A pH-sensitive interpenetrating network hydrogel

Abstract

The present invention relates to a pH-sensitive interpenetrating network hydrogel, which is composed of an aliphatic polyester, acrylic acid in an amount of 0.4 to 0.6 times the weight of the aliphatic polyester, a crosslinked acrylate in an amount of 0.05 to 0.1 times the weight of the aliphatic polyester, and potassium persulfate in an amount of 0.005 to 0.01 times the weight of the aliphatic polyester, by weight ratio; wherein the aliphatic polyester is obtained by ring-opening polymerization of diglycolic anhydride, 2-ethylhexyl glycidyl ether, and trimethylolpropane triglycidyl ether. The interpenetrating network hydrogel of the present invention has good swelling properties, mechanical properties, degradability, and pH responsiveness, and can be used for pH-responsive drug release.

Description

Technical Field

[0001] The present invention relates to polymer gels, and more particularly to interpenetrating network hydrogels, which are suitable for preparing oral preparations for pH-responsive release of non-steroidal anti-inflammatory drugs. Background Art

[0002] Oral dosage forms are commonly used pharmaceutical dosage forms, which have the advantages of good stability, low production cost, easy to carry, convenient to take, and high patient compliance. However, oral dosage forms are administered through the gastrointestinal tract. Since the pH value in the human digestive tract varies significantly, it can be used as a stimulus for drug controlled release. pH-responsive hydrogels can adjust their swelling behavior according to the changes in the gastrointestinal pH value to achieve slow or controlled release of drugs. In the acidic gastric environment, the hydrogel is in its original state and does not swell, and the carried drug is encapsulated inside the gel, protecting the drug; after transporting the drug to the neutral environment of the intestine, as the pH value increases, the hydrogel swells and releases the drug, and the drug is absorbed in the intestine to achieve the therapeutic effect. pH-responsive hydrogels refer to hydrogels that can swell or deswell in response to changes in the pH of the surrounding environment, and have been widely used in the biomedical field, especially in applications of drug delivery using gastrointestinal pH changes.

[0003] Acrylic acid contains acidic carboxyl groups, which are ionized to be anionic under neutral and alkaline conditions, and is widely used to prepare pH-sensitive hydrogels. Polyacrylic acid hydrogels can swell in alkaline solutions and shrink in acidic solutions. For example, Chen Li et al. synthesized a monomer with azobenzene groups on the side chain by using p-aminoazobenzene and acryloyl chloride, and copolymerized this monomer with acrylic acid (AA) to prepare a polyacrylic acid. It was found that this polyacrylic acid copolymer showed good pH and light responsiveness (Chen Li, Zhao Yiping, Li Shigeng, Wang Qingwen, Synthesis and properties of pH and light-responsive copolymers, Acta Scientiarum Naturalium Universitatis Nankaiensis, 2006, 01, 19-23). However, due to the lack of an effective energy diffusion mechanism and irregular cross-linking points in this polyacrylic acid, this type of polyacrylic acid hydrogel is brittle and is likely to erode before drug release, limiting its application in drug carriers.

[0004] In an interpenetrating polymer network (IPN), the mutual entanglement and penetration between molecular networks limit phase separation, reduce the degree of phase separation of the two entangled polymers, improve the compatibility between components, and exhibit forced compatibility. It is this forced compatibility that enables the stable combination of two polymers with very different properties or even different functions. Compared with other methods, the interpenetrating polymer network (IPN) technology can achieve complementary properties between components, increase the intelligent responsiveness of hydrogels, and can also be used to improve the mechanical strength of hydrogels. For example, Zhang et al. prepared a PDMAEMA / PDEA semi-interpenetrating polymer network hydrogel with dual temperature and pH responsiveness by free radical copolymerization (Zhang N, Liu M, Shen Y, et al. Preparation, properties, and drug release of thermo- and pH-sensitive poly((2-dimethylamino)ethyl methacrylate) / poly(N,N-diethylacrylamide)

[0005] semi-IPN hydrogels, Journal of Materials Science. 2011, 46(5): 1523-1534.). Compared with pure PDEA hydrogels, the PDMAEMA / PDEA semi-interpenetrating polymer network hydrogels not only have obvious temperature sensitivity but also obvious pH sensitivity. Through the study of the swelling ratio, it was found that the induction rate of the semi-interpenetrating polymer network hydrogel is faster than that of the pure PDEA hydrogel; while in the in vitro cumulative release of drugs, the release rate of the semi-interpenetrating polymer network hydrogel is slower than that of the pure PDEA hydrogel, which is of great significance in the field of drug controlled release. Yu Qiuling polymerized (MA-co-AM) macromolecules using maleic acid (MA), acrylamide (AM), and dimethylaminoethyl methacrylate (DM) as the main monomers; at the same time, polyvinyl alcohol (PVA) was introduced as the second reinforcing network; and finally, PVA / MA / AM hydrogels were synthesized under the action of hydrogen bonds, and the hydrogels showed good pH sensitivity (Master's thesis, Tianjin Polytechnic University, 2022, Preparation and application research of pH-responsive hydrogels). However, the above pH-sensitive hydrogels have poor biodegradability.

[0006] Aliphatic polyesters have a main chain composed of aliphatic structural units connected by easily hydrolyzable ester bonds. The main chain is flexible, and they have good biocompatibility and biodegradability. They are an important type of biomedical material and are widely used in the biomedical field, such as drug sustained release, surgical sutures, bone fixation materials, tissue engineering materials, etc. Currently, there are two methods for synthesizing aliphatic polyesters. The first is to prepare them by condensation using bifunctional monomers. For example, they are obtained by the condensation polymerization of dibasic acids and diols. The second is to use their ester compounds or lactone compounds as monomers for ring-opening copolymerization. For example, the patent application with the publication number CN106061935A prepared linear aliphatic polyesters using stearic acid, palmitic acid, 9-ketostearic acid, 10-ketostearic acid, and their mixtures and used them as plasticizers. However, since this aliphatic polyester is a linear polymer, it has the disadvantages of poor hydrophilicity and poor mechanical properties. At the same time, this linear aliphatic polyester does not have pH-responsive properties and cannot be used to prepare oral preparations for pH-responsive release of non-steroidal anti-inflammatory drugs. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a pH-sensitive interpenetrating network hydrogel, which has good swelling properties, mechanical properties, pH responsiveness, and degradability.

