the polymer prepared in Example 2.

[0054] Figure 5 This is the gel permeation chromatography (GPC) spectrum of the polymer prepared in Example 2.

[0055] Figure 6 The following is the hydrogen nuclear magnetic resonance spectrum of the polymer prepared in Example 2.

[0056] Figure 7 The following is the hydrogen nuclear magnetic resonance spectrum of the polymer prepared in Example 2.

[0057] Figure 8 The following is the hydrogen nuclear magnetic resonance spectrum of the polymer prepared in Example 2.

[0058] Fig. 9 The specific synthetic route of the polymer was obtained for comparative example.

[0059] Fig.10 It is the hydrogen nuclear magnetic resonance spectrum of the polymer prepared in comparative example.

[0060] Fig.11 This is a test graph of the responsiveness of the 1 mg / mL insulin sustained-release preparation obtained in Example 6 to glucose.

[0061] Fig.12 The single release curves of the insulin sustained-release preparations obtained in Examples 6 to 11 in glucose solution, wherein A to G are the single release curves of Examples 6 to 11, respectively.

[0062] Fig.13 This is the in vitro multiple-cycle cumulative release curve of the insulin sustained-release preparation obtained in Example 6 in glucose solution. DETAILED DESCRIPTION

[0063] The present invention will be further described in detail below in conjunction with the examples, but the embodiments of the present invention are not limited to the following examples.

[0064] The raw materials used in the present invention are all commercially available.

[0065] Example 1: Preparation of phenylboronic acid compounds

[0066] Specific routes such as Figure 1As shown. 4-Bromomethylphenylboronic acid (160 mg, 0.745 mmol) was dissolved in DMF (5 mL) and then dropped into dimethylaminopropyl acrylamide (232.8 mg, 1.49 mmol) dissolved in DMF (5 mL). The mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was dropped into ethyl acetate with a volume of 20 times or more to precipitate the precipitate. The mixture was stirred during the dropwise addition. After the precipitation was completed, the precipitate was filtered off and dried in a vacuum drying oven to obtain a crude product. The crude product was dissolved in a small amount of water and then purified by C18 reverse phase silica gel column chromatography. The sample was eluted with 10% methanol and freeze-dried to obtain a white transparent solid, which was a phenylboronic acid compound (hereinafter referred to as AAPBA) (159.8 mg, 58.0%). Its hydrogen spectrum and carbon spectrum are shown as follows: Figure 2 and Figure 3 shown.

[0067] Example 2: Preparation of polymer

[0068] AAPBA (50 mg, 0.227 mmol) obtained in Example 1 was added to the reaction flask, 400 μL of ethanol and 20 μL of water were added as solvents, N2 was bubbled to deoxygenate, 101 mg (97.1 μL, 0.909 mmol) of N-vinyl pyrrolidone was added, 1.51 mg of AIBN (accounting for 1% of the total mass of AAPBA and N-vinyl pyrrolidone) was dissolved therein, the temperature was raised to 65°C, and the reaction was carried out for 5 hours. The mixture was dialyzed and separated using a 7000 kDa dialysis membrane, and the water was changed 5 times. After the dialysis was completed, the mixture was freeze-dried to obtain a white solid (132 mg, 87.4%). The hydrogen spectrum of the polymer is shown in FIG. Figure 4 As shown, the gel permeation chromatography (GPC) spectrum of the polymer is as follows Figure 5 As shown, the weight average molecular weight (Mw) of the polymer is 15403 and the polydispersity coefficient (PD) is 2.03.

[0069] Examples 3-5: Preparation of polymers

[0070] The preparation methods of Examples 3 to 5 are the same as that of Example 2, with the differences shown in the following table.

