Biodegradable polymer, preparation method and sustained-release microneedle patch

Abstract

The present invention relates to a biodegradable polymer, a preparation method and a sustained-release microneedle patch, and belongs to the field of biomaterial technology. The polymer is polyethylene glycol-polysulfadimethoxine carbonate carbamate, and the polymer has good biocompatibility and biosafety. Through a series of simple synthesis methods, including acrylic acid reaction, Michael addition reaction, ring-opening reaction, and addition polymerization reaction, a PEG-PSCU polymer is finally obtained, which can be used to prepare a new sustained-release microneedle. Compared with traditional biodegradable microneedles, this new microneedle can not only efficiently load protein vaccines, but also further prolong the release time of these vaccines in different environments, including normal ground environment and simulated microgravity environment, and further enhance the mechanical strength of the microneedle itself.

Description

Technical Field

[0001] The invention relates to a biodegradable polymer, a preparation method and a sustained-release microneedle patch, and belongs to the technical field of biomaterials. Background Art

[0002] Immune diseases are often the primary threat to astronauts' lives. Although current spacecraft have rigorous microbial control procedures that eliminate or reduce the risk of microbial infection, studies have shown that herpes viruses, primarily varicella-zoster virus, often reside and remain dormant in neurons of the dorsal root ganglia of the spinal cord for life. Normally, they are suppressed by the immune system and remain dormant. As astronauts spend extended periods in space, microgravity and other factors can weaken the function of immune cells that suppress these viruses, leading to reactivation of latent herpes viruses. This can trigger a range of discomfort, including severe pain and, occasionally, visceral herpes zoster, seriously impacting astronauts' work, health, and even their lives. This serious issue has attracted the attention of the international scientific community. Currently, medical research primarily focuses on diseases that occur on Earth, and research into more effective treatment strategies for these space-related immune diseases is lacking.

[0003] Establishing an in-orbit long-acting vaccine delivery strategy could further prolong the duration of action of these vaccines in the body, potentially enabling long-term release with a single injection, achieving highly effective and low-toxic immune responses, and improving the convenience and compliance of astronauts in the challenging environment of space. Recently, polycarbonate-based copolymers have been shown to possess unique degradation properties, undergoing non-enzymatic hydrolysis to produce biocompatible acidic degradation products. Traditional biodegradable microneedles are primarily made from poly(lactic-co-glycolic acid) and its derivatives, but they are typically only able to release loaded drugs for a few days. Further efforts are needed to extend the duration of drug release from microneedles and enhance their mechanical strength. Summary of the Invention

[0004] In light of this, the present invention aims to provide a biodegradable polymer, preparation method, and sustained-release microneedle patch. Through a series of simple synthesis methods, including acrylation, Michael addition, ring-opening, and addition polymerization, a PEG-PSCU polymer is ultimately obtained, which can be used to prepare a novel sustained-release microneedle. Compared with traditional biodegradable microneedles, this novel microneedle is not only able to efficiently load protein vaccines, but also further prolongs the release time of these vaccines in different environments, including normal terrestrial environments and simulated microgravity environments, and further enhances the mechanical strength of the microneedle itself.

[0005] To achieve the above object, the technical solution of the present invention is as follows:

[0006] A biodegradable polymer, wherein the polymer is polyethylene glycol-polysulfadimethazine carbonate carbamate (PEG-PSCU), and the structural formula is:

[0007]

[0008] Among them, n is 33~48, and m is 5~6.

[0009] A method for preparing a biodegradable polymer of the present invention comprises the following steps:

[0010] (1) Dissolving sulfamethazine and an alkali metal hydroxide in a mixed solvent of acetone and water, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide; adding acryloyl chloride dropwise at -5 to 5°C in a protective gas atmosphere, stirring and mixing thoroughly, and then continuing to stir and react for 4 to 6 hours. After the reaction is completed, filtering, purifying, and drying to obtain sulfamethazine acrylate (abbreviated as SMA); wherein the molar ratio of sulfamethazine, alkali metal hydroxide, and acryloyl chloride is 5:6:6 to 5:7:7;

[0011] Preferably, in step (1), the volume ratio of acetone to water in the mixed solvent is 2:1 to 1:2.

[0012] Preferably, in step (1), the stirring rate is 800-1000 rpm / min.

[0013] (2) SMA and 1-thioglycerol are dissolved in a mixed solvent of methanol and dimethylformamide, and the mixture is stirred at 50-65°C for 24-48 hours. After the reaction, the mixture is cooled, filtered, purified, and dried to obtain sulfadimethoxine diol (abbreviated as SMD); the molar ratio of the reactants SMA and 1-thioglycerol is 20:21-20:25;

[0014] Preferably, in step (2), the volume ratio of methanol to dimethylformamide in the mixed solvent is 2:1 to 1:2.

