pH-responsive double-network gel microspheres and their preparation method and application

Abstract

The present invention discloses a double-network gel microsphere with pH response and its preparation method and application. The preparation method comprises: reacting indolepropionic acid with 2-hydroxyethyl vinyl ether under the catalytic action of EDC and NHS to prepare indolepropionic acid-2-hydroxyethyl vinyl ether polymer; reacting the indolepropionic acid-2-hydroxyethyl vinyl ether polymer with high-amylose starch under the catalytic action of p-toluenesulfonamide to prepare indolepropionic acid grafted starch; and mixing the indolepropionic acid grafted starch, sodium alginate and water as a dispersed phase; making a solution containing at least a surfactant as a continuous phase, and then using microfluidic technology to prepare double-network gel microspheres with pH response. The double-network gel microspheres with pH response prepared by the present invention have good thermal stability and pH responsiveness, and can achieve the processing of indolepropionic acid and polyphenols and the stability of oral delivery.

Description

Technical Field

[0001] The present invention belongs to the fields of food, biomaterials, microfluidics and embedding delivery technology, and particularly relates to a double-network gel microsphere with pH response, a preparation method and an application thereof. Background Art

[0002] Tryptophan is found in high concentrations in many foods, including cruciferous vegetables and meat, and can be broken down into a series of metabolites by intestinal microorganisms in the colon. Indolepropionic acid, as a metabolite of tryptophan, has multiple health benefits, including regulating plant growth and participating in the balance of human intestinal flora. Indolepropionic acid regulates intestinal immune homeostasis by binding to aryl hydrocarbon receptors and inhibiting proinflammatory cytokine levels and inflammatory responses. It has been reported that the concentration of indolepropionic acid in the feces of patients with colitis is reduced. Therefore, increasing the content of indolepropionic acid in the colon can effectively prevent and alleviate the symptoms of intestinal inflammation. However, the stability and bioavailability of indolepropionic acid in the body are limited, and an effective delivery system is needed to enhance its efficacy.

[0003] Dietary polyphenols not only have anti-inflammatory and anti-cancer properties, but also protect against chronic non-communicable diseases such as cardiovascular and cerebrovascular diseases, type 2 diabetes, and cognitive impairment. They can also regulate intestinal flora and enhance immunity, making them a recognized functional factor in healthy foods. However, dietary polyphenols are generally sensitive to light and heat, and are easily decomposed and oxidized during processing, resulting in insufficient daily intake. Furthermore, polyphenols are easily destroyed by the upper digestive tract in the human body, making them difficult to absorb and utilize in the intestines, thus preventing them from fully exerting their efficacy.

[0004] In the field of biomaterials, high-amylose starch and sodium alginate have been widely studied and applied due to their unique physicochemical properties and biocompatibility. High-amylose starch, due to its high resistant starch content and excellent barrier properties, is used to prepare oral matrices for controlled drug release. High-amylose starch is a resistant starch that resists breakdown by gastric acid and enzymes and is degraded by intestinal microorganisms to produce short-chain fatty acids. Therefore, high-amylose starch not only functions as a dietary fiber to promote intestinal motility but also releases short-chain fatty acids to promote the proliferation of probiotics. Given the resistance of high-amylose starch to small intestinal digestion, grafting indolepropionic acid onto high-amylose starch may be an effective method for the stable delivery of indolepropionic acid. Sodium alginate, a natural polysaccharide, is often used to prepare hydrogels for drug delivery and tissue engineering due to its excellent biocompatibility and gelation properties. However, single sodium alginate gels have low mechanical strength and are prone to structural deformation, defects, and even collapse when subjected to compression or shear, resulting in premature exposure of the embedded material. Summary of the Invention

[0005] The main purpose of the present invention is to provide a double-network gel microsphere with pH response and its preparation method and application, so as to overcome the shortcomings of the prior art.

[0006] To achieve the aforementioned object of the invention, the technical solutions adopted by the present invention include:

[0007] The embodiment of the present invention provides a method for preparing pH-responsive double-network gel microspheres, which comprises:

[0008] Under the catalysis of EDC and NHS, indolepropionic acid reacts with 2-hydroxyethyl vinyl ether to prepare indolepropionic acid-2-hydroxyethyl vinyl ether polymer;

[0009] Under the catalytic action of p-toluenesulfonamide, the indolepropionic acid-2-hydroxyethyl vinyl ether polymer is reacted with high-amylose starch to prepare indolepropionic acid grafted starch;

[0010] Furthermore, the indolepropionic acid grafted starch, sodium alginate and water are mixed as a dispersed phase; a solution containing a surfactant is used as a continuous phase, and then microfluidic technology is used to prepare double-network gel microspheres with pH response.

[0011] The embodiment of the present invention also provides pH-responsive double-network gel microspheres prepared by the aforementioned preparation method.

[0012] The embodiment of the present invention also provides the use of the aforementioned pH-responsive double-network gel microspheres in a drug delivery system.

[0013] An embodiment of the present invention also provides a method for preparing a pH-responsive drug delivery system, comprising:

[0014] Under the catalysis of EDC and NHS, indolepropionic acid reacts with 2-hydroxyethyl vinyl ether to prepare indolepropionic acid-2-hydroxyethyl vinyl ether polymer;

[0015] Under the catalytic action of p-toluenesulfonamide, the indolepropionic acid-2-hydroxyethyl vinyl ether polymer is reacted with high-amylose starch to prepare indolepropionic acid grafted starch;

[0016] Furthermore, the indolepropionic acid grafted starch, sodium alginate and water are mixed as a dispersed phase; an oil solution containing at least a surfactant and polyphenols is used as a continuous phase, and then a pH-responsive drug delivery system is prepared using microfluidic technology.