[0008] The technical solution of the present invention to solve the above problems is:

[0009] A pH-sensitive interpenetrating network hydrogel, which is composed of an aliphatic polyester, acrylic acid with a weight of 0.4 - 0.6 times that of the aliphatic polyester, a cross-linking agent acrylate with a weight of 0.05 - 0.1 times that of the aliphatic polyester, and potassium persulfate as an initiator with a weight of 0.005 - 0.01 times that of the aliphatic polyester according to the weight ratio; wherein,

[0010] The aliphatic polyester is prepared by the following method: Take diglycolic anhydride, 2-ethylhexyl glycidyl ether, trimethylolpropane triglycidyl ether, and zinc citrate in a molar ratio of 1:1:0.05 - 0.1:0.001 - 0.005, add them to DMF for dissolution, heat to 60 - 80 °C under nitrogen protection for ring-opening polymerization reaction for 5 - 10 h, cool to room temperature, add to n-hexane for precipitation, and collect the precipitate to obtain the aliphatic polyester; this aliphatic polyester has a network structure, and its weight average molecular weight is 1500 - 4000;

[0011] The cross-linking agent acrylate is one or more of triethylene glycol dimethacrylate, 1,6-hexanediol diacrylate, and 1,4-decanediol diacrylate.

[0012] In the above solution, the temperature of the ring-opening polymerization reaction is preferably 70 °C, and the reaction time is preferably 8 h.

[0013] In the above solution, the weight-average molecular weight of the saturated aliphatic polyester is preferably 2000 - 3000.

[0014] The pH-sensitive interpenetrating network hydrogel of the present invention is prepared by the following method: The aliphatic polyester, acrylic acid, crosslinking agent acrylate, and initiator potassium persulfate are added to DMF solvent which is 0.5 - 1.5 times the weight of the aliphatic polyester taken separately, dissolved and mixed evenly, reacted at 60 - 80 °C for 6 - 8 h, then repeatedly soaked and washed with distilled water, purified, and dried to a constant weight to obtain the product.

[0015] The pH-sensitive interpenetrating network hydrogel of the present invention is suitable for preparing an anti-inflammatory oral preparation. The oral preparation is composed of the above pH-responsive interpenetrating network hydrogel and an anti-inflammatory drug accounting for 0.1 - 0.5% by weight of the pH-responsive interpenetrating network hydrogel; wherein the anti-inflammatory drug is diclofenac sodium, berberine, indomethacin or celecoxib.

[0016] The above anti-inflammatory oral preparation is prepared by the following method: First, dissolve the anti-inflammatory drug in ethanol to a concentration of 0.1 - 0.5 mg / mL, and finally add the above pH-responsive interpenetrating network hydrogel, soak for 36 - 72 h, wash with distilled water, and freeze-dry to obtain the oral controlled-release drug preparation.

[0017] The aliphatic polyester with a network structure contained in the interpenetrating network hydrogel of the present invention is formed by ring-opening polymerization of diglycolic anhydride, 2-ethylhexyl glycidyl ether, trimethylolpropane triglycidyl ether, and zinc citrate dissolved in DMF. From the above-mentioned preparation method of the aliphatic polyester, it can be seen that in the ring-opening polymerization reaction system, trimethylolpropane triglycidyl ether, a multifunctional epoxy monomer, is used as the crosslinking agent, and the ring-opening polymerization reaction is carried out under the condition that the molar ratio of the total epoxy group functional group to the acid anhydride functional group is greater than 1.15. Obviously, the obtained polymer is an aliphatic polyester with a network structure. Further, from the above preparation method of the pH-sensitive interpenetrating network hydrogel, it can be seen that acrylic acid crosslinks with acrylate of triethylene glycol dimethacrylate in the aliphatic polyester with a network structure, and a curing reaction occurs under the action of the initiator potassium persulfate to form an interpenetrating network structure.

[0018] Since the interpenetrating network hydrogel contains a polyacrylic acid network with a carboxyl three-dimensional reticular structure that cannot move freely, the degree of carboxyl dissociation is different in solutions with different pH values, resulting in different electrostatic repulsion effects between the interpenetrating networks of the hydrogel, causing changes in the swelling ratio and mechanical properties. For example, in acidic solutions, hydrogen bonds between carboxyl groups form associations, and the swelling ratio of the interpenetrating network hydrogel is relatively low; as the pH increases, carboxyl groups gradually ionize into carboxylate ions, hydrogen bonds in the interpenetrating network begin to dissociate, and the electrostatic repulsion between ions increases, resulting in an increase in the swelling ratio, thus exhibiting pH sensitivity. It can be seen that the pH-sensitive interpenetrating network hydrogel described in this application is suitable for preparing sustained-release oral preparations, and the sustained-release oral preparations can release drugs in a non-acidic environment. Therefore, when the pH-sensitive interpenetrating network hydrogel described in this application is loaded with non-steroidal anti-inflammatory drugs to make an anti-inflammatory and analgesic sustained-release oral preparation, the non-steroidal anti-inflammatory drugs in the preparation will not be absorbed and metabolized by the gastric mucosa in an acidic environment, resulting in side effects such as abdominal discomfort, heartburn, nausea, and vomiting; however, when the sustained-release oral preparation enters the intestine, the non-steroidal anti-inflammatory drugs are rapidly released and absorbed and metabolized by the intestinal mucosa in a non-acidic environment, thereby effectively avoiding the side effects caused by gastric mucosa absorption and metabolism. Description of the Drawings

[0019] Figure 1 It is a drug release curve diagram of the pH-sensitive interpenetrating network hydrogel loaded with non-steroidal anti-inflammatory drugs at different pH values in Example 1 below. Specific Embodiments

[0020] Example 1

[0021] 1. Synthesis of Aliphatic Polyester

[0022] 10 mmol of diglycolic anhydride, 10 mmol of 2-ethylhexyl glycidyl ether, 0.75 mmol of trimethylolpropane triglycidyl ether, and 0.025 mmol of zinc citrate were added to 10 mL of DMF. Under nitrogen protection, the temperature was raised to 70 °C for ring-opening polymerization reaction for 8 h, and then cooled to room temperature. It was precipitated in n-hexane to obtain the saturated aliphatic polyester.

[0023] The weight-average molecular weight and weight-average molecular weight of the obtained aldehyde-group-containing aliphatic polyester were measured using a Jasco Gulliversystem (PU-980, CO-965, RI-930, and UV-1570) gel permeation chromatograph. Equipped with polystyrene gel columns (Shodex columns K804, K805, and J806), using DMF as the eluent, polystyrene as the standard for calibration, and measuring at 30 °C. The detection result showed that the weight-average molecular weight of the aliphatic polyester was 2216.

[0024] The above aliphatic polyester is obtained by ring-opening copolymerization of diglycol anhydride, 2-ethylhexyl glycidyl ether, and trimethylolpropane triglycidyl ether. Among them, trimethylolpropane triglycidyl ether is a multi-functional raw material and acts as a cross-linking agent, resulting in the formation of a cross-linked structure in the polymerization product. Moreover, among the reaction components, diglycol anhydride contains 10 mmol of acid anhydride functional groups, 2-ethylhexyl glycidyl ether contains 10 mmol of epoxy functional groups, and trimethylolpropane triglycidyl ether contains 2.25 mmol of epoxy functional groups, with a total of 12.25 mmol of epoxy functional groups. The molar ratio between the acid anhydride functional groups and the epoxy functional groups is 1:1.225, and the polymer obtained by ring-opening copolymerization under this condition is a network structure.