[0015] (3) Drying SMD, trimethyl carbonate and stannous octoate; dissolving the reactants with anhydrous 1,4-dioxane, heating to 110-120°C under a protective gas atmosphere and reacting for 18-36 hours; cooling, filtering, purifying and drying after the reaction to obtain a sulfamethazine-linked polytrimethyl carbonate monomer (abbreviated as SM-TMC); wherein the molar ratio of SMD, trimethyl carbonate and stannous octoate is 45:45:1-50:50:1;

[0016] Preferably, in step (3), the drying condition is vacuum drying at 50-60°C.

[0017] (4) The polyethylene glycol modified with hydroxyl groups at both ends and the organotin catalyst are dried, and the monomer SM-TMC is added at 55-60°C, and then dissolved in anhydrous tetrahydrofuran, and then diisocyanate is added. The mixture is stirred and reacted at 60-65°C for 2-6 hours. After the reaction is completed, the mixture is cooled, filtered, purified and dried to obtain the final PEG-PSCU copolymer; wherein the relative molecular mass of the polyethylene glycol modified with hydroxyl groups at both ends is 2050-4000 g / mol; and the molar ratio of the polyethylene glycol modified with hydroxyl groups at both ends, the organotin catalyst, SM-TMC and the diisocyanate is 50:2:250:275.

[0018] Preferably, in step (4), the drying condition is vacuum drying at 110-120°C.

[0019] Preferably, in step (4), the organotin catalyst is dibutyltin dilaurate and / or stannous octoate.

[0020] Preferably, in step (4), the diisocyanate is one or more of hexamethylene diisocyanate, diphenylmethane diisocyanate, toluene diisocyanate and isophorone diisocyanate.

[0021] A sustained-release microneedle patch comprises a needle tip layer and a patch layer, wherein the biodegradable material loaded with active components in the needle tip layer adopts a biodegradable polymer described in the present invention; the active components are hydrophilic protein vaccines or nano nucleic acid vaccines.

[0022] Preferably, the active component is VZV glycoprotein E.

[0023] A method for preparing the sustained-release microneedle patch of the present invention comprises the following steps:

[0024] Active components are added to the biodegradable polymer solution, which is then dripped into the microneedle holes in the microneedle mold and dried to prepare a needle tip layer; PVA solution is then added, dried to prepare a patch layer, and then frozen and demolded to obtain a sustained-release microneedle patch;

[0025] The concentration of the biodegradable polymer solution is 20-25wt%, the dissolution condition is an aqueous solution with a pH of 8.0-10.0, the mass ratio of the volume of the biodegradable polymer solution to the active component is 120-150μl:10-15μg, and the drying conditions for preparing the needle tip layer are vacuum drying at 35-37°C; the concentration of the PVA solution is 15-20wt%, and the drying conditions for preparing the patch layer are vacuum drying at 20-25°C; the freezing temperature is -20--70°C, and the freezing time is 12-24h.

[0026] An application of a sustained-release microneedle patch, wherein the sustained-release microneedle patch is used for sustained-release and delivery of active components under simulated microgravity.

[0027] Beneficial effects

[0028] This invention provides a polyethylene glycol-poly(sulfamethazine carbonate urethane) (PEG-PSCU) polymer. While containing a carbonate that can be non-enzymatically hydrolyzed, this polymer also incorporates a polyurethane that is difficult to hydrolyze. The synergistic effect of these two components slows the degradation of the overall polymer. The polyurethane also increases the polymer's rigidity, further enhancing the mechanical strength of the resulting microneedles. This material also exhibits excellent biocompatibility and biosafety.

[0029] The present invention provides a method for preparing a PEG-PSCU polymer. Through a series of simple synthesis methods, including acrylation, Michael addition, ring-opening, and addition polymerization, the resulting polyethylene glycol-poly(sulfamethazine carbonate urethane) (PEG-PSCU) polymer is suitable for large-scale batch production and has good industrial application prospects.