[0017] The embodiment of the present invention also provides a pH-responsive drug delivery system prepared by the aforementioned preparation method.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] (1) The present invention effectively solves the problem of low oral bioavailability of indolepropionic acid and polyphenols by co-delivering indolepropionic acid and polyphenols, thereby improving their absorption and utilization efficiency in the body, thereby improving bioavailability;

[0020] (2) The indolepropionic acid grafted starch polymer prepared by the present invention has pH responsiveness and can respond under a specific pH environment to achieve controlled release of drugs, thereby improving the efficacy of drugs and reducing side effects;

[0021] (3) The present invention introduces acetal bonds and calcium ion induction to prepare pH-responsive double-network gel microspheres and pH-responsive drug delivery systems, thereby enhancing the mechanical strength and stability of the gel microspheres;

[0022] (4) The present invention utilizes microfluidic technology to precisely control the size and uniformity of gel microspheres, providing a more precise and controllable carrier for drug delivery;

[0023] (5) The present invention prepares a novel grafted starch polymer by grafting indolepropionic acid onto high-amylose starch, thereby broadening the application field of starch-based materials;

[0024] (6) The preparation method of the present invention is simple to operate, easy to scale up for production, and conducive to industrial application;

[0025] (7) Through the optimized preparation process, the present invention achieves efficient encapsulation of indolepropionic acid and polyphenols, thereby increasing the drug loading capacity;

[0026] (8) The present invention uses high-amylose starch and sodium alginate as the main raw materials, and the prepared gel microspheres and drug delivery systems have good biocompatibility and are suitable for oral drug delivery;

[0027] (9) The raw materials and solvents used in the preparation process of the present invention are easily degradable, environmentally friendly, and meet the requirements of green chemistry;

[0028] (10) The drug delivery system prepared by the present invention can not only be used for the delivery of indolepropionic acid and polyphenols, but can also be extended to the delivery of other drugs or active ingredients, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0030] Figure 1is a schematic diagram of a microfluidic device in a typical embodiment of the present invention;

[0031] Figure 2 Graph showing the release rate of indolepropionic acid from the indolepropionic acid grafted high-amylose starch prepared in Examples 1-4 of the present invention in solutions with different pH values;

[0032] Figure 3 Graph showing the particle size of indolepropionic acid grafted high-amylose starch / sodium alginate gel microspheres prepared in Examples 1-4 of the present invention;

[0033] Figure 4 This is a graph showing the cytotoxicity of the indolepropionic acid grafted high-amylose starch / sodium alginate solution prepared in Examples 1-4 of the present invention;

[0034] Figure 5 3 is a graph showing the release rate of gallic acid under different pH conditions from the indolepropionic acid grafted high-amylose starch / sodium alginate / gallic acid gel microspheres prepared in Example 4 of the present invention;

[0035] Figure 6 3 is a graph showing the release rate of gallic acid from the indolepropionic acid grafted high-amylose starch / sodium alginate / gallic acid gel microspheres prepared in Example 4 of the present invention under different temperature conditions;

[0036] Figure 7 The figure is a reaction flow chart of the preparation process of indolepropionic acid grafted high-amylose starch in a typical embodiment of the present invention. DETAILED DESCRIPTION

[0037] In view of the defects of the existing technology, the inventors of this case have proposed the technical solution of the present invention after long-term research and extensive practice. The technical solution mainly uses high-amylose starch and sodium alginate as raw materials, introduces acetal bonds to prepare pH-responsive indolepropionic acid grafted starch polymers, and then mixes them with sodium alginate aqueous solution. Finally, microfluidic technology is used to prepare oral microgel beads for co-delivering indolepropionic acid and polyphenols to solve the problem of low oral bioavailability of indolepropionic acid and polyphenols.

[0038] The technical solution of the present invention will be described clearly and completely below. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0039] Specifically, as one aspect of the technical solution of the present invention, a method for preparing pH-responsive double-network gel microspheres includes:

[0040] Under the catalysis of EDC and NHS, indolepropionic acid reacts with 2-hydroxyethyl vinyl ether to prepare indolepropionic acid-2-hydroxyethyl vinyl ether polymer;

[0041] Under the catalytic action of p-toluenesulfonamide, the indolepropionic acid-2-hydroxyethyl vinyl ether polymer is reacted with high-amylose starch to prepare indolepropionic acid grafted starch;

[0042] Furthermore, the indolepropionic acid grafted starch, sodium alginate and water are mixed as a dispersed phase; a solution containing a surfactant is used as a continuous phase, and then microfluidic technology is used to prepare double-network gel microspheres with pH response.

[0043] In some preferred embodiments, the preparation method specifically comprises: mixing indolepropionic acid, EDC, NHS and a solvent and stirring at room temperature for 8-12 hours to form a mixed solution, then adding 2-hydroxyethyl vinyl ether (HEVE) and stirring at 40-60° C. for 18-24 hours, and then dialyzing, centrifuging, washing, and freeze-drying to obtain indolepropionic acid-2-hydroxyethyl vinyl ether polymer.

[0044] Specifically, the preparation method of the indolepropionic acid-2-hydroxyethyl vinyl ether polymer (indolepropionic acid-HEVE polymer) includes: dissolving 5% (w / v) indolepropionic acid, 2.5% (w / v) EDC and 1% (w / v) NHS in DMF, stirring at 300 rpm at room temperature for 12 hours to obtain a homogeneous transparent solution, adding 1% (v / v) 2-hydroxyethyl vinyl ether (HEVE) to the solution, magnetically stirring in a 40°C water bath for 24 hours, dialyzing for three days, centrifuging and washing the precipitate three times, and freeze-drying to obtain indolepropionic acid-HEVE polymer powder.

[0045] In some preferred embodiments, the preparation method specifically includes: mixing high-amylose starch, indolepropionic acid-2-hydroxyethyl vinyl ether polymer, p-toluenesulfonamide (p-TSA) and a solvent and stirring the mixture at room temperature for 48 hours, followed by dialysis, centrifugation, washing, and freeze-drying to obtain indolepropionic acid grafted starch.

[0046] Specifically, the preparation method of the indolepropionic acid grafted starch includes: adding 4% (w / v) high-amylose starch, 2% (w / v) indolepropionic acid-HEVE and 0.1% (w / v) p-TSA to a DMF solution, stirring at room temperature for 48 hours, placing the mixture in a dialysis bag with a molecular weight cutoff of 8k-14kDa, dialyzing in distilled water for one week, centrifuging and washing the precipitate three times, and freeze-drying to obtain the indolepropionic acid grafted high-amylose starch.

[0047] The reaction flow chart of the preparation process of indolepropionic acid grafted high amylose starch in the present invention is as follows: Figure 7 shown.

[0048] In some preferred embodiments, the preparation method specifically comprises:

[0049] mixing indolepropionic acid grafted starch, sodium alginate and water to form a first mixed solution;

[0050] forming a second mixed solution from a solution containing a surfactant;

[0051] In addition, using microfluidic technology, the first mixed solution is passed into the first channel (microfluidic chip channel 1) as the dispersed phase, and the second mixed solution is passed into the second channel (microfluidic chip channel 2) of the microfluidic chip as the continuous phase. The generated microspheres are then allowed to stand and solidify in a calcium chloride solution to obtain pH-responsive double-network gel microspheres.