[0025] 2. Interpenetrating network hydrogel

[0026] 2.1. Synthesis of interpenetrating network hydrogel

[0027] Take 10 g of the synthesized aliphatic polyester, 5.5 g of acrylic acid, 0.8 g of triethylene glycol dimethacrylate, and 0.075 g of potassium persulfate, add them to 13 mL of DMF, mix evenly, load into a mold, and react at 60 °C for 8 h; then soak and wash repeatedly with distilled water, purify, and dry to constant weight to obtain the interpenetrating network hydrogel.

[0028] In the above reaction, acrylic acid and cross-linked acrylate are cross-linked and polymerized under the initiation of potassium persulfate to form an interpenetrating network structure with the network-structured aliphatic polyester.

[0029] 2.2. Swelling ratio of interpenetrating network hydrogel

[0030] At room temperature, take the interpenetrating network hydrogel, weigh it precisely to obtain W o ; soak it in water at room temperature until it reaches swelling equilibrium, wipe off the excess water on the surface of the scaffold with filter paper, and measure the mass of the hydrogel again to obtain W e , and calculate the swelling ratio of the interpenetrating network hydrogel according to the following formula. Swelling ratio (%) = (W e - W0) / W0. Its swelling ratio is obtained as 1213%.

[0031] 2.3. Tensile strength of pH-responsive interpenetrating network hydrogel

[0032] Detect the elongation at break of the prepared pH-responsive interpenetrating network hydrogel on a Zwick / Roell 2202 universal material testing machine (Zwick Company, Germany).

[0033] Detect according to the above method, and the elongation at break of the prepared pH-responsive interpenetrating network hydrogel is 522%.

[0034] 2.3. pH responsiveness of interpenetrating network hydrogel

[0035] Weigh a certain mass of dry gel and place it separately in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. After swelling equilibrium, weigh it and calculate the swelling ratio at different pH values. The results are shown in Table 1.

[0036] Table 1 Swelling ratio of pH-responsive interpenetrating network hydrogels at different pH values

[0037] pH 2 3 4 5 6 7 8 9 10 11 12 Swelling ratio 956 973 985 1011 1155 1241 1290 1351 1442 1633 1729

[0038] The above-mentioned pH-responsive interpenetrating network hydrogel contains a polyacrylic acid network and has a large number of carboxyl stereonetwork structures that cannot move freely. In acidic solutions, hydrogen bonds between carboxyl groups will associate, and the swelling ratio of the interpenetrating network hydrogel changes less; as the pH increases, carboxyl groups in the solution gradually ionize into carboxylate ions, hydrogen bonds in the interpenetrating network hydrogel begin to dissociate, and the electrostatic repulsion between ions increases significantly, resulting in an increase in the swelling ratio, thus showing significant pH sensitivity. As can be seen from the above table, the swelling ratio of the pH-responsive interpenetrating network hydrogel changes less under acidic and neutral conditions; while under alkaline conditions, the swelling ratio increases significantly.

[0039] At room temperature, take the pH-responsive interpenetrating network hydrogel and immerse it in buffer solutions with different pH values. Wait until it reaches swelling equilibrium, and then use a Zwick / Roell 2202 universal material testing machine (Zwick Company, Germany) to detect its elongation rate. The results are shown in Table 2.

[0040] Table 2 Elongation rate of pH-responsive interpenetrating network hydrogels at different pH values

[0041] pH 2 3 4 5 6 7 8 9 10 11 12 Elongation ratio 551 549 546 542 538 532 540 441 425 376 326

[0042] The above-mentioned pH-responsive interpenetrating network hydrogel contains a polyacrylic acid network and has a large number of carboxyl stereonetwork structures that cannot move freely. In acidic solutions, hydrogen bonds between carboxyl groups will associate, and the mechanical properties of the interpenetrating network hydrogel are relatively high; as the pH increases, carboxyl groups in the solution gradually ionize into carboxylate ions, hydrogen bonds in the interpenetrating network hydrogel begin to dissociate, and the electrostatic repulsion between ions increases significantly, resulting in a decrease in mechanical properties, thus showing significant pH sensitivity. As can be seen from the above table, the elongation rate of the pH-responsive interpenetrating network hydrogel changes less under acidic and neutral conditions; while under alkaline conditions, the elongation rate decreases significantly.

[0043] 3. Drug-loaded pH-responsive interpenetrating network hydrogel

[0044] 3.1. Preparation of drug-loaded interpenetrating network hydrogel

[0045] Take 2 g of the above pH-responsive interpenetrating network hydrogel and soak it in a 0.4 mg / mL sodium diclofenac ethanol solution for 36 h. Wash it with distilled water and freeze-dry it to constant weight to obtain the drug-loaded pH-responsive interpenetrating network hydrogel.

[0046] 3.2. Drug loading of the drug-loaded interpenetrating network hydrogel

[0047] Take the above drug-loaded pH-responsive interpenetrating network hydrogel, weigh it accurately to obtain W1; soak it in DMF for 7 days, take the DMF solution, detect the ultraviolet absorption of the DMF solution, and use the high-performance liquid method to calculate the weight of sodium diclofenac in DMF as W2. Calculate the drug loading of the drug-loaded interpenetrating network hydrogel according to the following formula. Drug loading (μg / g) = W2 / W1. The drug loading is obtained as 4532 μg / g.

[0048] 3.3. Drug release behavior of the drug-loaded interpenetrating network hydrogel

[0049] At room temperature, drug release experiments are carried out in buffer solutions with pH values of 4.01, 6.8, and 9.18. Put the drug-loaded interpenetrating network hydrogel into a bottle containing 30 mL of buffer solution (pH values are 4.01, 7.4, and 10.8 respectively), oscillate at a constant temperature, and regularly take 3 mL of buffer solution for measuring the drug release rate, and supplement an equal volume of fresh blank buffer solution. Use the high-performance liquid method to determine the concentration of sodium diclofenac in the medium, calculate and plot the drug cumulative release curve. The results are as Figure 1 shown.