[0030] The present application discloses a sustained-release microneedle patch, in which the biocompatible biodegradable polymer PEG-PSCU is used to prepare the needle tip layer portion in the microneedle patch, and the internal loaded vaccine is released as it slowly degrades under physiological conditions; it is intended to use a water-soluble material to prepare the patch layer portion in the microneedle patch, and there is no vaccine load inside, and the two together constitute a separable sustained-release microneedle, a new intelligent delivery system; and due to the presence of an interface between the biodegradable material and the water-soluble material constituting the needle tip layer, the intradermal interstitial fluid can quickly dissolve the water-soluble material in contact, so that the patch layer portion can be smoothly removed, leaving only the needle tip layer in the skin, avoiding the discomfort caused by long-term attachment of the microneedle patch. The present invention uses the biodegradable polymer as the preparation material for the sustained-release microneedle, and the prepared microneedle can not only meet the efficient load of the vaccine, improve its mechanical strength, but also enhance its sustained-release effect on the loaded vaccine under normal conditions and simulated microgravity. It is expected to be widely used in vaccine intradermal delivery under normal conditions and simulated microgravity environments. The above design also provides a new perspective for vaccine delivery in the field of aerospace antiviral immunotherapy and brings novel design concepts.

[0031] In the technical solution of the present invention, the key conditions that have a significant impact on the biodegradable polymer and the sustained-release microneedles prepared therefrom are as follows:

[0032] 1. Based on the overall polymer structure provided above and the values ​​of n and m therein, the proportion of polyethylene glycol in the polymer and its molecular weight directly determine the hydrophilicity and stability of the sustained-release microneedle structure; if the proportion of polyethylene glycol is too high, the hydrophilicity of the polymer will be enhanced, but the original balance of the hydrophilic and hydrophobic ratio of the polymer will be disrupted. Conversely, if the proportion of polyethylene glycol is too low, the hydrophilicity of the polymer will be reduced, and the original balance of the hydrophilic and hydrophobic ratio of the polymer will also be disrupted.

[0033] 2. The molar ratio of polyethylene glycol, organotin catalyst, SM-TMC, and diisocyanate directly determines whether the biodegradable polymer can be synthesized and whether the ideal hydrophilic-hydrophobic ratio can be achieved; if this molar ratio is not met, the polymer will not be successfully synthesized.

[0034] 3. The proportion of SM-TMC in the polymer determines the function of sustained-release microneedles, which are soluble under alkaline conditions and capable of sustained release under weak acid conditions. If the proportion of SM-TMC is too high, the rigidity of the polymer will be enhanced, but the original balance of the hydrophilic-hydrophobic ratio of the polymer will be disrupted. Conversely, if the proportion of SM-TMC is too low, the rigidity of the polymer will be reduced, and the original balance of the hydrophilic-hydrophobic ratio of the polymer will also be disrupted.

[0035] 4. The concentration and drying conditions of PEG-PSCU directly determine whether sustained-release microneedles can be formed. If the polymer concentration is too low, a solid needle tip cannot be formed. If the polymer concentration is too high, the dissolution of the polymer in the first step is directly limited. If the drying conditions are insufficient, the material will eventually take on a hydrogel state, and dry microneedles cannot be formed. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 Schematic diagram of the working process of the biodegradable microneedles loaded with VZV-specific glycoprotein E in Example 1 of the present invention.

[0037] Figure 2 This is the H-NMR spectrum of the PEG-PSCU polymer in Example 1 of the present invention.

[0038] Figure 3 Scanning microscope images of the biodegradable microneedle in Example 1 of the present invention at different times under a simulated microgravity environment.

[0039] Figure 4 This is the release curve of VZV-specific glycoprotein E from the biodegradable microneedle loaded with VZV-specific glycoprotein E in Example 1 of the present invention. DETAILED DESCRIPTION

[0040] The present invention will be further described in detail below with reference to specific examples. Unless otherwise specified, the raw materials and operating techniques involved in the following examples are conventional raw materials and techniques in the prior art.

[0041] Example 1

[0042] (1) Sulfadimethoxine (0.10 mol) and sodium hydroxide (0.12 mol) were dissolved in a mixed solvent of acetone and water (100 ml, 1:1 v / v). Acryloyl chloride (0.12 mol) was added dropwise at -5°C and stirred thoroughly. The mixture was stirred and reacted for 4 h. After the reaction, sulfadimethoxine acrylate (abbreviated as SMA) was obtained by filtration, purification, and drying.

[0043] (2) SMA (20 mmol) and 1-thioglycerol (21 mmol) were dissolved in a mixed solvent of methanol and dimethylformamide (80 ml, 1:1 v / v), heated and stirred at 50 °C, reacted for 24 h, and then cooled, filtered, purified, and dried to obtain sulfadimethoxine diol (abbreviated as SMD).

[0044] (3) SMD (10 mmol), trimethyl carbonate (10 mmol), and stannous octoate (0.2 mmol) were placed in a vacuum dryer at 50 °C; the reactants were dissolved in anhydrous 1,4-dioxane, and the temperature was slowly raised to 110 °C under nitrogen. After the reaction for 18 h, the mixture was cooled, filtered, purified, and dried to obtain a sulfamethazine-linked polytrimethyl carbonate monomer (abbreviated as SM-TMC).