[0052] Furthermore, the inner diameter of the circular capillary used in the microfluidic chip channel 1 is 180-260 μm.

[0053] Furthermore, the inner diameter of the circular capillary of the microfluidic chip channel 2 is 120-200 μm.

[0054] Specifically, the preparation method of the pH-responsive double-network gel microspheres includes:

[0055] Sodium alginate and indolepropionic acid grafted starch were mixed at a mass ratio of 10:1, 5:1 and 1:1 and dissolved in distilled water to prepare a 1% (w / v) mixed solution;

[0056] The mixed solution was passed into channel 1 of the microfluidic chip as the dispersed phase, and the mixed solution containing 2% surfactant was passed into channel 2 of the microfluidic chip as the continuous phase. After the microspheres were uniformly generated, they could be collected into centrifuge tubes and allowed to stand in calcium chloride for 30 minutes to solidify.

[0057] In some more specific embodiments, the method for preparing the pH-responsive double-network gel microspheres comprises:

[0058] Step 1: Preparation of indolepropionic acid-HEVE polymer: Indolepropionic acid and 2-hydroxyethyl vinyl ether (HEVE) were used as raw materials to prepare indolepropionic acid-HEVE under the catalysis of EDC and NHS. After dialysis for three days, the precipitate was washed by centrifugation three times and freeze-dried to obtain indolepropionic acid-HEVE polymer powder;

[0059] Step 2: Preparation of indolepropionic acid grafted starch: The indolepropionic acid-HEVE prepared in step 1.1 is mixed with high-amylose starch, and the indolepropionic acid-HEVE and high-amylose starch are combined under the catalysis of p-toluenesulfonamide (p-TSA) to prepare pH-responsive indolepropionic acid grafted starch;

[0060] Step 3: preparing an indolepropionic acid grafted starch / sodium alginate mixed solution: sodium alginate and indolepropionic acid grafted starch were mixed at a mass ratio of 10:1, 5:1, and 1:1, and dissolved in distilled water to prepare a 1% (w / v) mixed solution;

[0061] Step 4. Preparation of indolepropionic acid grafted starch / sodium alginate gel microspheres: The solution prepared in step 3 was passed into channel 1 of the microfluidic chip as the dispersed phase, and a solution containing 2% surfactant was passed into channel 2 of the microfluidic chip as the continuous phase. After the microspheres were uniformly generated, they were collected into centrifuge tubes and allowed to stand in calcium chloride for 30 minutes to solidify.

[0062] Another aspect of the embodiments of the present invention further provides pH-responsive double-network gel microspheres prepared by the aforementioned preparation method.

[0063] Another aspect of the embodiments of the present invention further provides the use of the aforementioned pH-responsive double-network gel microspheres in a drug delivery system.

[0064] Another aspect of the embodiments of the present invention further provides a method for preparing a pH-responsive drug delivery system, comprising:

[0065] Under the catalysis of EDC and NHS, indolepropionic acid reacts with 2-hydroxyethyl vinyl ether to prepare indolepropionic acid-2-hydroxyethyl vinyl ether polymer;

[0066] Under the catalytic action of p-toluenesulfonamide, the indolepropionic acid-2-hydroxyethyl vinyl ether polymer is reacted with high-amylose starch to prepare indolepropionic acid grafted starch;

[0067] Furthermore, the indolepropionic acid grafted starch, sodium alginate and water are mixed as a dispersed phase; an oil solution containing at least a surfactant and polyphenols is used as a continuous phase, and then a pH-responsive drug delivery system is prepared using microfluidic technology.

[0068] In some preferred embodiments, the preparation method specifically includes: mixing indolepropionic acid, EDC, NHS and a solvent and stirring at room temperature for 8-12 hours to form a mixed solution, then adding 2-hydroxyethyl vinyl ether and stirring at 40-60°C for 18-24 hours, and then dialyzing, centrifuging, washing, and freeze-drying to obtain indolepropionic acid-2-hydroxyethyl vinyl ether polymer.

[0069] Specifically, the preparation method of the indolepropionic acid-2-hydroxyethyl vinyl ether polymer (indolepropionic acid-HEVE polymer) includes: dissolving 5% (w / v) indolepropionic acid, 2.5% (w / v) EDC and 1% (w / v) NHS in DMF, stirring at 300 rpm at room temperature for 12 hours to obtain a homogeneous transparent solution, adding 1% (v / v) 2-hydroxyethyl vinyl ether (HEVE) to the solution, magnetically stirring in a 40°C water bath for 24 hours, dialyzing for three days, centrifuging and washing the precipitate three times, and freeze-drying to obtain indolepropionic acid-HEVE polymer powder.

[0070] In some preferred embodiments, the preparation method specifically includes: mixing high-amylose starch, indolepropionic acid-2-hydroxyethyl vinyl ether polymer, p-toluenesulfonamide and a solvent and stirring the mixture at room temperature for 48 hours, followed by dialysis, centrifugation, washing and freeze-drying to obtain indolepropionic acid grafted starch.

[0071] Specifically, the preparation method of the indolepropionic acid grafted starch includes: adding 4% (w / v) high-amylose starch, 2% (w / v) indolepropionic acid-HEVE and 0.1% (w / v) p-TSA to a DMF solution, stirring at room temperature for 48 hours, placing the mixture in a dialysis bag with a molecular weight cutoff of 8k-14kDa, dialyzing in distilled water for one week, centrifuging and washing the precipitate three times, and freeze-drying to obtain the indolepropionic acid grafted high-amylose starch.

[0072] In some preferred embodiments, the preparation method specifically comprises:

[0073] mixing indolepropionic acid grafted starch, sodium alginate and water to form a third mixed solution;

[0074] forming a fourth mixed solution from an oil solution containing a surfactant and polyphenols;

[0075] In addition, using microfluidic technology, the third mixed solution is passed into the first channel of the microfluidic chip (microfluidic chip channel 1) as the dispersed phase, and the fourth mixed solution is passed into the second channel of the microfluidic chip (microfluidic chip channel 2) as the continuous phase. The generated microspheres are then allowed to stand and solidify in a calcium chloride solution to obtain pH-responsive double-network gel microspheres.