[0050] As Figure 1 shown, after 10 h, the cumulative release rate of sodium diclofenac at pH 4.01 or 7.4 is less than that at pH 10.8. This is because under acidic or neutral conditions, the hydrogen bonds between carboxyl groups in the interpenetrating network hydrogel will associate to form a dense network structure with a low swelling rate, inhibiting drug release. At the same time, under acidic or neutral conditions, sodium diclofenac can form hydrogen bonds with the carboxyl groups on the interpenetrating network hydrogel, reducing the release of sodium diclofenac. Under alkaline conditions, the carboxyl groups on the interpenetrating network hydrogel gradually ionize into carboxylate ions, the hydrogen bonds in the interpenetrating network begin to dissociate, and the electrostatic repulsion between ions increases significantly, forming a dense network structure with a high swelling rate, promoting drug release. At the same time, under alkaline conditions, the hydrogen bonds formed between sodium diclofenac and the carboxyl groups on the interpenetrating network hydrogel begin to dissociate, promoting the release of sodium diclofenac. Therefore, the interpenetrating network hydrogel shows pH-responsive drug release performance.

[0051] Example 2

[0052] 1. Synthesis of aliphatic polyesters

[0053] Take 10 mmol of diglycolic anhydride, 10 mmol of 2-ethylhexyl glycidyl ether, 1 mmol of trimethylolpropane triglycidyl ether, and 0.05 mmol of zinc citrate, add them to 15 mL of DMF, heat to 80 °C under nitrogen protection for ring-opening polymerization for 12 h, cool to room temperature, and precipitate in n-hexane to obtain the saturated aliphatic polyester.

[0054] The prepared aliphatic polyester was detected by the same method as in Example 1, and the detected result showed that the weight-average molecular weight of the aliphatic polyester was 3997.

[0055] The above-mentioned aliphatic polyester is obtained by ring-opening copolymerization of diglycolic anhydride, 2-ethylhexyl glycidyl ether, and trimethylolpropane triglycidyl ether. Among them, trimethylolpropane triglycidyl ether is a polyfunctional raw material and acts as a cross-linking agent, resulting in the formation of a cross-linked structure in the polymerization product. Moreover, in the reaction components, diglycolic anhydride contains 10 mmol of acid anhydride functional groups, 2-ethylhexyl glycidyl ether contains 10 mmol of epoxy functional groups, and trimethylolpropane triglycidyl ether contains 3 mmol of epoxy functional groups, with a total of 13 mmol of epoxy functional groups. The molar ratio between the acid anhydride functional groups and the epoxy functional groups is 1:1.3, and the polymer obtained by ring-opening copolymerization under this condition is a network structure.

[0056] 2. Interpenetrating network hydrogel

[0057] 2.1. Synthesis of interpenetrating network hydrogel

[0058] Take 10 g of the synthesized aliphatic polyester, 6 g of acrylic acid, 0.3 g of triethylene glycol dimethacrylate, 0.4 g of 1,6-hexanediol diacrylate, 0.3 g of 1,4-decanediol diacrylate, and 0.1 g of potassium persulfate, add them to 15 mL of DMF, mix evenly, load into a mold, and react at 80 °C for 6 h; then soak and wash repeatedly with distilled water, purify, and dry to constant weight to obtain the interpenetrating network hydrogel.

[0059] In the above reaction, acrylic acid and cross-linked acrylate are cross-linked and polymerized under the initiation of potassium persulfate to form an interpenetrating network structure with the network-structured aliphatic polyester.

[0060] 2.2. Swelling ratio of interpenetrating network hydrogel

[0061] The swelling ratio of the prepared interpenetrating network hydrogel detected according to the method described in Example 1 was 1153%.

[0062] 2.3. Tensile strength of pH-responsive interpenetrating network hydrogel

[0063] The tensile ratio of the prepared interpenetrating network hydrogel detected according to the method described in Example 1 was 521%.

[0064] 2.3. pH Responsiveness of Interpenetrating Network Hydrogels

[0065] Take a certain mass of dry gel and place it separately in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. After swelling equilibrium, weigh it and calculate the swelling ratio at different pH values. The results are shown in Table 3 below.

[0066] Table 3 Swelling Ratio of pH-Responsive Interpenetrating Network Hydrogels at Different pH Values

[0067] pH 2 3 4 5 6 7 8 9 10 11 12 Swelling ratio 1105 1108 1110 1116 1125 1155 1122 1153 1312 1423 1544

[0068] As can be seen from the above table, for the pH-responsive interpenetrating network hydrogel, the change in swelling ratio is relatively small under acidic and neutral conditions; while under alkaline conditions, the swelling ratio increases significantly.

[0069] At room temperature, take the pH-responsive interpenetrating network hydrogel and immerse it in buffer solutions with different pH values. After it reaches swelling equilibrium, use a Zwick / Roell 2202 universal material testing machine (Zwick Company, Germany) to detect its elongation rate. The results are shown in Table 4 below.

[0070] Table 4 Elongation Rate of pH-Responsive Interpenetrating Network Hydrogels at Different pH Values

[0071] pH 2 3 4 5 6 7 8 9 10 11 12 Elongation ratio 539 536 534 531 529 528 511 466 432 404 392

[0072] As can be seen from the above table, for the pH-responsive interpenetrating network hydrogel, the change in elongation rate is relatively small under acidic and neutral conditions; while under alkaline conditions, the elongation rate decreases significantly.

[0073] 3. Drug-Loaded pH-Responsive Interpenetrating Network Hydrogels

[0074] 3.1. Preparation of Drug-Loaded Interpenetrating Network Hydrogels

[0075] Take 2 g of the above-mentioned pH-responsive interpenetrating network hydrogel and soak it in a 0.5 mg / mL berberine ethanol solution for 72 h. Wash it with distilled water and freeze-dry it to constant weight to obtain the drug-loaded pH-responsive interpenetrating network hydrogel.

[0076] 3.2. Drug Loading Capacity of Drug-Loaded Interpenetrating Network Hydrogels

[0077] Use the method described in Example 1 to detect the drug loading capacity of the drug-loaded interpenetrating network hydrogel. Its drug loading capacity is obtained as 5085 μg / g. 3.3. Drug Release Behavior of Drug-Loaded Interpenetrating Network Hydrogels

[0078] The method described in Example 1 was used to detect the drug release behavior of the drug-loaded interpenetrating network hydrogel. The results showed that under the condition of pH 4.01, the cumulative release rate of berberine was 36.4% after 10 hours. At the same time, under the condition of pH 7.4, the cumulative release rate of berberine was 38.1% after 10 hours. And under the condition of pH 10.8, the cumulative release rate of berberine was 63.7% after 10 hours. This shows that as the pH of the medium increases, the drug release effect improves. Therefore, the interpenetrating network hydrogel shows pH-responsive drug release performance.

[0079] Example 3

[0080] 1. Synthesis of aliphatic polyester

[0081] Take 10 mmol of diglycolic anhydride, 10 mmol of 2-ethylhexyl glycidyl ether, 0.5 mmol of trimethylolpropane triglycidyl ether and 0.01 mmol of zinc citrate, add them to 10 mL of DMF, heat to 60 °C under nitrogen protection for ring-opening polymerization reaction for 6 h, cool to room temperature, and precipitate in n-hexane to obtain the saturated aliphatic polyester.