[0071] Table 1: Differences in the preparation methods of Examples 2 to 5

[0072]

[0073] Example 6: Preparation of sustained-release insulin preparation

[0074] FITC-porcine insulin (1 mg) and the polymer obtained in Example 2 (1 mg) were dissolved in 0.2 mL of HCl aqueous solution (0.1 M), mixed, and NaOH aqueous solution (1 M) was added to adjust the pH to 7.4 to obtain an insulin sustained-release preparation.

[0075] The volume was made up to 1 mL with PBS (10 mM, pH 7.4), and the supernatant was removed after centrifugation. The mixture was resuspended in 1 mL of PBS for washing. The washing operation was repeated three times, and the insulin concentration of the supernatant was detected each time. Finally, an insulin sustained-release preparation with an insulin concentration of 1 mg / mL was prepared for subsequent experiments.

[0076] Examples 7-11: Preparation of sustained-release insulin preparations

[0077] The preparation methods of Examples 7 to 11 are the same as that of Example 6, with the differences shown in the following table.

[0078] Table 2: Differences in the preparation methods of Examples 6 to 11

[0079]

[0080] The test method of loading rate: the concentration of insulin in the supernatant washed three times in the process of preparing the insulin sustained-release preparation in test examples 6 to 11 is measured to obtain the total amount of insulin washed away; loading rate = (total amount of insulin added - total amount of insulin washed away) / total amount of insulin added * 100%

[0081] Comparative Example: Preparation of amino polymer and insulin sustained-release preparation

[0082] (1) Preparation of polymer

[0083] Specific routes such as Fig. 9 As shown. 3-Acrylamidophenylboronic acid (100 mg, 0.524 mmol), 2-aminoethyl methacrylate hydrochloride (86.71 mg, 0.524 mmol) were added to the reaction bottle, 4 ml of ethanol was added as solvent, N2 was bubbled to deoxygenate, 349 mg (335.6 μL, 3.14 mmol) of N-vinyl pyrrolidone was added, 5.36 mg of AIBN (1% of the total mass of all monomers) was dissolved therein, the temperature was raised to 65°C, and the reaction was carried out for 5 hours. The mixture was separated by dialysis with a 7000 kDa dialysis membrane, and the water was changed 5 times. After dialysis, the mixture was freeze-dried to obtain a white solid (476 mg, 88.1%). The hydrogen spectrum of the polymer is shown as follows Fig.10 shown.

[0084] (2) Preparation of sustained-release insulin preparations

[0085] FITC-porcine insulin (1 mg) and the polymer obtained in step (1) (1 mg) were dissolved in 0.2 mL of HCl aqueous solution (0.1 M), mixed and added with NaOH aqueous solution (1 M) to adjust the pH to 7.4 to obtain an insulin sustained-release preparation with an amino group at the benzyl position.

[0086] The volume was made up to 1 mL with PBS (10 mM, pH 7.4), and the supernatant was removed after centrifugation. The mixture was resuspended in 1 mL of PBS for washing. The washing operation was repeated three times, and the insulin concentration of the supernatant was detected each time. Finally, an insulin sustained-release preparation with an insulin concentration of 1 mg / mL was prepared for subsequent experiments.

[0087] The loading rate of the insulin sustained-release preparation of the comparative example obtained by the above-mentioned loading rate testing method is 26.11%, indicating that the electrostatic adsorption effect of quaternary ammonium salt on insulin in Examples 6 to 11 is better than that of primary amine.

[0088] Sample analysis

[0089] 1. Test on the responsiveness of insulin sustained-release preparations to glucose

[0090] Drawing of standard curve: Weigh 1 mg FITC-porcine insulin in an EP tube, add 0.1 mL of HCl solution (0.1 M), add 0.15 mL of NaOH solution (0.1 M) to completely dissolve the insulin, add PBS (10 mM, pH 7.4) to make the volume 1 mL, and obtain 1 mg / mL FITC-porcine insulin. Use 1 mg / mL FITC-porcine insulin mother solution to prepare 1, 5, 10, 20, 40, 80, 160 μg / mL insulin solutions, take 100*3 μL respectively, use an enzyme reader to test the fluorescence intensity at 525 nm excited by 495 nm, and finally draw a linear standard curve of fluorescence intensity-insulin concentration.