[0076] Furthermore, the inner diameter of the circular capillary used in the microfluidic chip channel 1 is 180-260 μm.

[0077] Furthermore, the inner diameter of the circular capillary of the microfluidic chip channel 2 is 120-200 μm.

[0078] In some preferred embodiments, the high-amylose starch includes any one or more combinations of high-amylose corn starch, high-amylose wheat starch, and isoamylase-hydrolyzed corn starch, but is not limited thereto.

[0079] In some preferred embodiments, the polyphenols include any one or more combinations of gallic acid, ursolic acid, ferulic acid, berberine, magnolol, and coumarin, but are not limited thereto.

[0080] In some preferred embodiments, the surfactant includes any one or more combinations of Tween 80, Span 20, Span 40, and Span 60, but is not limited thereto.

[0081] In some preferred embodiments, the solvent includes DMF and / or DMSO, but is not limited thereto.

[0082] In some preferred embodiments, the oil solution includes any one or more combinations of corn oil, soybean oil, palm oil, and sunflower oil, but is not limited thereto.

[0083] In some more specific embodiments, the method for preparing the pH-responsive drug delivery system comprises:

[0084] S1. Preparation of indolepropionic acid-HEVE polymer: Using high-amylose corn starch, indolepropionic acid, and 2-hydroxyethyl vinyl ether (HEVE) as raw materials, indolepropionic acid-HEVE was first prepared under the catalysis of EDC and NHS. After dialysis for three days, the precipitate was washed by centrifugation three times and freeze-dried to obtain indolepropionic acid-HEVE polymer powder.

[0085] S2. Preparation of indolepropionic acid grafted starch: The indolepropionic acid-HEVE prepared in S1 was mixed with high-amylose starch, and the indolepropionic acid-HEVE and high-amylose starch were combined under the catalysis of p-toluenesulfonamide (p-TSA) to prepare pH-responsive indolepropionic acid grafted starch.

[0086] S3. Prepare an indolepropionic acid grafted starch / sodium alginate mixed solution: Sodium alginate and indolepropionic acid grafted starch are mixed at mass ratios of 10:1, 5:1 and 1:1, and dissolved in distilled water to prepare a 1% (w / v) mixed solution.

[0087] S4. Preparation of indolepropionic acid grafted starch / sodium alginate gel microspheres (i.e., pH-responsive double-network gel microspheres): The solution prepared in S3 was passed into channel 1 of the microfluidic chip as the dispersed phase, and an oil solution containing 2% of a surfactant was passed into channel 2 of the microfluidic chip as the continuous phase. After the microspheres were uniformly generated, they were received into a centrifuge tube in channel 3, and the collected microspheres were allowed to stand in calcium chloride for 30 minutes to solidify.

[0088] S5. Preparation of indolepropionic acid grafted starch / sodium alginate / polyphenol gel microspheres (i.e., a pH-responsive drug delivery system): The indolepropionic acid grafted starch / sodium alginate aqueous solution prepared in S4 was introduced into channel 1 of the microfluidic chip as the dispersed phase, and an oil solution containing 2% surfactant and 1% (w / v) polyphenol was introduced into channel 2 of the microfluidic chip as the continuous phase. After the microspheres were uniformly generated, they were collected into centrifuge tubes and allowed to stand in calcium chloride for 30 minutes to solidify.

[0089] As a further technical solution, the polyphenols described in step S5 are gallic acid, ursolic acid, ferulic acid, berberine, magnolol and coumarin.

[0090] As a further technical solution, the preparation method of the indolepropionic acid-HEVE polymer described in step S1 includes the following steps: 5% (w / v) indolepropionic acid, 2.5% (w / v) EDC, and 1% (w / v) NHS are dissolved in DMF and stirred at 300 rpm at room temperature for 12 hours to obtain a homogeneous transparent solution. 1% (v / v) 2-hydroxyethyl vinyl ether (HEVE) is added to the solution and magnetically stirred in a 40°C water bath for 24 hours. The mixture is placed in a dialysis bag with a molecular weight cutoff of 8k-14kDa and dialyzed in distilled water for three days to obtain indolepropionic acid-EGVE. After centrifugation, the supernatant is removed, the sediment is washed with distilled water three times, and then stored in a refrigerator at -20°C for 12 hours. It is then freeze-dried at -50°C and a vacuum degree of 20Pa for 24 hours to obtain an indolepropionic acid-EGVE complex powder.

[0091] As a further technical solution, the method for preparing indolepropionic acid-grafted high-amylose starch described in step S2 comprises the following steps: 4% (w / v) high-amylose starch, 2% (w / v) indolepropionic acid-HEVE, and 0.1% (w / v) p-TSA are added to a DMF solution, stirred at room temperature for 48 hours, and then placed in a dialysis bag with a molecular weight cutoff of 8k-14kDa and dialyzed in distilled water for one week. The liquid inside the dialysis bag is centrifuged, the precipitate is washed three times with distilled water, and then stored in a refrigerator at -20°C for 12 hours. The mixture is then freeze-dried at -50°C and a vacuum of 20Pa for 24 hours to obtain the indolepropionic acid-grafted starch.

[0092] As a further technical solution, the method for preparing the indolepropionic acid grafted starch / sodium alginate gel microspheres described in step S4 includes the following steps: adding a 1% (w / v) mixed solution of sodium alginate and indolepropionic acid grafted starch prepared in step S3 to the dispersed phase reservoir and passing it through channel 1 of the microfluidic chip; adding an oil solution containing 2% (w / v) surfactant and 1% (w / v) polyphenol to the continuous phase reservoir and passing it through channel 2 of the microfluidic chip.

[0093] Furthermore, the pressure of channel 1 (dispersed phase, 250 mbar) and the pressure of channel 2 (continuous phase, 250 mbar) were set to exhaust the air in the pipeline and the chip.

[0094] Furthermore, after the pipeline and the chip are filled with liquid, the entire system is switched from pressure control to flow rate control, and the flow rate of channel 1 (2 mL / h) and the flow rate of channel 2 (2 mL / h) are set.

[0095] Furthermore, after the microspheres are generated uniformly and stably, they can be collected in channel 3; after a period of time, the collection is stopped, the microspheres are sealed in a centrifuge tube, and allowed to stand in a 2% calcium chloride solution for 10 minutes to solidify.

[0096] Furthermore, the inner diameter of the circular capillary for the mobile phase selected in the microfluidic chip is 240 μm, and the inner diameter of the circular capillary for the continuous phase is 180 μm.