[0045] (4) Polyethylene glycol (1 mmol) with a molecular weight of 2050 g / mol and modified with hydroxyl groups at both ends and dibutyltin dilaurate (0.04 mmol) were placed in a vacuum dryer at 110 °C. When the temperature dropped to 55 °C, the monomer SM-TMC (5 mmol) was added. The reactants were dissolved in anhydrous tetrahydrofuran, and hexamethylene diisocyanate (5.5 mmol) was added. The mixture was heated and stirred at 60 °C. After the reaction for 2 h, the mixture was cooled, filtered, purified, and dried to obtain the final PEG-PSCU copolymer.

[0046] (5) For each microneedle patch, 10 μg of the vaccine model, VZV glycoprotein E, was added to 120 μl of a 20 wt% PEG-PSCU solution dissolved at pH 8.0. The solution was then dropped into the microneedle hole in the microneedle mold and vacuum-dried at 35°C to prepare the needle tip layer. 15 wt% PVA solution was then added and vacuum-dried at 20°C to prepare the patch layer. After the overall preparation, the entire microneedle patch, which had not been separated from the mold, was placed at -20°C for 12 h, then removed and demolded to obtain a sustained-release microneedle patch with sufficient mechanical strength.

[0047] The action process of the biodegradable microneedles loaded with VZV-specific glycoprotein E in the present invention is as follows: Figure 1 As shown, biodegradable microneedles loaded with VZV-specific glycoprotein E can release vaccines such as VZV-specific glycoprotein E for a long time in a simulated microgravity environment, stimulate intradermal dendritic cells for a long time, and then induce subsequent adaptive immunity.

[0048] The H-NMR spectrum of the PEG-PSCU polymer in this example is as follows: Figure 2 As shown, the structural formula of the PEG-PSCU polymer is:

[0049] ;

[0050] Among them, n is 33 and m is 5.

[0051] The scanning microscope results of the biodegradable microneedles in this embodiment at different times in a simulated microgravity environment are shown in FIG. Figure 3 As shown, the microneedle maintained its original morphology in a simulated microgravity environment.

[0052] The release curve of VZV-specific glycoprotein E from the biodegradable microneedles loaded with VZV-specific glycoprotein E in this embodiment is shown in FIG. Figure 4 As shown, a phosphate buffer solution (pH 7.4) was used to simulate the intradermal interstitial fluid environment, and the microneedle patch was placed in this phosphate buffer solution. The released solutions were collected at different time points under normal environment (bMN-Norm) and simulated microgravity environment (bMN-SMG), and the protein concentration was detected. The results showed that the microneedles were able to release VZV-specific glycoprotein E for a long time under simulated microgravity environment. Traditional soluble microneedles prepared based on polyvinyl alcohol were used as a control for the release rate. Similarly, the released solutions were collected at different time points under normal environment (dMN-Norm) and simulated microgravity environment (dMN-SMG), and the protein concentration was detected. The results showed that the traditional soluble microneedles quickly released the loaded vaccine.

[0053] Example 2

[0054] (1) Sulfadimethoxine (0.10 mol) and sodium hydroxide (0.14 mol) were dissolved in a mixed solvent of acetone and water (100 ml, 1:1 v / v). Acryloyl chloride (0.14 mol) was added dropwise at 5°C and stirred thoroughly. The mixture was stirred and reacted for 6 h. After the reaction, sulfadimethoxine acrylate (abbreviated as SMA) was obtained by filtration, purification, and drying.

[0055] (2) SMA (20 mmol) and 1-thioglycerol (21 mmol) were dissolved in a mixed solvent of methanol and dimethylformamide (80 ml, 1:1 v / v), heated and stirred at 50 °C, reacted for 24 h, and then cooled, filtered, purified, and dried to obtain sulfadimethoxine diol (abbreviated as SMD).

[0056] (3) SMD (10 mmol), trimethyl carbonate (10 mmol), and stannous octoate (0.2 mmol) were placed in a vacuum dryer at 50 °C; the reactants were dissolved in anhydrous 1,4-dioxane, and the temperature was slowly raised to 110 °C under nitrogen. After the reaction for 18 h, the mixture was cooled, filtered, purified, and dried to obtain a sulfamethazine-linked polytrimethyl carbonate monomer (abbreviated as SM-TMC).