[0082] The prepared aliphatic polyester was detected by the same method as in Example 1, and the detection result showed that the weight-average molecular weight of the aliphatic polyester was 1503.

[0083] The above aliphatic polyester was obtained by ring-opening copolymerization of diglycolic anhydride, 2-ethylhexyl glycidyl ether and trimethylolpropane triglycidyl ether. Among them, trimethylolpropane triglycidyl ether is a multi-functional raw material and acts as a cross-linking agent, resulting in the formation of a cross-linked structure in the polymerization product. And in the reaction components, diglycolic anhydride contains 10 mmol of acid anhydride functional groups. 2-ethylhexyl glycidyl ether contains 10 mmol of epoxy functional groups, and trimethylolpropane triglycidyl ether contains 1.5 mmol of epoxy functional groups, and the total epoxy functional groups are 11.5 mmol. The molar ratio between the acid anhydride functional group and the epoxy functional group is 1:1.15, and the polymer obtained by ring-opening copolymerization under this condition is a network structure.

[0084] 2. Interpenetrating network hydrogel

[0085] 2.1. Synthesis of interpenetrating network hydrogel

[0086] Take 10 g of the synthesized aliphatic polyester, 4 g of acrylic acid, 0.3 g of 1,6-hexanediol diacrylate, 0.2 g of 1,4-decanediol diacrylate and 0.05 g of potassium persulfate, add them to 5 mL of DMF, mix evenly, load into a mold, and react at 70 °C for 6.5 h; then soak and wash repeatedly with distilled water, purify, and dry to constant weight to obtain the interpenetrating network hydrogel.

[0087] In the above reaction, acrylic acid and crosslinked acrylate undergo crosslinking polymerization under the initiation of potassium persulfate, forming an interpenetrating network structure with the aliphatic polyester of the network structure.

[0088] 2.2. Swelling ratio of the interpenetrating network hydrogel

[0089] The swelling ratio of the prepared interpenetrating network hydrogel detected according to the method described in Example 1 is 1053%.

[0090] 2.3. Tensile strength of the pH-responsive interpenetrating network hydrogel

[0091] The elongation at break of the prepared interpenetrating network hydrogel detected according to the method described in Example 1 is 491%.

[0092] 2.3. pH responsiveness of the interpenetrating network hydrogel

[0093] Take a certain mass of dry gel and place it separately in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. After swelling equilibrium, weigh it and calculate the swelling ratio at different pH values. The results are shown in Table 5.

[0094] Table 5 Swelling ratio of the pH-responsive interpenetrating network hydrogel at different pH values

[0095] pH 1 2 3 4 5 6 7 8 9 10 11 12 Swelling ratio 983 986 989 993 995 1003 1022 1123 1222 1323 1444 1521

[0096] As can be seen from the above table, for the pH-responsive interpenetrating network hydrogel, the swelling ratio changes little under acidic and neutral conditions; while under alkaline conditions, the swelling ratio increases significantly.

[0097] At room temperature, take the pH-responsive interpenetrating network hydrogel and immerse it in buffer solutions with different pH values. After it reaches swelling equilibrium, use the Zwick / Roell 2202 universal material testing machine (Zwick Company, Germany) to detect its elongation at break. The results are shown in Table 6.

[0098] Table 6 Elongation at break of the pH-responsive interpenetrating network hydrogel at different pH values

[0099] pH 2 3 4 5 6 7 8 9 10 11 12 Elongation ratio 513 512 510 509 507 505 481 406 382 344 302

[0100] As can be seen from the above table, for the pH-responsive interpenetrating network hydrogel, the elongation at break changes little under acidic and neutral conditions; while under alkaline conditions, the elongation at break decreases significantly.

[0101] 3. Drug-loaded pH-responsive interpenetrating network hydrogel

[0102] 3.1. Preparation of the drug-loaded interpenetrating network hydrogel

[0103] Take 2 g of the above pH-responsive interpenetrating network hydrogel and soak it in an indomethacin ethanol solution with a concentration of 0.1 mg / mL for 36 h. Wash it with distilled water and freeze-dry it to a constant weight to obtain a drug-loaded pH-responsive interpenetrating network hydrogel.

[0104] 3.3. Drug loading of the drug-loaded interpenetrating network hydrogel

[0105] Detect the drug loading of the drug-loaded interpenetrating network hydrogel by the method described in Example 1. The obtained drug loading is 1011 μg / g.

[0106] 3.4. Drug release behavior of the drug-loaded interpenetrating network hydrogel

[0107] Detect the drug release behavior of the drug-loaded interpenetrating network hydrogel by the method described in Example 1. The results show that under the condition of pH 4.01, the cumulative release rate of indomethacin is 42.5% after 10 h. At the same time, under the condition of pH 7.4, the cumulative release rate of indomethacin is 43.1% after 10 h. And under the condition of pH 10.8, the cumulative release rate of indomethacin is 68.2% after 10 h. This shows that as the medium pH increases, the drug release effect improves. Therefore, the interpenetrating network hydrogel shows pH-responsive drug release performance.

[0108] Example 4

[0109] 1. Synthesis of aliphatic polyester

[0110] 10 mmol of diglycolic anhydride, 10 mmol of 2-ethylhexyl glycidyl ether, 0.55 mmol of trimethylolpropane triglycidyl ether and 0.027 mmol of zinc citrate are added to 12 mL of DMF. Under nitrogen protection, the temperature is raised to 70 °C for ring-opening polymerization reaction for 8 h, and then cooled to room temperature. It is precipitated in n-hexane to obtain the saturated aliphatic polyester.

[0111] Detect the prepared aliphatic polyester by the same method as in Example 1. The test results show that the weight-average molecular weight of the aliphatic polyester is 2019.

[0112] The above aliphatic polyester is obtained by ring-opening copolymerization of diglycolic anhydride, 2-ethylhexyl glycidyl ether and trimethylolpropane triglycidyl ether. Among them, trimethylolpropane triglycidyl ether is a polyfunctional raw material and acts as a cross-linking agent, resulting in the formation of a cross-linked structure of the polymerization product. And in the reaction components, diglycolic anhydride contains 10 mmol of acid anhydride functional groups. 2-ethylhexyl glycidyl ether contains 10 mmol of epoxy functional groups, and trimethylolpropane triglycidyl ether contains 1.65 mmol of epoxy functional groups, and the total epoxy functional groups are 11.65 mmol. The molar ratio between the acid anhydride functional group and the epoxy functional group is 1:1.165, and the polymer obtained by ring-opening copolymerization under this condition is a network structure.