[0097] As a further technical solution, the preparation of indolepropionic acid grafted starch / sodium alginate / polyphenol gel microspheres described in step S5 includes the following steps: the indolepropionic acid grafted starch / sodium alginate aqueous solution prepared in S4 is introduced into channel 1 of the microfluidic chip as a dispersed phase, and an oil solution containing 2% surfactant and 1% (w / v) polyphenol is introduced into channel 2 of the microfluidic chip as a continuous phase. After the microspheres are uniformly generated, they can be collected into a centrifuge tube and the collected microspheres are allowed to stand in calcium chloride for 30 minutes to solidify.

[0098] Furthermore, the pressure of channel 1 (dispersed phase, 250 mbar) and the pressure of channel 2 (continuous phase, 250 mbar) were set to exhaust the air in the pipeline and the chip.

[0099] Furthermore, after the pipeline and the chip are filled with liquid, the entire system is switched from pressure control to flow rate control, and the flow rate of channel 1 (2 mL / h) and the flow rate of channel 2 (2 mL / h) are set.

[0100] Furthermore, after the microspheres are generated uniformly and stably, they can be collected in channel 3; after a period of time, the collection is stopped, the microspheres are sealed in a centrifuge tube, and allowed to stand in a 2% calcium chloride solution for 10 minutes to solidify.

[0101] Furthermore, the inner diameter of the circular capillary for the mobile phase selected in the microfluidic chip is 240 μm, and the inner diameter of the circular capillary for the continuous phase is 180 μm.

[0102] The schematic diagram of the microfluidic device used in the present invention is as follows Figure 1 shown.

[0103] Another aspect of the embodiments of the present invention further provides a pH-responsive drug delivery system prepared by the aforementioned preparation method.

[0104] The pH-responsive drug delivery system prepared by the present invention has the advantages of improving drug efficacy, reducing side effects, and accurately controlling release, and is of great significance for improving the oral bioavailability of drugs.

[0105] The present invention provides a double-network gel microsphere with pH response and its preparation method and application. The method introduces a pH-responsive bond (acetal bond) into indolepropionic acid and high-amylose starch to prepare a grafted starch polymer with indolepropionic acid that is specifically cleaved and released at pH 5-7. The indolepropionic acid grafted starch is cross-linked with sodium alginate through calcium ions, and a double-network gel microsphere for co-delivering indolepropionic acid and polyphenols is prepared by microfluidic technology. The introduction of the acetal bond gives the gel microspheres pH responsiveness, avoiding the damage of indolepropionic acid and polyphenols by the oral and gastric environments. Indolepropionic acid, as a prebiotic, can regulate intestinal flora, promote the decomposition of short-chain fatty acids in the intestine, improve the intestinal flora microenvironment and prevent intestinal inflammation. The double-network gel microspheres with pH-responsive release of indolepropionic acid grafted starch / sodium alginate prepared by the present invention have good thermal stability and pH responsiveness, and can achieve the processing of indolepropionic acid and polyphenols and the stability of oral delivery.

[0106] The technical solution of the present invention is further described in detail below in conjunction with several preferred embodiments and the accompanying drawings. This embodiment is implemented on the premise of the technical solution of the invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0107] Unless otherwise specified, the experimental materials used in the following examples can be purchased from conventional biochemical reagent companies.

[0108] Example 1

[0109] A preparation method and application of pH-responsive indolepropionic acid grafted starch / sodium alginate double-network gel microspheres, comprising the following steps:

[0110] S1. Preparation of indolepropionic acid-HEVE polymer: 5% (w / v) indolepropionic acid, 2.5% (w / v) EDC and 1% (w / v) NHS were dissolved in DMF and stirred at 300 rpm at room temperature for 12 hours to obtain a homogeneous transparent solution. 1% (v / v) 2-hydroxyethyl vinyl ether (HEVE) was added to the solution and magnetically stirred in a 40°C water bath for 24 hours. The mixture was placed in a dialysis bag with a molecular weight cutoff of 8k-14kDa and dialyzed in distilled water for three days to obtain indolepropionic acid-HEVE. After centrifugation, the supernatant was removed, the sediment was washed with distilled water three times, and then stored in a -20°C refrigerator for 12 hours. The indolepropionic acid-HEVE polymer powder was obtained by vacuum freeze drying at -50°C and a vacuum degree of 20Pa for 24 hours.

[0111] S2. Preparation of indolepropionic acid grafted starch: 4% (w / v) high-amylose starch, 2% (w / v) indolepropionic acid-HEVE, and 0.1% (w / v) p-TSA were added to a DMF solution. After stirring at room temperature for 48 hours, the mixture was placed in a dialysis bag with a molecular weight cutoff of 8k-14kDa and dialyzed in distilled water for one week. The liquid inside the dialysis bag was centrifuged, and the precipitate was washed three times with distilled water and stored in a refrigerator at -20°C for 12 hours. It was then freeze-dried at -50°C and a vacuum degree of 20Pa for 24 hours to obtain indolepropionic acid grafted starch.

[0112] S3. Prepare an indolepropionic acid grafted starch / sodium alginate mixed solution: Mix sodium alginate and indolepropionic acid grafted starch in a mass ratio of 10:1, dissolve in distilled water to prepare a 1% (w / v) mixed solution, and stir thoroughly at room temperature until the powder is evenly dispersed;

[0113] S4. Preparation of indolepropionic acid grafted starch / sodium alginate gel microspheres: A 1% (w / v) mixed solution of sodium alginate and indolepropionic acid grafted starch prepared in step S3 was added to the dispersed phase reservoir and passed through channel 1 of the microfluidic chip. A mixed oil solution containing 2% (w / v) of the surfactant Tween 80 was added to the continuous phase reservoir and passed through channel 2 of the microfluidic chip. The microfluidic chip was connected to a peristaltic pump via capillary glass tubing. The inner diameter of the circular capillary for the mobile phase was 240 μm, and the inner diameter of the circular capillary for the continuous phase was 180 μm. The pressures of channel 1 (dispersed phase, 250 mbar) and channel 2 (continuous phase, 250 mbar) were set to expel air from the pipeline and chip. After the pipeline and chip were filled with liquid, the entire system was switched from pressure control to flow rate control, and the flow rates of channel 1 and channel 2 were set to 2 mL / h. After the microspheres are uniformly generated, they can be collected into 1.5 mL centrifuge tubes. After a period of time, the collection is stopped, the tubes are sealed, and the tubes are placed in a 2% calcium chloride solution for 10 minutes to solidify.