[0057] (4) Polyethylene glycol (1 mmol) with a molecular weight of 2050 g / mol and modified with hydroxyl groups at both ends and dibutyltin dilaurate (0.04 mmol) were placed in a vacuum dryer at 110 °C. When the temperature dropped to 55 °C, the monomer SM-TMC (5 mmol) was added. The reactants were dissolved in anhydrous tetrahydrofuran, and hexamethylene diisocyanate (5.5 mmol) was added. The mixture was heated and stirred at 60 °C. After the reaction for 2 h, the mixture was cooled, filtered, purified, and dried to obtain the final PEG-PSCU copolymer.

[0058] (5) For each microneedle patch, 10 μg of the vaccine model, VZV glycoprotein E, was added to 120 μl of a 20 wt% PEG-PSCU solution dissolved at pH 8.0. The solution was then dropped into the microneedle hole in the microneedle mold and vacuum-dried at 35°C to prepare the needle tip layer. 15 wt% PVA solution was then added and vacuum-dried at 20°C to prepare the patch layer. After the overall preparation, the entire microneedle patch, which had not been separated from the mold, was placed at -20°C for 12 h, then removed and demolded to obtain a sustained-release microneedle patch with sufficient mechanical strength.

[0059] The performance of the sustained-release microneedle patch described in this example is similar to that of Example 1.

[0060] Example 3

[0061] (1) Sulfadimethoxine (0.10 mol) and sodium hydroxide (0.14 mol) were dissolved in a mixed solvent of acetone and water (100 ml, 1:1 v / v). Acryloyl chloride (0.14 mol) was added dropwise at 5°C and stirred thoroughly. The mixture was stirred and reacted for 6 h. After the reaction, sulfadimethoxine acrylate (abbreviated as SMA) was obtained by filtration, purification, and drying.

[0062] (2) SMA (20 mmol) and 1-thioglycerol (25 mmol) were dissolved in a mixed solvent of methanol and dimethylformamide (80 ml, 1:1 v / v), heated and stirred at 65 °C for 48 h, and then cooled, filtered, purified, and dried to obtain sulfadimethoxine diol (abbreviated as SMD).

[0063] (3) SMD (10 mmol), trimethyl carbonate (10 mmol), and stannous octoate (0.2 mmol) were placed in a vacuum dryer at 50 °C; the reactants were dissolved in anhydrous 1,4-dioxane, and the temperature was slowly raised to 110 °C under nitrogen. After the reaction for 18 h, the mixture was cooled, filtered, purified, and dried to obtain a sulfamethazine-linked polytrimethyl carbonate monomer (abbreviated as SM-TMC).

[0064] (4) Polyethylene glycol (1 mmol) with a molecular weight of 2050 g / mol and modified with hydroxyl groups at both ends and dibutyltin dilaurate (0.04 mmol) were placed in a vacuum dryer at 110 °C. When the temperature dropped to 55 °C, the monomer SM-TMC (5 mmol) was added. The reactants were dissolved in anhydrous tetrahydrofuran, and hexamethylene diisocyanate (5.5 mmol) was added. The mixture was heated and stirred at 60 °C. After the reaction for 2 h, the mixture was cooled, filtered, purified, and dried to obtain the final PEG-PSCU copolymer.

[0065] (5) For each microneedle patch, 10 μg of the vaccine model, VZV glycoprotein E, was added to 120 μl of a 20 wt% PEG-PSCU solution dissolved at pH 8.0. The solution was then dropped into the microneedle hole in the microneedle mold and vacuum-dried at 35°C to prepare the needle tip layer. 15 wt% PVA solution was then added and vacuum-dried at 20°C to prepare the patch layer. After the overall preparation, the entire microneedle patch, which had not been separated from the mold, was placed at -20°C for 12 h, then removed and demolded to obtain a sustained-release microneedle patch with sufficient mechanical strength.

[0066] The performance of the sustained-release microneedle patch described in this example is similar to that of Example 1.

[0067] Example 4

[0068] (1) Sulfadimethoxine (0.10 mol) and sodium hydroxide (0.14 mol) were dissolved in a mixed solvent of acetone and water (100 ml, 1:1 v / v). Acryloyl chloride (0.14 mol) was added dropwise at 5°C and stirred thoroughly. The mixture was stirred and reacted for 6 h. After the reaction, sulfadimethoxine acrylate (abbreviated as SMA) was obtained by filtration, purification, and drying.

[0069] (2) SMA (20 mmol) and 1-thioglycerol (25 mmol) were dissolved in a mixed solvent of methanol and dimethylformamide (80 ml, 1:1 v / v), heated and stirred at 65 °C for 48 h, and then cooled, filtered, purified, and dried to obtain sulfadimethoxine diol (abbreviated as SMD).