[0091] The 1 mg / mL insulin sustained-release preparation obtained in Example 6 was cyclically exposed to glucose solutions at concentrations of 100 and 400 mg / dL (n=3). At the beginning of the experiment, the insulin sustained-release preparation (equivalent to 1 mg of insulin) was centrifuged and then mixed with 1 mL of glucose solution (400 mg / dL). After incubation on a shaker at 37°C and 400 rpm for 10 minutes, the suspension was centrifuged again and the supernatant was collected to determine the insulin concentration, and then 1 mL of glucose solution (100 mg / dL) was added. After 10 minutes, the suspension was centrifuged again and the supernatant was collected to determine the insulin concentration, and then 1 mL of glucose solution (400 mg / dL) was added. This process was repeated three times. The insulin concentration of the supernatant in the EP tube was quantitatively determined using a fluorescence method, and the insulin concentration was calculated using a standard curve.

[0092] Fig.11The responsiveness test diagram of the 1mg / mL insulin sustained-release preparation obtained for Example 6 to glucose. As shown in the figure, in three high-sugar-normal blood sugar cycles, the amount of insulin sustained-release preparation released in high-sugar solution is greater than that in normal blood sugar solution, which fully verifies that this insulin sustained-release preparation has the ability to release insulin in response to high-concentration glucose, thereby providing long-acting ultra-low-dose insulin to maintain blood sugar stability under normal blood sugar, and providing a high-dose insulin to reduce blood sugar to a normal range when blood sugar rises. The amount released each time will be slightly reduced on the one hand because the stored insulin will decline with the release of insulin, and the other party is because centrifugation causes the insulin sustained-release preparation to aggregate.

[0093] 2. Single Kinetic Release Test of Sustained-Release Insulin Preparations

[0094] First, the insulin sustained-release preparations of Examples 6 to 11 were prepared into 160 μg / ml PBS solutions as mother solutions. Samples were added to the microplate reader according to the following groups:

[0095] PBS group: 50 μL mother solution + 125 μL PBS;

[0096] 100G group: 50 μL mother solution + 17.5 μL 10 mg / mL glucose + 107.5 μL PBS;

[0097] 400G group: 50μL mother solution + 70μL 100mg / mL glucose + 55μL PBS; after preparing the solution, put the 96-well plate into the microplate reader, set the total test time to 12h, test every 5min, shake for 10s during each test, and test the fluorescence intensity at 525nm under 495nm excitation each time. Finally, make the change of fluorescence intensity over time. The results are as follows Fig.12 As shown in A to F.

[0098] The 1 mg / mL insulin sustained-release preparation obtained in Example 6 was respectively mixed with sugar solutions of different concentrations in a 96-well plate to finally prepare a release solution with a total amount of 100 μL per well and an insulin concentration of 500 μg / mL. Three release groups were set up, including PBS, 100 mg / dL glucose (100G), and 400 mg / dL glucose (400G). After the solution was prepared, the 96-well plate was sent to the microplate reader, and the total test time was set to 4 hours. The test was performed every 2.5 minutes, and the test was shaken for 10 seconds during each test. The fluorescence intensity at 525 nm under 495 nm excitation was tested each time. Finally, the change of fluorescence intensity over time was made. The results are as follows: Fig.12 As shown in G in .

[0099] Fig.12 The single release curve of the insulin sustained-release preparation obtained in Examples 6 to 11 in glucose solution. Fig.12 As shown in A to G, under normal blood sugar environment, i.e., 100G group, the insulin sustained-release preparation will release a small amount of insulin to provide slow and continuous insulin and allow high-dose injection. Under high blood sugar environment, i.e., 400G group, a large number of phenylboronic acid groups combined with glucose will accelerate the release of insulin and thus lower blood sugar.