[0114] Example 2

[0115] S1. Preparation of indolepropionic acid-HEVE polymer: 5% (w / v) indolepropionic acid, 2.5% (w / v) EDC and 1% (w / v) NHS were dissolved in DMF and stirred at 300 rpm at room temperature for 12 hours to obtain a homogeneous transparent solution. 1% (v / v) 2-hydroxyethyl vinyl ether (HEVE) was added to the solution and magnetically stirred in a 40°C water bath for 24 hours. The mixture was placed in a dialysis bag with a molecular weight cutoff of 8k-14kDa and dialyzed in distilled water for three days to obtain indolepropionic acid-HEVE. After centrifugation, the supernatant was removed, the sediment was washed with distilled water three times, and then stored in a -20°C refrigerator for 12 hours. It was then freeze-dried at -50°C and a vacuum degree of 20Pa for 24 hours to obtain an indolepropionic acid-HEVE complex powder.

[0116] S2. Preparation of indolepropionic acid grafted starch: 4% (w / v) high-amylose starch, 2% (w / v) indolepropionic acid-HEVE, and 0.1% (w / v) p-TSA were added to a DMF solution. After stirring at room temperature for 48 hours, the mixture was placed in a dialysis bag with a molecular weight cutoff of 8k-14kDa and dialyzed in distilled water for one week. The liquid inside the dialysis bag was centrifuged, and the precipitate was washed three times with distilled water and stored in a refrigerator at -20°C for 12 hours. It was then freeze-dried at -50°C and a vacuum degree of 20Pa for 24 hours to obtain indolepropionic acid grafted starch.

[0117] S3. Prepare an indolepropionic acid grafted starch / sodium alginate mixed solution: Sodium alginate and indolepropionic acid grafted starch are mixed in a mass ratio of 5:1 and dissolved in distilled water to prepare a 1% (w / v) mixed solution. Stir thoroughly at room temperature until the powder is evenly dispersed.

[0118] S4. Preparation of indolepropionic acid grafted starch / sodium alginate gel microspheres: A 1% (w / v) mixed solution of sodium alginate and indolepropionic acid grafted starch prepared in step S3 was added to the dispersed phase reservoir and passed through channel 1 of the microfluidic chip. A mixed oil solution containing 2% (w / v) of the surfactant Tween 80 was added to the continuous phase reservoir and passed through channel 2 of the microfluidic chip. The microfluidic chip was connected to a peristaltic pump via capillary glass tubing. The inner diameter of the circular capillary for the mobile phase was 240 μm, and the inner diameter of the circular capillary for the continuous phase was 180 μm. The pressures of channel 1 (dispersed phase, 250 mbar) and channel 2 (continuous phase, 250 mbar) were set to expel air from the pipeline and chip. After the pipeline and chip were filled with liquid, the entire system was switched from pressure control to flow rate control, and the flow rates of channel 1 and channel 2 were set to 2 mL / h. After the microspheres are uniformly generated, they can be collected into 1.5 mL centrifuge tubes. After a period of time, the collection is stopped, the tubes are sealed, and the tubes are placed in a 2% calcium chloride solution for 10 minutes to solidify.

[0119] Example 3

[0120] S1. Preparation of indolepropionic acid-HEVE polymer: 5% (w / v) indolepropionic acid, 2.5% (w / v) EDC and 1% (w / v) NHS were dissolved in DMF and stirred at 300 rpm at room temperature for 12 hours to obtain a homogeneous transparent solution. 1% (v / v) 2-hydroxyethyl vinyl ether (HEVE) was added to the solution and magnetically stirred in a 40°C water bath for 24 hours. The mixture was placed in a dialysis bag with a molecular weight cutoff of 8k-14kDa and dialyzed in distilled water for three days to obtain indolepropionic acid-HEVE. After centrifugation, the supernatant was removed, the sediment was washed with distilled water three times, and then stored in a -20°C refrigerator for 12 hours. It was then freeze-dried at -50°C and a vacuum degree of 20Pa for 24 hours to obtain an indolepropionic acid-HEVE complex powder.

[0121] S2. Preparation of indolepropionic acid grafted starch: 4% (w / v) high-amylose starch, 2% (w / v) indolepropionic acid-HEVE, and 0.1% (w / v) p-TSA were added to a DMF solution. After stirring at room temperature for 48 hours, the mixture was placed in a dialysis bag with a molecular weight cutoff of 8k-14kDa and dialyzed in distilled water for one week. The liquid inside the dialysis bag was centrifuged, and the precipitate was washed three times with distilled water and stored in a refrigerator at -20°C for 12 hours. It was then freeze-dried at -50°C and a vacuum degree of 20Pa for 24 hours to obtain indolepropionic acid grafted starch.

[0122] S3. Prepare an indolepropionic acid grafted starch / sodium alginate mixed solution: Sodium alginate and indolepropionic acid grafted starch are mixed in a mass ratio of 1:1 and dissolved in distilled water to prepare a 1% (w / v) mixed solution. Stir thoroughly at room temperature until the powders are evenly dispersed.

[0123] S4. Preparation of indolepropionic acid grafted starch / sodium alginate gel microspheres: A 1% (w / v) mixed solution of sodium alginate and indolepropionic acid grafted starch prepared in step S3 was added to the dispersed phase reservoir and passed through channel 1 of the microfluidic chip. A mixed oil solution containing 2% (w / v) of the surfactant Tween 80 was added to the continuous phase reservoir and passed through channel 2 of the microfluidic chip. The microfluidic chip was connected to a peristaltic pump via capillary glass tubing. The inner diameter of the circular capillary for the mobile phase was 240 μm, and the inner diameter of the circular capillary for the continuous phase was 180 μm. The pressures of channel 1 (dispersed phase, 250 mbar) and channel 2 (continuous phase, 250 mbar) were set to expel air from the pipeline and chip. After the pipeline and chip were filled with liquid, the entire system was switched from pressure control to flow rate control, and the flow rates of channel 1 and channel 2 were set to 2 mL / h. After the microspheres are uniformly generated, they can be collected into 1.5 mL centrifuge tubes. After a period of time, the collection is stopped, the tubes are sealed, and the tubes are placed in a 2% calcium chloride solution for 10 minutes to solidify.

