Acid-responsive gel materials, methods of making and using the same, and acid-responsive gel formulations, methods of making and using the same

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to an acid-responsive gel material, a preparation method and application thereof, and an acid-responsive gel preparation, a preparation method and application thereof. The acid-responsive gel material comprises the following preparation raw materials: a gel matrix material, a polyphenol compound, a metal salt, a pH regulator and a solvent. The application adopts preparation components with good biological safety and good biocompatibility. The gel material provided by the application has acid-responsive characteristics, and is in a flowing liquid state when used, so as to be convenient for reaching a lesion. The gel material can be locally solidified to form a gel in an acid environment. The preparation prepared from the acid-responsive material can form an in-situ gel drug depot at a lesion, has a long-acting and slow-releasing effect, and solves the problem of limited in-situ treatment methods for tumors and related diseases and inflammatory diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an acid-responsive gel material, its preparation method and application, and an acid-responsive gel formulation, its preparation method and application. Background Technology

[0002] Gastric cancer is a common malignant tumor of the digestive tract, characterized by high malignancy and poor prognosis. Treatment primarily involves a combination of chemotherapy and surgery. However, intravenous administration of high-concentration chemotherapy drugs can cause significant systemic toxicity and severe side effects, leading many patients to discontinue chemotherapy due to intolerance. Therefore, finding suitable dosing regimens that improve patient compliance, enhance drug bioavailability, and reduce systemic toxicity is of paramount clinical importance.

[0003] Currently, oral drug delivery systems in clinical practice are mainly solid and liquid formulations. Due to factors such as volume and fluidity, these solutions empty from the stomach quickly, often failing to achieve local drug retention. Gels are a commonly used drug carrier, effectively increasing local drug concentration and enabling local drug delivery while reducing the toxic side effects of systemic administration. Furthermore, gels possess sustained-release properties, allowing for a continuous and slow release of the drug, reducing the frequency and duration of administration. Currently, there are limited in-situ treatment options available both domestically and internationally for gastric tumors and related diseases. Therefore, developing a safe, effective, and convenient in-situ therapeutic gel is of significant clinical importance. Summary of the Invention

[0004] The purpose of this invention is to provide an acid-responsive gel material, its preparation method and application, and an acid-responsive gel formulation, its preparation method and application. The formulation prepared from the acid-responsive gel material provided by this invention can form an in-situ gel drug reservoir at the lesion site and has a long-lasting sustained-release effect.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] This invention provides an acid-responsive gel material, comprising the following raw materials:

[0007] Gel matrix materials, polyphenolic compounds, metal salts, pH adjusters, and solvents.

[0008] Preferably, the gel matrix material includes one or more of alginate and its derivatives, cellulose and its derivatives, chitosan and its derivatives, and polysaccharide gum and its derivatives;

[0009] The mass of the gel matrix material is not less than 0.1% of the mass of the acid-responsive gel material.

[0010] Preferably, the polyphenolic compounds include one or more of the following: tannic acid, gallic acid, propyl gallate, epigallocatechin, epigallocatechin gallate, epicatechin gallate, salvianolic acid, proanthocyanidins, theaflavins, alginic acid, ellagic acid, flavonoids, phenolic acids, polyphenol amides, and polydopamine.

[0011] The mass of the polyphenolic compound is not less than 0.1% of the mass of the acid-responsive gel material.

[0012] Preferably, the metal salt includes one or more of calcium salt, manganese salt, zinc salt, iron salt, aluminum salt, silver salt, copper salt and cobalt salt;

[0013] The mass of the metal salt is not less than 0.01% of the mass of the acid-responsive gel material.

[0014] The present invention also provides a method for preparing the acid-responsive gel material described in the above technical solution, comprising the following steps:

[0015] After mixing polyphenolic compounds, metal salts and solvents, a pH adjuster is added to adjust the pH of the system to ≥7, thus obtaining a metal-phenolic network solution.

[0016] The metal phenolic network solution and the gel matrix material are mixed and swollen to obtain the acid-responsive gel material.

[0017] The present invention also provides the application of the acid-responsive gel material described in the above technical solution or the acid-responsive gel material prepared by the preparation method described in the above technical solution in the preparation of acid-responsive gel formulations or as a tissue isolation solution.

[0018] The present invention also provides an acid-responsive gel formulation, comprising a gel material, a pharmaceutical active ingredient, and a solvent;

[0019] The gel material is the acid-responsive gel material described in the above technical solution or the acid-responsive gel material prepared by the preparation method described in the above technical solution;

[0020] The active pharmaceutical ingredient includes one or more of chemotherapy drugs, targeted drugs, anti-inflammatory drugs, and nucleic acid drugs.