[0113] 2. Interpenetrating network hydrogel

[0114] 2.1. Synthesis of interpenetrating network hydrogel

[0115] Take 10 g of synthesized aliphatic polyester, 4.5 g of acrylic acid, 0.65 of triethylene glycol dimethacrylate and 0.075 g of potassium persulfate, add them to 12 mL of DMF, load into a mold, and react at 75 °C for 7.5 h; then soak and wash repeatedly with distilled water, purify, and dry to constant weight to obtain the interpenetrating network hydrogel.

[0116] In the above reaction, acrylic acid and crosslinked acrylate are crosslinked and polymerized under the initiation of potassium persulfate to form an interpenetrating network structure with the aliphatic polyester in the network structure.

[0117] 2.2. Swelling ratio of interpenetrating network hydrogel

[0118] The swelling ratio of the prepared interpenetrating network hydrogel detected according to the method described in Example 1 is 1229%.

[0119] 2.3. Tensile strength of pH-responsive interpenetrating network hydrogel

[0120] The tensile ratio of the prepared interpenetrating network hydrogel detected according to the method described in Example 1 is 588%.

[0121] 2.3. pH responsiveness of interpenetrating network hydrogel

[0122] Take a certain mass of dry gel and put it into buffer solutions with pH values of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 respectively. After swelling equilibrium, weigh it and calculate the swelling ratio at different pH values. The results are shown in Table 7.

[0123] Table 7 Swelling ratio of pH-responsive interpenetrating network hydrogel at different pH values

[0124] pH 2 3 4 5 6 7 8 9 10 11 12 Swelling ratio 1182 1187 1190 1195 1198 1220 1229 1331 1422 1561 1611

[0125] It can be known from the above table that the swelling ratio of the pH-responsive interpenetrating network hydrogel changes little under acidic and neutral conditions; while under alkaline conditions, the swelling ratio increases significantly.

[0126] At room temperature, take the pH-responsive interpenetrating network hydrogel, soak it in buffer solutions with different pH values, wait for it to reach swelling equilibrium, and test its tensile ratio on a Zwick / Roell 2202 universal material testing machine (Zwick Company, Germany). The results are shown in Table 8.

[0127] Table 8 Tensile ratio of pH-responsive interpenetrating network hydrogel at different pH values

[0128] pH 2 3 4 5 6 7 8 9 10 11 12 Elongation ratio 585 586 583 582 580 579 570 521 483 455 435

[0129] As can be seen from the above table, the elongation rate of the pH-responsive interpenetrating network hydrogel changes little under acidic and neutral conditions; while under alkaline conditions, the elongation rate decreases significantly.

[0130] 3. Drug-loaded pH-responsive interpenetrating network hydrogel

[0131] 3.1. Preparation of drug-loaded interpenetrating network hydrogel

[0132] Take 2 g of the above pH-responsive interpenetrating network hydrogel and soak it in a celecoxib ethanol solution with a concentration of 0.15 mg / mL for 48 h, wash it with distilled water, and freeze-dry it to constant weight to obtain the drug-loaded pH-responsive interpenetrating network hydrogel.

[0133] 3.2. Drug loading of drug-loaded interpenetrating network hydrogel

[0134] The method described in Example 1 was used to detect the drug loading of the drug-loaded interpenetrating network hydrogel. The obtained drug loading was 1772 μg / g.

[0135] 3.3. Drug release behavior of drug-loaded interpenetrating network hydrogel

[0136] The method described in Example 1 was used to detect the drug release behavior of the drug-loaded interpenetrating network hydrogel. The results showed that under the condition of pH 4.01, the cumulative release rate of celecoxib was 36.2% after 10 h. At the same time, under the condition of pH 7.4, the cumulative release rate of celecoxib was 36.6% after 10 h. And under the condition of pH 10.8, the cumulative release rate of celecoxib was 59.4% after 10 h. This shows that as the pH of the medium increases, the drug release effect improves. Therefore, the interpenetrating network hydrogel shows pH-responsive drug release performance.

[0137] Example 5

[0138] 1. Synthesis of aliphatic polyester

[0139] Take 10 mmol of diglycolic anhydride, 10 mmol of 2-ethylhexyl glycidyl ether, 0.8 mmol of trimethylolpropane triglycidyl ether and 0.01 mmol of zinc citrate, add them to 14 mL of DMF, heat to 70 °C under nitrogen protection for ring-opening polymerization reaction for 10 h, cool to room temperature, and precipitate in n-hexane to obtain the saturated aliphatic polyester.

[0140] The same method as in Example 1 was used to detect the prepared aliphatic polyester. The test results showed that the weight-average molecular weight of the aliphatic polyester was 3008.

[0141] The above-mentioned aliphatic polyester is obtained by ring-opening copolymerization of diglycol anhydride, 2-ethylhexyl glycidyl ether, and trimethylolpropane triglycidyl ether. Among them, trimethylolpropane triglycidyl ether is a polyfunctional raw material and acts as a cross-linking agent, resulting in the formation of a cross-linked structure in the polymerization product. Moreover, among the reaction components, diglycol anhydride contains 10 mmol of acid anhydride functional groups, 2-ethylhexyl glycidyl ether contains 10 mmol of epoxy functional groups, and trimethylolpropane triglycidyl ether contains 2.4 mmol of epoxy functional groups, with a total of 12.4 mmol of epoxy functional groups. The molar ratio between the acid anhydride functional groups and the epoxy functional groups is 1:1.24, and the polymer obtained by ring-opening copolymerization under this condition is a network structure.

[0142] 2. Interpenetrating network hydrogel

[0143] 2.1. Synthesis of interpenetrating network hydrogel

[0144] Take 10 g of the synthesized aliphatic polyester, 5.5 g of acrylic acid, 0.4 g of 1,6-hexanediol diacrylate, 0.3 g of triethylene glycol dimethacrylate, and 0.065 g of potassium persulfate, add them to 10 mL of DMF, mix evenly, load into a mold, and react at 65 °C for 8 h; then soak and wash repeatedly with distilled water, purify, and dry to constant weight to obtain the interpenetrating network hydrogel.

[0145] In the above reaction, acrylic acid and cross-linked acrylate are cross-linked and polymerized under the initiation of potassium persulfate to form an interpenetrating network structure with the network-structured aliphatic polyester.

[0146] 2.2. Swelling ratio of interpenetrating network hydrogel

[0147] The swelling ratio of the prepared interpenetrating network hydrogel was detected according to the method described in Example 1 to be 1150%.

[0148] 2.3. Tensile strength of pH-responsive interpenetrating network hydrogel

[0149] The elongation at break of the prepared interpenetrating network hydrogel was detected according to the method described in Example 1 to be 522%.