[0124] Example 4

[0125] S1. Preparation of indolepropionic acid-HEVE polymer: 5% (w / v) indolepropionic acid, 2.5% (w / v) EDC and 1% (w / v) NHS were dissolved in DMF and stirred at 300 rpm at room temperature for 12 hours to obtain a homogeneous transparent solution. 1% (v / v) 2-hydroxyethyl vinyl ether (HEVE) was added to the solution and magnetically stirred in a 40°C water bath for 24 hours. The mixture was placed in a dialysis bag with a molecular weight cutoff of 8k-14kDa and dialyzed in distilled water for three days to obtain indolepropionic acid-HEVE. After centrifugation, the supernatant was removed, the sediment was washed with distilled water three times, and then stored in a -20°C refrigerator for 12 hours. It was then freeze-dried at -50°C and a vacuum degree of 20Pa for 24 hours to obtain an indolepropionic acid-HEVE complex powder.

[0126] S2. Preparation of indolepropionic acid grafted starch: 4% (w / v) high-amylose starch, 2% (w / v) indolepropionic acid-HEVE, and 0.1% (w / v) p-TSA were added to a DMF solution. After stirring at room temperature for 48 hours, the mixture was placed in a dialysis bag with a molecular weight cutoff of 8k-14kDa and dialyzed in distilled water for one week. The liquid inside the dialysis bag was centrifuged, and the precipitate was washed three times with distilled water and stored in a refrigerator at -20°C for 12 hours. It was then freeze-dried at -50°C and a vacuum degree of 20Pa for 24 hours to obtain indolepropionic acid grafted starch.

[0127] S3. Prepare an indolepropionic acid grafted starch / sodium alginate mixed solution: Sodium alginate and indolepropionic acid grafted starch are mixed in a mass ratio of 5:1 and dissolved in distilled water to prepare a 1% (w / v) mixed solution. Stir thoroughly at room temperature until the powders are evenly dispersed.

[0128] S4. Preparation of indolepropionic acid grafted starch / sodium alginate / gallic acid gel microspheres: The solution prepared in S3 was passed into channel 1 of the microfluidic chip as the dispersed phase, and a mixed oil solution containing 2% surfactant Tween 80 and 1% (w / v) gallic acid was passed into channel 2 of the microfluidic chip as the continuous phase. After the microspheres were uniformly generated, they were received into a centrifuge tube in channel 3, and the collected microspheres were allowed to stand in calcium chloride for 30 minutes to solidify.

[0129] Comparative Example 1

[0130] The preparation method is basically the same as that of Example 1, except that: indolepropionic acid is not added in step S2, and high-amylose corn starch and sodium alginate are used to prepare double-network gel microspheres in steps S3 and S4.

[0131] Comparative Example 2

[0132] The preparation method is basically the same as that of Example 1, except that the indolepropionic acid grafted starch in step S3 is replaced by a physical mixture of indolepropionic acid and high-amylose starch.

[0133] Figure 2 Graphs showing the release rates of indolepropionic acid in solutions of different pH values ​​for indolepropionic acid grafted high-amylose starch prepared in Examples 1-4 and Comparative Example 2 of the present invention; Figure 2 Under the same pH conditions, in Examples 1-3, as the amount of indolepropionic acid grafted starch added gradually increased, the release of indolepropionic acid gradually increased, with the release rate reaching its maximum at pH 5. This is because the chemical bond introduced between indolepropionic acid and high-amylose starch is pH-responsive and more easily breaks at pH 5 to release indolepropionic acid. Example 2 had the highest release rate, as the double-network gel microsphere structure formed by sodium alginate and indolepropionic acid grafted starch at a mass ratio of 5:1 is more compact, better protecting indolepropionic acid from the low-acid environment. In Example 4, the release rate of indolepropionic acid decreased, as the addition of polyphenols made the gel microsphere system more compact, limiting the release of indolepropionic acid. The release rate of indolepropionic acid in Comparative Example 2 at pH 3 was significantly higher than that in Example 1. This is because sodium alginate easily forms a gel network under low pH conditions, limiting the escape of indolepropionic acid. However, the release of free indolepropionic acid increased compared to Example 1, where it was covalently linked to starch via acetal bonds. In addition, the release rate of IPA increased at pH 5 and pH 7, but there was no significant pH-sensitive trend. This was due to the collapse of the alginate gel network above pH 5, which led to the overflow of the entrapped IPA. Figure 3 Figure 1 shows the particle size of indolepropionic acid-grafted high-amylose starch / sodium alginate gel microspheres prepared in Examples 1-4 of the present invention. In Examples 1-3, the particle size gradually increases with increasing indolepropionic acid-grafted high-amylose starch content. This is because the formation of a double-network gel increases the complexity of solvent fusion, resulting in an increase in solute in the solution system and an increase in particle size. The particle size of Example 4 is smaller than that of Example 3 but larger than that of Example 2. This is because the addition of gallic acid makes the double-network gel structure more compact, resulting in a smaller particle size compared to Example 3. However, the addition of gallic acid makes the solution system more complex, resulting in a slightly larger particle size than Example 2. The particle size of Comparative Examples 1 and 2 is significantly smaller than that of Examples 1-4. This is because, compared to the chemically modified starches in the examples, the starches not grafted with indolepropionic acid retain the physical and chemical properties of high-amylose corn starch, with their swelling rate and gelatinization recovery properties unchanged. Therefore, the prepared gel microspheres have smaller particle sizes. Figure 4The cytotoxicity of the indolepropionic acid grafted high-amylose starch / sodium alginate solutions prepared in Examples 1-4 of the present invention was determined. Caco-2 cells were used as model cells to determine the toxicity of the indolepropionic acid grafted high-amylose starch / sodium alginate solutions. Cell viability decreased slightly with increasing concentration, but remained above 90% even at 100 μg / mL, demonstrating good cell safety. Example 4 had a cell viability of 87.2% at a concentration of 100 μg / mL, which is attributed to the cytotoxicity of the released gallic acid, which led to decreased cell viability. In Comparative Examples 1 and 2, the effect of increasing concentration on cytotoxicity was negligible, demonstrating good cell safety.

[0134] Figure 5 This is a graph showing the release rate of gallic acid under different pH conditions from the indolepropionic acid grafted high-amylose starch / sodium alginate / gallic acid gel microspheres prepared in Example 4 of the present invention. The release rate of gallic acid is highest under a pH of 5. This is because gallic acid is encapsulated in the double-network gel microspheres composed of indolepropionic acid grafted high-amylose starch and sodium alginate. At pH 5, the acetal bond breaks, and the gel structure decomposes to release a large amount of gallic acid.