[0021] Preferably, the mass of the active pharmaceutical ingredient is not less than 0.1% of the mass of the acid-responsive gel formulation.

[0022] This invention also provides a method for preparing the acid-responsive gel formulation described above, comprising the following steps:

[0023] The gel material, the active pharmaceutical ingredient, and the solvent are mixed to obtain the acid-responsive gel formulation.

[0024] The present invention also provides the application of the acid-responsive gel formulation described in the above technical solution or the acid-responsive gel formulation prepared by the preparation method described in the above technical solution in the preparation of drugs.

[0025] This invention provides an acid-responsive gel material comprising the following raw materials: gel matrix material, polyphenolic compound, metal salt, pH adjuster and solvent.

[0026] This invention uses formulation components with good biosafety and biocompatibility. The gel material provided by this invention has acid-responsive properties, is in a flowing liquid state for easy delivery to the lesion, and can locally solidify into a gel in an acidic environment.

[0027] Furthermore, this invention also provides an acid-responsive gel formulation, comprising a gel material, a pharmaceutically active ingredient, and a solvent; the gel material is the acid-responsive gel material described in the above-mentioned technical solution or the acid-responsive gel material prepared by the preparation method described in the above-mentioned technical solution; the pharmaceutically active ingredient includes one or more of chemotherapeutic drugs, targeted drugs, anti-inflammatory drugs, and nucleic acid drugs. This invention provides a gel formulation that can protect the pharmaceutically active ingredient, forming an in-situ gel drug reservoir at the lesion site, and has a long-lasting sustained-release effect. In addition, the formulation provided by this invention can be used in various ways, with convenient administration routes and high patient compliance. Furthermore, the gel formulation provided by this invention can carry multiple pharmaceutically active ingredients, enabling broad-spectrum treatment of gastrointestinal related diseases, and is an excellent drug sustained-release carrier, solving the problem of limited in-situ treatment methods for tumors and related diseases and inflammatory diseases. Attached Figure Description

[0028] Figure 1 This is a diagram illustrating the gelation mechanism of the acid-responsive gel formulation in this invention.

[0029] Figure 2 The diagram shows the acid-responsive gel material obtained in Example 1 and its gel state after mixing with a gastric acid simulation solution.

[0030] Figure 3 This is a diagram showing the gelation process of the acid-responsive gel material obtained in Example 1 in the mouse stomach;

[0031] Figure 4 Image showing the size of a tumor detected by gastric ultrasound in test case 2;

[0032] Figure 5 This is a diagram showing the tumor volume and growth monitored by gastric ultrasound in Test Example 2.

[0033] Figure 6 This is a diagram showing the tumor volume and growth monitored by gastric ultrasound in test case 3.

[0034] Figure 7The tumor size map is obtained from in vivo imaging fluorescence signal monitoring in test example 4;

[0035] Figure 8 This is a diagram illustrating the effect of inhibiting abdominal adhesions in test case 5.

[0036] Figure 9 This is a diagram showing the tumor volume growth monitored by gastric ultrasound in test case 6.

[0037] Figure 10 The image shows the effect of testing the inhibition of chronic sinusitis in Example 7;

[0038] Figure 11 To test the mouse survival curve of the tumor recurrence model in Example 8;

[0039] Figure 12 Inflammation markers for the radiotherapy protection model in Test Example 9. Detailed Implementation

[0040] This invention provides an acid-responsive gel material, comprising the following raw materials:

[0041] Gel matrix materials, polyphenolic compounds, metal salts, pH adjusters, and solvents.

[0042] In this invention, unless otherwise specified, all raw materials are commercially available products well known to those skilled in the art.

[0043] The acid-responsive gel material provided by the present invention includes a raw material gel matrix material, wherein the gel matrix material includes one or more of alginate and its derivatives, cellulose and its derivatives, chitosan and its derivatives, and polysaccharide gum and its derivatives.

[0044] In this invention, the alginate preferably includes one or more of sodium alginate, potassium alginate, calcium alginate, and lithium alginate, and more preferably sodium alginate. The alginate derivative preferably includes one or more of oxidized sodium alginate, oxidized potassium alginate, oxidized calcium alginate, and oxidized lithium alginate.

[0045] In this invention, the cellulose preferably includes one or more of sodium carboxymethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl hydroxyethyl cellulose, carboxymethyl hydroxypropyl cellulose, and carboxymethyl ethyl cellulose, and is more preferably carboxymethyl cellulose.