[0150] 2.3. pH responsiveness of interpenetrating network hydrogel

[0151] Take a certain mass of dry gel and place it separately in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. After swelling to equilibrium, weigh it and calculate the swelling ratio at different pH values. The results are shown in Table 9.

[0152] Table 9 Swelling ratio of pH-responsive interpenetrating network hydrogel at different pH values

[0153] pH 2 3 4 5 6 7 8 9 10 11 12 Swelling ratio 1151 1148 1150 1152 1158 1157 1178 1236 1399 1498 1613

[0154] As can be seen from the above table, the swelling ratio of the pH-responsive interpenetrating network hydrogel changes little under acidic and neutral conditions; while under alkaline conditions, the swelling ratio increases significantly.

[0155] At room temperature, a pH-responsive interpenetrating network hydrogel was taken and immersed in buffer solutions with different pH values. After it reached swelling equilibrium, the tensile rate was detected using a Zwick / Roell 2202 universal material testing machine (Zwick Company, Germany). The results are shown in Table 10.

[0156] Table 10 Tensile rates of pH-responsive interpenetrating network hydrogels at different pH values

[0157] pH 2 3 4 5 6 7 8 9 10 11 12 Elongation ratio 530 534 532 533 532 531 524 500 468 403 344

[0158] As can be seen from the above table, the tensile rate of the pH-responsive interpenetrating network hydrogel changes little under acidic and neutral conditions; while under alkaline conditions, the tensile rate decreases significantly.

[0159] 3. Drug-loaded pH-responsive interpenetrating network hydrogel

[0160] 3.1. Preparation of drug-loaded interpenetrating network hydrogel

[0161] 2 g of the above-mentioned pH-responsive interpenetrating network hydrogel was taken and immersed in an indomethacin ethanol solution with a concentration of 0.35 mg / mL for 72 h, washed with distilled water, and freeze-dried to constant weight to obtain a drug-loaded pH-responsive interpenetrating network hydrogel.

[0162] 3.2. Drug loading of drug-loaded interpenetrating network hydrogel

[0163] The method described in Example 1 was used to detect the drug loading of the drug-loaded interpenetrating network hydrogel. The obtained drug loading was 3629 μg / g.

[0164] 3.2. Drug release behavior of drug-loaded interpenetrating network hydrogel

[0165] The method described in Example 1 was used to detect the drug release behavior of the drug-loaded interpenetrating network hydrogel. The results showed that under the condition of pH 4.01, the cumulative release rate of indomethacin was 44.1% after 10 h. At the same time, under the condition of pH 7.4, the cumulative release rate of indomethacin was 44.3% after 10 h. And under the condition of pH 10.8, the cumulative release rate of indomethacin was 70.2% after 10 h. This shows that as the pH of the medium increases, the drug release effect improves. Therefore, the interpenetrating network hydrogel shows pH-responsive drug release performance.

[0166] Example 6

[0167] 1. Synthesis of aliphatic polyester

[0168] Take 10 mmol of diglycolic anhydride, 10 mmol of 2-ethylhexyl glycidyl ether, 0.9 mmol of trimethylolpropane triglycidyl ether and 0.04 mmol of zinc citrate, add them to 9 mL of DMF, heat to 70 °C under nitrogen protection for ring-opening polymerization reaction for 9 h, cool to room temperature, and precipitate in n-hexane to obtain the saturated aliphatic polyester.

[0169] The prepared aliphatic polyester was detected by the same method as in Example 1, and the detection result showed that the weight-average molecular weight of the aliphatic polyester was 2551.

[0170] The above-mentioned aliphatic polyester is obtained by ring-opening copolymerization of diglycolic anhydride, 2-ethylhexyl glycidyl ether and trimethylolpropane triglycidyl ether. Among them, trimethylolpropane triglycidyl ether is a multi-functional raw material and acts as a cross-linking agent, resulting in the formation of a cross-linked structure in the polymerization product. And in the reaction components, diglycolic anhydride contains 10 mmol of acid anhydride functional groups. 2-ethylhexyl glycidyl ether contains 10 mmol of epoxy functional groups, and trimethylolpropane triglycidyl ether contains 2.7 mmol of epoxy functional groups, and the total epoxy functional groups are 12.7 mmol. The molar ratio between the acid anhydride functional group and the epoxy functional group is 1:1.27, and the polymer obtained by ring-opening copolymerization under this condition is a network structure.

[0171] 2. Interpenetrating network hydrogel

[0172] 2.1. Synthesis of interpenetrating network hydrogel

[0173] Take 10 g of the synthesized aliphatic polyester, 5.2 g of acrylic acid, 0.3 g of 1,6-hexanediol diacrylate, 0.3 g of triethylene glycol dimethacrylate and 0.07 g of potassium persulfate, add them to 9 mL of DMF, mix evenly, load into a mold, and react at 70 °C for 6.5 h; then soak and wash repeatedly with distilled water, purify, and dry to constant weight to obtain the interpenetrating network hydrogel.

[0174] In the above reaction, acrylic acid and cross-linked acrylate are cross-linked and polymerized under the initiation of potassium persulfate to form an interpenetrating network structure with the network-structured aliphatic polyester.

[0175] 2.2. Swelling ratio of interpenetrating network hydrogel

[0176] At room temperature, take the pH-responsive interpenetrating network hydrogel and measure its weight; soak it in deionized water at room temperature, wait until it reaches swelling equilibrium, wipe off the excess water on the surface of the scaffold with filter paper, measure the mass of the hydrogel again, and finally calculate the swelling ratio. The obtained swelling ratio is 1111%.

[0177] 2.3. Tensile strength of pH-responsive interpenetrating network hydrogel

[0178] The prepared pH-responsive interpenetrating network hydrogel was tested for its elongation at break on a Zwick / Roell 2202 universal material testing machine (Zwick, Germany).

[0179] Tested according to the above method, the elongation at break of the prepared pH-responsive interpenetrating network hydrogel was 503%.

[0180] 2.3. pH responsiveness of the interpenetrating network hydrogel

[0181] A certain mass of dry gel was placed separately into buffer solutions with pH values of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. After swelling equilibrium, it was weighed and the swelling ratio at different pH values was calculated. The results are shown in Table 11.

[0182] Table 11 Swelling ratio of the pH-responsive interpenetrating network hydrogel at different pH values

[0183] pH 2 3 4 5 6 7 8 9 10 11 12 Swelling ratio 1118 1120 1117 1119 1121 1120 1134 1169 1236 1333 1423

[0184] As can be seen from the above table, for the pH-responsive interpenetrating network hydrogel, the swelling ratio changes slightly under acidic and neutral conditions; while under alkaline conditions, the swelling ratio increases significantly.