[0070] (3) SMD (9 mmol), trimethyl carbonate (9 mmol), and stannous octoate (0.2 mmol) were placed in a vacuum dryer at 60 °C; the reactants were dissolved in anhydrous 1,4-dioxane, and the temperature was slowly raised to 120 °C under nitrogen. After the reaction for 36 h, the mixture was cooled, filtered, purified, and dried to obtain sulfamethazine-linked polytrimethyl carbonate monomer (abbreviated as SM-TMC).

[0071] (4) Polyethylene glycol (1 mmol) with a molecular weight of 2050 g / mol and modified with hydroxyl groups at both ends and dibutyltin dilaurate (0.04 mmol) were placed in a vacuum dryer at 110 °C. When the temperature dropped to 55 °C, the monomer SM-TMC (5 mmol) was added. The reactants were dissolved in anhydrous tetrahydrofuran, and hexamethylene diisocyanate (5.5 mmol) was added. The mixture was heated and stirred at 60 °C. After the reaction for 2 h, the mixture was cooled, filtered, purified, and dried to obtain the final PEG-PSCU copolymer.

[0072] (5) For each microneedle patch, 10 μg of the vaccine model, VZV glycoprotein E, was added to 120 μl of a 20 wt% PEG-PSCU solution dissolved at pH 8.0. The solution was then dropped into the microneedle hole in the microneedle mold and vacuum-dried at 35°C to prepare the needle tip layer. 15 wt% PVA solution was then added and vacuum-dried at 20°C to prepare the patch layer. After the overall preparation, the entire microneedle patch, which had not been separated from the mold, was placed at -20°C for 12 h, then removed and demolded to obtain a sustained-release microneedle patch with sufficient mechanical strength.

[0073] The performance of the sustained-release microneedle patch described in this example is similar to that of Example 1.

[0074] Example 5

[0075] (1) Sulfadimethoxine (0.10 mol) and sodium hydroxide (0.14 mol) were dissolved in a mixed solvent of acetone and water (100 ml, 1:1 v / v). Acryloyl chloride (0.14 mol) was added dropwise at 5°C and stirred thoroughly. The mixture was stirred and reacted for 6 h. After the reaction, sulfadimethoxine acrylate (abbreviated as SMA) was obtained by filtration, purification, and drying.

[0076] (2) SMA (20 mmol) and 1-thioglycerol (25 mmol) were dissolved in a mixed solvent of methanol and dimethylformamide (80 ml, 1:1 v / v), heated and stirred at 65 °C for 48 h, and then cooled, filtered, purified, and dried to obtain sulfadimethoxine diol (abbreviated as SMD).

[0077] (3) SMD (9 mmol), trimethyl carbonate (9 mmol), and stannous octoate (0.2 mmol) were placed in a vacuum dryer at 60 °C; the reactants were dissolved in anhydrous 1,4-dioxane, and the temperature was slowly raised to 120 °C under nitrogen. After the reaction for 36 h, the mixture was cooled, filtered, purified, and dried to obtain sulfamethazine-linked polytrimethyl carbonate monomer (abbreviated as SM-TMC).

[0078] (4) Polyethylene glycol (1 mmol) with a molecular weight of 4000 g / mol and modified with hydroxyl groups at both ends and dibutyltin dilaurate (0.04 mmol) were placed in a vacuum dryer at 110 °C. When the temperature dropped to 60 °C, the monomer SM-TMC (5 mmol) was added. The reactants were dissolved in anhydrous tetrahydrofuran, and hexamethylene diisocyanate (5.5 mmol) was added. The mixture was heated and stirred at 65 °C. After the reaction for 6 h, the mixture was cooled, filtered, purified, and dried to obtain the final PEG-PSCU copolymer.

[0079] (5) For each microneedle patch, 10 μg of the vaccine model, VZV glycoprotein E, was added to 120 μl of a 20 wt% PEG-PSCU solution dissolved at pH 8.0. The solution was then dropped into the microneedle hole in the microneedle mold and vacuum-dried at 35°C to prepare the needle tip layer. 15 wt% PVA solution was then added and vacuum-dried at 20°C to prepare the patch layer. After the overall preparation, the entire microneedle patch, which had not been separated from the mold, was placed at -20°C for 12 h, then removed and demolded to obtain a sustained-release microneedle patch with sufficient mechanical strength.

[0080] The performance of the sustained-release microneedle patch described in this example is similar to that of Example 1.

[0081] Example 6

[0082] (1) Sulfadimethoxine (0.10 mol) and sodium hydroxide (0.14 mol) were dissolved in a mixed solvent of acetone and water (100 ml, 1:1 v / v). Acryloyl chloride (0.14 mol) was added dropwise at 5°C and stirred thoroughly. The mixture was stirred and reacted for 6 h. After the reaction, sulfadimethoxine acrylate (abbreviated as SMA) was obtained by filtration, purification, and drying.