[0046] In this invention, the chitosan preferably includes hydroxypropyl chitosan or carboxymethyl chitosan; the chitosan derivative preferably includes one or more of chitosan lactate, chitosan quaternary ammonium salt, chitosan hydrochloride, chitosan nitrate, chitosan sulfate and chitosan acetate.

[0047] In this invention, the polysaccharide gum preferably includes one or more of gelatin, gellan gum, pectin, konjac gum, carrageenan, guar gum, locust bean gum, xanthan gum, and gum arabic, and is more preferably gellan gum. In this invention, the mass of the gel matrix material is preferably not less than 0.1% of the mass of the acid-responsive gel material, and more preferably 1-2%.

[0048] The acid-responsive gel material provided by this invention comprises a polyphenolic compound as a preparation raw material. The polyphenolic compound preferably includes one or more of the following: tannic acid, gallic acid, propyl gallate, epigallocatechin, epigallocatechin gallate, epicatechin gallate, salvianolic acid, proanthocyanidins, theaflavins, alginic acid, ellagic acid, flavonoids, phenolic acids, polyphenol amides, and polydopamine. More preferably, it comprises tannic acid or polydopamine. In this invention, the mass of the polyphenolic compound is preferably not less than 0.1% of the mass of the acid-responsive gel material, and more preferably 1-5%.

[0049] The acid-responsive gel material provided by this invention comprises a raw material metal salt, wherein the metal salt preferably includes one or more of calcium salt, manganese salt, zinc salt, iron salt, aluminum salt, silver salt, copper salt, and cobalt salt; the calcium salt preferably includes calcium chloride, the manganese salt preferably includes manganese chloride, the zinc salt preferably includes zinc chloride, the iron salt preferably includes ferric chloride, the aluminum salt preferably includes aluminum chloride, the silver salt preferably includes silver chloride, the copper salt preferably includes copper chloride, and the cobalt salt preferably includes cobalt chloride. In this invention, the mass of the metal salt is preferably not less than 0.01% of the mass of the acid-responsive gel material, and more preferably 0.1% to 0.5%.

[0050] The acid-responsive gel material provided by this invention includes a pH adjuster for preparation. This invention does not specifically limit the type of pH adjuster; any reagent capable of achieving the desired pH value is acceptable. In this invention, the pH adjuster preferably includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, and ammonia water. This invention does not specifically limit the amount of the pH adjuster used; it only needs to be sufficient to adjust the pH value to the desired level during the preparation process.

[0051] The acid-responsive gel material provided by this invention includes a raw material solvent. This invention does not specifically limit the type of solvent, as long as it can disperse the gel material. Preferably, it includes one or more of water for injection, physiological saline, phosphate buffered saline solution, glucose solution, enzyme-free water, and cell culture medium, and more preferably, water for injection or physiological saline.

[0052] The present invention also provides a method for preparing the acid-responsive gel material described in the above technical solution, comprising the following steps:

[0053] After mixing polyphenolic compounds, metal salts and solvents, a pH adjuster is added to adjust the pH of the system to ≥7, thus obtaining a metal-phenolic network solution.

[0054] The metal phenolic network solution and the gel matrix material are mixed and swollen to obtain the acid-responsive gel material.

[0055] In this invention, the mixing of all raw materials is preferably carried out under stirring conditions. In this invention, the pH adjuster is preferably used in the form of an aqueous solution of the pH adjuster, and the concentration of the aqueous solution of the pH adjuster is preferably 1 mol / L. In this invention, the pH value of the system is preferably 7-8, more preferably 7.4.

[0056] The present invention also provides the application of the acid-responsive gel material described in the above technical solution or the acid-responsive gel material prepared by the preparation method described in the above technical solution in the preparation of acid-responsive gel formulations or as a tissue isolation solution.

[0057] The present invention also provides an acid-responsive gel formulation, comprising a gel material, a pharmaceutical active ingredient, and a solvent;

[0058] The gel material is the acid-responsive gel material described in the above technical solution or the acid-responsive gel material prepared by the preparation method described in the above technical solution;

[0059] The active pharmaceutical ingredient includes one or more of chemotherapy drugs, targeted drugs, anti-inflammatory drugs, and nucleic acid drugs.