[0185] At room temperature, a pH-responsive interpenetrating network hydrogel was taken and immersed in buffer solutions with different pH values. After reaching swelling equilibrium, it was tested for its elongation at break on a Zwick / Roell 2202 universal material testing machine (Zwick, Germany). The results are shown in Table 12.

[0186] Table 12 Elongation at break of the pH-responsive interpenetrating network hydrogel at different pH values

[0187] pH 2 3 4 5 6 7 8 9 10 11 12 Elongation ratio 504 505 502 504 503 501 486 457 426 403 322

[0188] As can be seen from the above table, for the pH-responsive interpenetrating network hydrogel, the elongation at break changes slightly under acidic and neutral conditions; while under alkaline conditions, the elongation at break decreases significantly.

[0189] 3. Drug-loaded pH-responsive interpenetrating network hydrogel

[0190] 3.1. Preparation of the drug-loaded interpenetrating network hydrogel

[0191] 2 g of the above pH-responsive interpenetrating network hydrogel was immersed in an indomethacin ethanol solution with a concentration of 0.3 mg / mL for 72 h, washed with distilled water, and freeze-dried to constant weight to obtain the drug-loaded pH-responsive interpenetrating network hydrogel.

[0192] 3.2. Drug loading of the drug-loaded interpenetrating network hydrogel

[0193] The drug loading of the drug-loaded interpenetrating network hydrogel was detected by the method described in Example 1. The drug loading was obtained as 2969 μg / g.

[0194] 3.3 Drug release behavior of the drug-loaded interpenetrating network hydrogel

[0195] The drug release behavior of the drug-loaded interpenetrating network hydrogel was detected by the method described in Example 1. The results showed that under the condition of pH 4.01, the cumulative release rate of indomethacin was 44.8% after 10 hours. At the same time, under the condition of pH 6.8, the cumulative release rate of indomethacin was 44.5% after 10 hours. And under the condition of pH 9.18, the cumulative release rate of indomethacin was 71.6% after 10 hours. This shows that as the medium pH increases, the drug release effect improves. Therefore, the interpenetrating network hydrogel shows pH-responsive drug release performance.

[0196] Example 7 (comparative experiment)

[0197] Comparative experiment 1

[0198] 1. Control 1 was prepared as follows:

[0199] 5.5 g of acrylic acid, 0.8 g of triethylene glycol dimethacrylate and 0.075 g of potassium persulfate were added to 10 mL of DMF, mixed evenly, reacted at 60 °C for 8 h, then repeatedly soaked, washed, purified and dried to constant weight to obtain cross-linked polyacrylic acid.

[0200] 2. Control 2 was the aliphatic polyester prepared in Example 1.

[0201] 3. The sample was the interpenetrating network hydrogel prepared in Example 1.

[0202] 4. Detection method

[0203] The swelling ratio and elongation ratio of the sample and Controls 1 and 2 were detected respectively by the method described in Example 1. The results are shown in Table 13.

[0204] Table 13 Comparison of swelling ratio and elongation ratio

[0205] Swelling ratio (%) Elongation ratio (%) Sample 1213 522 Reference substance 2 57 64 Reference substance 1 776 253

[0206] As can be seen from Table 13, the swelling ratio and elongation ratio of the sample are significantly better than those of Controls 1 and 2.

[0207] Comparative experiment 2 (comparison of degradation effects)

[0208] The sample in this comparative experiment was the interpenetrating network hydrogel prepared by the method described in Example 1, and Control 3 was the pH-responsive hydrogel prepared by the method described in the comparative literature (Master's thesis, Tianjin Polytechnic University, 2022, Preparation and Application Research of pH-Responsive Hydrogels).

[0209] 2. Study on Degradation Behavior

[0210] Take reference substance 3, weigh it accurately to obtain W1; add it to 1M NaOH aqueous solution, heat under reflux for 12 h, dry to constant weight, and measure the mass of the pH-responsive hydrogel again to obtain W2. Calculate the erosion rate of the pH-responsive hydrogel according to the following formula. Erosion rate % = (W1 - W 2) ) / W1 * 100. The obtained erosion rate is 24.3%.

[0211] Take the sample, weigh it accurately to obtain W3; add it to 1M NaOH aqueous solution, heat under reflux for 12 h, dry to constant weight, and measure the mass of the interpenetrating network hydrogel again to obtain W4. Calculate the erosion rate of the interpenetrating network hydrogel according to the following formula. Erosion rate % = (W3 - W4) / W3 * 100. The obtained erosion rate is 75.8%.

[0212] From the above results, it can be seen that compared with reference substance 3, the degradation effect of the interpenetrating network hydrogel described in the present invention is significantly better than that of reference substance 3.

Claims

1. A pH-sensitive interpenetrating network hydrogel, which is prepared from an aliphatic polyester, acrylic acid with a weight of 0.4 to 0.6 times that of the aliphatic polyester, a crosslinking agent acrylate with a weight of 0.05 to 0.1 times that of the aliphatic polyester, and potassium persulfate with a weight of 0.005 to 0.01 times that of the aliphatic polyester according to a weight ratio; wherein, The aliphatic polyester is prepared by the following method: taking diglycolic anhydride, 2-ethylhexyl glycidyl ether, trimethylolpropane triglycidyl ether, and zinc citrate in a molar ratio of 1:1:0.05 to 0.1:0.001 to 0.005, adding them to DMF for dissolution, heating to 60 to 80 °C under nitrogen protection for ring-opening polymerization reaction for 5 to 10 h, cooling to room temperature, adding to n-hexane for precipitation, and collecting the precipitate to obtain the aliphatic polyester; the aliphatic polyester is a network structure, and its weight-average molecular weight is 1500 to 4000; The crosslinking agent acrylate is one or more of triethylene glycol dimethacrylate, 1,6-hexanediol diacrylate, and 1,4-decanediol diacrylate.

2. The pH-sensitive interpenetrating network hydrogel according to claim 1, wherein The temperature of the ring-opening polymerization reaction is 70 °C and the time is 8 h.

3. A pH-sensitive interpenetrating network hydrogel according to claim 1 or 2, which is prepared as follows: taking the aliphatic polyester, acrylic acid, crosslinking agent acrylate, and potassium persulfate and adding them to separately taken DMF, mixing evenly; reacting at 60 to 80 °C for 6 to 8 h; then soaking and washing repeatedly with distilled water, purifying, and drying to constant weight to obtain the pH-sensitive interpenetrating network hydrogel.

4. An anti-inflammatory oral preparation, which is composed of the pH-responsive interpenetrating network hydrogel according to claim 1 or 2 and an anti-inflammatory drug with a weight of 0.1 to 0.5% of the weight of the pH-responsive interpenetrating network hydrogel according to a weight ratio; wherein the anti-inflammatory drug is diclofenac sodium, berberine, indomethacin, or celecoxib.

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