[0083] (2) SMA (20 mmol) and 1-thioglycerol (25 mmol) were dissolved in a mixed solvent of methanol and dimethylformamide (80 ml, 1:1 v / v), heated and stirred at 65 °C for 48 h, and then cooled, filtered, purified, and dried to obtain sulfadimethoxine diol (abbreviated as SMD).

[0084] (3) SMD (9 mmol), trimethyl carbonate (9 mmol), and stannous octoate (0.2 mmol) were placed in a vacuum dryer at 60 °C; the reactants were dissolved in anhydrous 1,4-dioxane, and the temperature was slowly raised to 120 °C under nitrogen. After the reaction for 36 h, the mixture was cooled, filtered, purified, and dried to obtain sulfamethazine-linked polytrimethyl carbonate monomer (abbreviated as SM-TMC).

[0085] (4) Polyethylene glycol (1 mmol) with a molecular weight of 4000 g / mol and modified with hydroxyl groups at both ends and dibutyltin dilaurate (0.04 mmol) were placed in a vacuum dryer at 110 °C. When the temperature dropped to 60 °C, the monomer SM-TMC (5 mmol) was added. The reactants were dissolved in anhydrous tetrahydrofuran, and hexamethylene diisocyanate (5.5 mmol) was added. The mixture was heated and stirred at 65 °C. After the reaction for 6 h, the mixture was cooled, filtered, purified, and dried to obtain the final PEG-PSCU copolymer.

[0086] (5) For each microneedle patch, 15 μg of the vaccine model - VZV glycoprotein E was added to 150 μl of 25 wt% PEG-PSCU solution dissolved at pH 10.0, and then dropped into the microneedle hole in the microneedle mold and vacuum dried at 35°C to prepare the needle tip layer; 20 wt% PVA solution was continued to be added and vacuum dried at 25°C to prepare the patch layer; after the overall preparation, the entire microneedle patch that had not been separated from the mold was placed at -70°C for 24 h, then taken out and demolded to obtain a sustained-release microneedle patch with sufficient mechanical strength.

[0087] The performance of the sustained-release microneedle patch described in this example is similar to that of Example 1.

[0088] Comparative Example 1

[0089] (1) Sulfadimethoxine (0.10 mol) and sodium hydroxide (0.12 mol) were dissolved in a mixed solvent of acetone and water (100 ml, 1:1 v / v). Acryloyl chloride (0.12 mol) was added dropwise at -5°C and stirred thoroughly. The mixture was stirred and reacted for 4 h. After the reaction, sulfadimethoxine acrylate (abbreviated as SMA) was obtained by filtration, purification, and drying.

[0090] (2) SMA (20 mmol) and 1-thioglycerol (21 mmol) were dissolved in a mixed solvent of methanol and dimethylformamide (80 ml, 1:1 v / v), heated and stirred at 50 °C, reacted for 24 h, and then cooled, filtered, purified, and dried to obtain sulfadimethoxine diol (abbreviated as SMD).

[0091] (3) SMD (10 mmol), trimethyl carbonate (10 mmol), and stannous octoate (0.2 mmol) were placed in a vacuum dryer at 50 °C; the reactants were dissolved in anhydrous 1,4-dioxane, and the temperature was slowly raised to 110 °C under nitrogen. After the reaction for 18 h, the mixture was cooled, filtered, purified, and dried to obtain a sulfamethazine-linked polytrimethyl carbonate monomer (abbreviated as SM-TMC).

[0092] (4) Polyethylene glycol (0.1 mmol) with a molecular weight of 2050 g / mol and modified with hydroxyl groups at both ends and dibutyltin dilaurate (0.1 mmol) were placed in a vacuum dryer at 110°C. When the temperature dropped to 60°C, the monomer SM-TMC (0.5 mmol) was added. The reactants were dissolved in anhydrous tetrahydrofuran, and hexamethylene diisocyanate (10 mmol) was added. The mixture was heated and stirred at 60°C. After the reaction for 2 h, the mixture was cooled, filtered, purified, and dried. Due to the inappropriate ratio of the reactants, the final PEG-PSCU copolymer could not be obtained.

[0093] (5) Since PEG-PSCU copolymer was not obtained, microneedles could not be prepared.

[0094] In summary, the invention includes but is not limited to the above embodiments. Any equivalent replacement or partial improvement made under the spirit and principle of the present invention shall be deemed to be within the scope of protection of the present invention.