[0100] III. In vitro multiple cycle cumulative release test of insulin sustained-release preparations

[0101] The insulin sustained-release preparation obtained in Example 6 was resuspended in PBS with pH 7.4 to make the final insulin concentration 1 mg / dL. Added into the EP tube, the final glucose concentration was 100 mg / dL and 400 mg / dL, and the final insulin concentration was 500 μg / mL (n=3). Each release experiment was carried out for 1 hour, and 10 cycles were performed. After each cycle, 90% of the supernatant was centrifuged and taken out, and the same volume and concentration of sugar solution without insulin were added. 100 μL of the released supernatant was added to a 96-well plate and the fluorescence intensity value of FITC-insulin was detected by an enzyme marker. The concentration of insulin was calculated using a standard curve, and the drawing of the standard curve was as described above. The cumulative release amount was calculated according to the following formula:

[0102] Q n =C1×V1+C2×V2×0.9+C3×V3×0.9+……+C n ×V n ×0.9

[0103] Where Q n is the cumulative release amount in the nth cycle, C n is the insulin concentration of the supernatant detected in the nth cycle, V n is the total volume of the released liquid in the nth cycle.

[0104] Fig.13 This is the in vitro multiple cycle cumulative release curve of the insulin sustained-release preparation in glucose solution obtained in Example 6. During the long-term multiple cumulative release process, the insulin sustained-release preparation still maintains responsiveness to the glucose solution, and its responsiveness to the 400 mg / dL glucose solution is better than that to the 100 mg / dL glucose solution.

[0105] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A phenylboronic acid compound, characterized in that The structure of the phenylboronic acid compound is shown in formula (1), R1 is selected from a hydrogen atom, a C1-C6 alkyl group, and a halogen; R2 and R3 are each independently selected from a C1-C6 alkyl group.

2. The method for preparing a phenylboronic acid compound according to claim 1, characterized in that: The following steps are involved: The product is prepared by one-step reaction of N-(3-aminopropyl)acrylamide substituted with dialkyl on the terminal amino group and 4-bromomethylphenylboronic acid substituted on the benzene ring in N,N-dimethylformamide.

3. A polymer, characterized in that The polymer is obtained by a free radical copolymerization reaction of the phenylboronic acid compound according to claim 1, a monomer containing A and an initiator in a solvent, and the structure of the polymer is shown in formula (2): In formula (2), A is One of n=5~1000,m=1~200, is the connection position, R1 is selected from a hydrogen atom, a C1-C6 alkyl group, and a halogen; R2 and R3 are each independently selected from a C1-C6 alkyl group.

4. The polymer according to claim 3, characterized in that The molar ratio of the phenylboronic acid compound to the monomer containing A is 1-2:3-19.

5. The polymer according to claim 3, characterized in that The initiator is an azo initiator or an inorganic peroxide initiator.

6. The polymer according to claim 3, characterized in that The volume ratio of the total mass of the monomer containing A and the phenylboronic acid compound to the solvent is 100-400 mg / mL.

7. An insulin sustained-release preparation, characterized in that: The invention comprises the polymer described in any one of claims 3 to 6 and insulin.

8. The insulin sustained-release preparation according to claim 7, characterized in that: The insulin is porcine insulin, human insulin, recombinant human insulin or FITC-porcine insulin; the mass ratio of the polymer to the insulin is 1-4:1-4.

9. The method for preparing the sustained-release insulin preparation according to claim 7 or 8, characterized in that: The method comprises the following steps: dissolving the polymer described in any one of claims 3 to 6 and insulin in acidified water, adjusting the pH to neutral with alkaline solution to form an insulin complex, adding PBS solution to adjust the insulin concentration, resuspending after centrifugation, and obtaining an insulin sustained-release preparation.

10. Use of the sustained-release insulin preparation according to claim 7 or 8 in the preparation of a drug for treating diabetes.

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