[0135] Figure 6 This graph shows the release rate of gallic acid from the indolepropionic acid-grafted high-amylose starch / sodium alginate / gallic acid gel microspheres prepared in Example 4 of the present invention at different temperatures. Gallic acid release gradually increases with increasing temperature. This is because the gel structure is unstable at high temperatures, and starch gelatinization leads to the disintegration of the double network structure, resulting in the release of large amounts of gallic acid.

[0136] In addition, the inventors of this case also referred to the aforementioned embodiments and conducted experiments using other raw materials, process operations, and process conditions described in this specification, and obtained relatively ideal results.

[0137] It should be understood that the technical solution of the present invention is not limited to the above-mentioned specific implementation cases. Any technical variations made according to the technical solution of the present invention without departing from the scope of protection of the purpose of the present invention and the claims shall fall within the scope of protection of the present invention.

Claims

1. A method for preparing pH-responsive double-network gel microspheres, characterized in that: include: Under the catalysis of EDC and NHS, indolepropionic acid reacts with 2-hydroxyethyl vinyl ether to prepare indolepropionic acid-2-hydroxyethyl vinyl ether polymer; Under the catalytic action of p-toluenesulfonamide, the indolepropionic acid-2-hydroxyethyl vinyl ether polymer is reacted with high-amylose starch to prepare indolepropionic acid grafted starch; Furthermore, the indolepropionic acid grafted starch, sodium alginate and water are mixed as a dispersed phase; a solution containing a surfactant is used as a continuous phase, and then microfluidic technology is used to prepare double-network gel microspheres with pH response.

2. The preparation method according to claim 1, characterized in that Specifically include: Indolepropionic acid, EDC, NHS and a solvent are mixed and stirred at room temperature for 8-12 hours to form a mixed solution. 2-Hydroxyethyl vinyl ether is then added and stirred at 40-60° C. for 18-24 hours. The mixture is then dialyzed, centrifuged, washed and freeze-dried to obtain an indolepropionic acid-2-hydroxyethyl vinyl ether polymer.

3. The preparation method according to claim 1, characterized in that Specifically include: High amylose starch, indolepropionic acid-2-hydroxyethyl vinyl ether polymer, p-toluenesulfonamide and solvent were mixed and stirred at room temperature for 48 hours, and then dialyzed, centrifuged, washed and freeze-dried to obtain indolepropionic acid grafted starch.

4. The preparation method according to claim 1, characterized in that Specifically include: mixing indolepropionic acid grafted starch, sodium alginate and water to form a first mixed solution; forming a second mixed solution from a solution containing a surfactant; Furthermore, using microfluidic technology, the first mixed solution is introduced into the first channel of a microfluidic chip as a dispersed phase, and the second mixed solution is introduced into the second channel of a microfluidic chip as a continuous phase. The generated microspheres are then allowed to stand and solidify in a calcium chloride solution to produce pH-responsive double-network gel microspheres. The inner diameter of the circular capillary used in the first channel of the microfluidic chip is 180-260 μm; the inner diameter of the circular capillary used in the second channel of the microfluidic chip is 120-200 μm.

5. Double-network gel microspheres with pH response prepared by the preparation method according to any one of claims 1 to 4.

6. Use of the pH-responsive double-network gel microspheres according to claim 5 in a drug delivery system.

7. A method for preparing a pH-responsive drug delivery system, characterized in that: include: Under the catalysis of EDC and NHS, indolepropionic acid reacts with 2-hydroxyethyl vinyl ether to prepare indolepropionic acid-2-hydroxyethyl vinyl ether polymer; Under the catalytic action of p-toluenesulfonamide, the indolepropionic acid-2-hydroxyethyl vinyl ether polymer is reacted with high-amylose starch to prepare indolepropionic acid grafted starch; Furthermore, the indolepropionic acid grafted starch, sodium alginate and water are mixed as a dispersed phase; an oil solution containing at least a surfactant and polyphenols is used as a continuous phase, and then a pH-responsive drug delivery system is prepared using microfluidic technology.

8. The preparation method according to claim 7, characterized in that Specifically comprising: mixing indolepropionic acid, EDC, NHS and a solvent and stirring at room temperature for 8-12 hours to form a mixed solution, then adding 2-hydroxyethyl vinyl ether and stirring at 40-60° C. for 18-24 hours, and then dialyzing, centrifuging, washing, and freeze-drying to obtain an indolepropionic acid-2-hydroxyethyl vinyl ether polymer; And / or, the preparation method specifically comprises: mixing high-amylose starch, indolepropionic acid-2-hydroxyethyl vinyl ether polymer, p-toluenesulfonamide and a solvent and stirring at room temperature for 48 hours, followed by dialysis, centrifugation, washing and freeze-drying to obtain indolepropionic acid grafted starch; And / or, the preparation method specifically comprises: mixing indolepropionic acid grafted starch, sodium alginate and water to form a third mixed solution; forming a fourth mixed solution from an oil solution containing a surfactant and polyphenols; Furthermore, using microfluidic technology, the third mixed solution is introduced into the first channel of the microfluidic chip as a dispersed phase, and the fourth mixed solution is introduced into the second channel of the microfluidic chip as a continuous phase. The generated microspheres are then allowed to stand and solidify in a calcium chloride solution to obtain pH-responsive double-network gel microspheres. The inner diameter of the circular capillary used in the first channel of the microfluidic chip is 180-260 μm; the inner diameter of the circular capillary used in the second channel of the microfluidic chip is 120-200 μm.

9. The preparation method according to claim 8, characterized in that: The high-amylose starch includes any one or more combinations of high-amylose corn starch, high-amylose wheat starch, and isoamylase-hydrolyzed corn starch; And / or, the polyphenols include any one or more of gallic acid, ursolic acid, ferulic acid, berberine, magnolol, and coumarin; And / or, the surfactant includes any one or more combinations of Tween 80, Span 20, Span 40, and Span 60; and / or, the solvent comprises DMF and / or DMSO; And / or, the oil solution includes any one or more combinations of corn oil, soybean oil, palm oil, and sunflower oil.

10. A pH-responsive drug delivery system prepared by the preparation method according to any one of claims 7 to 9.

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