Claims

1. A biodegradable polymer, characterized in that: The polymer is polyethylene glycol-polysulfadimethoxine carbonate carbamate, and the structural formula is: Among them, n is 33~48, and m is 5~6.

2. A method for preparing a biodegradable polymer according to claim 1, characterized in that: The method comprises the following steps: (1) Dissolving sulfamethazine and an alkali metal hydroxide in a mixed solvent of acetone and water, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide; adding acryloyl chloride dropwise at -5 to 5°C in a protective gas atmosphere, stirring and mixing thoroughly, and then continuing to stir and react for 4 to 6 hours. After the reaction is completed, filtering, purifying, and drying to obtain SMA; wherein the molar ratio of sulfamethazine, alkali metal hydroxide, and acryloyl chloride is 5:6:6 to 5:7:7; (2) dissolving SMA and 1-thioglycerol in a mixed solvent of methanol and dimethylformamide, stirring and reacting at 50-65°C for 24-48 hours, cooling, filtering, purifying, and drying to obtain SMD; wherein the molar ratio of SMA to 1-thioglycerol is 20:21-20:25; (3) drying SMD, trimethyl carbonate and stannous octoate; dissolving SMD, trimethyl carbonate and stannous octoate in anhydrous 1,4-dioxane, heating to 110-120°C under a protective gas atmosphere and reacting for 18-36 hours; cooling, filtering, purifying and drying after the reaction to obtain SM-TMC; wherein the molar ratio of SMD, trimethyl carbonate and stannous octoate is 45:45:1-50:50:1; (4) The polyethylene glycol modified with hydroxyl groups at both ends and the organotin catalyst are dried, and the monomer SM-TMC is added at 55-60°C, and then dissolved in anhydrous tetrahydrofuran, and then diisocyanate is added. The mixture is stirred and reacted at 60-65°C for 2-6 hours. After the reaction is completed, the mixture is cooled, filtered, purified and dried to obtain the final PEG-PSCU copolymer; wherein the relative molecular mass of the polyethylene glycol modified with hydroxyl groups at both ends is 2050-4000 g / mol; and the molar ratio of the polyethylene glycol modified with hydroxyl groups at both ends, the organotin catalyst, SM-TMC and the diisocyanate is 50:2:250:

275.

3. The method for preparing a biodegradable polymer according to claim 2, wherein: In step (1), the volume ratio of acetone to water in the mixed solvent is 2:1 to 1:2; and the stirring rate is 800 to 1000 rpm / min.

4. The method for preparing a biodegradable polymer according to claim 2, wherein: In step (2), the volume ratio of methanol to dimethylformamide in the mixed solvent is 2:1 to 1:

2.

5. The method for preparing a biodegradable polymer according to claim 2, wherein: In step (3), the drying condition is vacuum drying at 50-60°C.

6. The method for preparing a biodegradable polymer according to claim 2, wherein: In step (4), the drying condition is vacuum drying at 110-120°C; The organotin catalyst is dibutyltin dilaurate and / or stannous octoate; The diisocyanate is one or more of hexamethylene diisocyanate, diphenylmethane diisocyanate, toluene diisocyanate and isophorone diisocyanate.

7. A sustained-release microneedle patch, characterized in that: It comprises a needle tip layer and a patch layer, wherein the biodegradable material loaded with active components in the needle tip layer adopts the biodegradable polymer according to claim 1; and the active component is a hydrophilic protein vaccine or a nano nucleic acid vaccine.

8. The sustained-release microneedle patch according to claim 7, characterized in that: The active component is VZV glycoprotein E.

9. A method for preparing the sustained-release microneedle patch according to claim 7 or 8, characterized in that: The method comprises the following steps: Active components are added to the biodegradable polymer solution, which is then dripped into the microneedle holes in the microneedle mold and dried to prepare a needle tip layer; PVA solution is then added, dried to prepare a patch layer, and then frozen and demolded to obtain a sustained-release microneedle patch; The concentration of the biodegradable polymer solution is 20-25wt%, the dissolution condition is an aqueous solution with a pH of 8.0-10.0, the mass ratio of the volume of the biodegradable polymer solution to the active component is 120-150μl:10-15μg, and the drying conditions for preparing the needle tip layer are vacuum drying at 35-37°C; the concentration of the PVA solution is 15-20wt%, and the drying conditions for preparing the patch layer are vacuum drying at 20-25°C; the freezing temperature is -20--70°C, and the freezing time is 12-24h.

10. A use of the sustained-release microneedle patch according to claim 7 or 8, characterized in that: The sustained-release microneedle patch is used for sustained-release and delivery of active components under simulated microgravity.

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