[0060] In this invention, the chemotherapeutic drugs preferably include one or more of cyclophosphamide, docetaxel, 10-hydroxycamptothecin, camptothecin, cisplatin, carboplatin, cycloplatin, carmustine, nimustine, rubitecan, 9-aminocamptothecin, vincristine, capecitabine, desmethylcantharidin, epirubicin, doxorubicin, daunorubicin, doxorubicin, oxaliplatin, gemcitabine, pemetrexed, temozolomide, teniposide, etoposide, vinorelbine, vinorelbine, cytarabine, methotrexate, tegafur, mitomycin, mitoxantrone, topotecan, irinotecan, arsenic trioxide, and 5-fluorouracil, and more preferably one or more of oxaliplatin, cyclophosphamide, docetaxel, and doxorubicin.

[0061] In this invention, the targeted drug preferably includes one or more of trastuzumab, ramucirumab, nivolumab, pembrolizumab, anlotinib, apatinib, bevacizumab, gefitinib, erlotinib, and cetuximab, and more preferably one or more of gefitinib and erlotinib.

[0062] In this invention, the anti-inflammatory drug preferably includes one or more of the following: aspirin, sodium salicylate, magnesium salicylate, magnesium choline salicylate, disalicylate, diflunisal, ibuprofen, phenoxyibuprofen, ketoibuprofen, indomethacin, flurbibuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, diclofenac sodium, fenprofen, ketorolac, tetraclofenamic acid, sulindac, tometidine, and dexamethasone, and more preferably dexamethasone.

[0063] In this invention, the nucleic acid drug preferably includes one or more of miRNA, lncRNA, siRNA, circRNA, saRNA and piRNA, and more preferably one or more of miRNA and siRNA.

[0064] In this invention, the mass of the active pharmaceutical ingredient is preferably not less than 0.1% of the mass of the acid-responsive gel formulation.

[0065] In this invention, the type of solvent is preferably the same as the type of solvent specified in the above technical solution, and will not be repeated here.

[0066] This invention also provides a method for preparing the acid-responsive gel formulation described above, comprising the following steps:

[0067] The gel material, the active pharmaceutical ingredient, and the solvent are mixed to obtain the acid-responsive gel formulation.

[0068] The present invention does not impose any special limitations on the mixing process; any process well known to those skilled in the art can be used.

[0069] The present invention also provides the application of the acid-responsive gel formulation described in the above technical solution or the acid-responsive gel formulation prepared by the preparation method described in the above technical solution in the preparation of drugs.

[0070] In this invention, the drug preferably includes a gastric drug, an oral drug, a nasopharyngeal drug, an esophageal drug, or an intestinal drug.

[0071] In this invention, the application environment of the acid-responsive gel formulation is preferably an acidic environment. When the acid-responsive gel formulation comes into contact with an acidic environment, the metallophenolic network in the gel formulation degrades, releasing free cations. These cations combine with the gel matrix material to form an in-situ gel, thereby sustaining the release of the active pharmaceutical ingredient and exerting a local therapeutic effect.

[0072] In this invention, the preferred methods of administration of the acid-responsive gel preparation include oral administration, spraying, infusion, local injection, or topical application.

[0073] In this invention, when the active pharmaceutical ingredient in the acid-responsive gel preparation is a chemotherapy drug or a targeted drug, it is preferred to use it in conjunction with different treatment methods; the treatment methods preferably include radiotherapy or photoacoustic therapy.

[0074] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0075] Example 1

[0076] Weigh 1 wt% tannic acid and 0.1 wt% zinc chloride and dissolve them in 1 mL of water for injection. Then, adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution and stir to mix evenly to obtain a metal phenolic network solution. Then, add 1 wt% sodium alginate to the metal phenolic network solution and stir thoroughly to swell to obtain the acid-responsive gel material.

[0077] Example 2

[0078] The acid-responsive gel material was prepared according to the method of Example 1, except that the concentration of tannic acid was 3 wt% and the concentration of zinc chloride was 0.3 wt%.

[0079] Example 3

[0080] The acid-responsive gel material was prepared according to the method of Example 1, except that the concentration of tannic acid was 5 wt% and the concentration of zinc chloride was 0.5 wt%.

[0081] Example 4

[0082] The acid-responsive gel material was prepared according to Example 1, except that the sodium alginate concentration was 1.5 wt% and the zinc chloride concentration was 0.3 wt%.

[0083] Example 5

[0084] The acid-responsive gel material was prepared according to Example 1, except that the concentration of sodium alginate was 1.5 wt%, the concentration of tannic acid was 3 wt%, and the concentration of zinc chloride was 0.5 wt%.

[0085] Example 6

[0086] The acid-responsive gel material was prepared according to Example 1, except that the concentration of sodium alginate was 1.5 wt% and the concentration of tannic acid was 5 wt%.

[0087] Example 7

[0088] The acid-responsive gel material was prepared according to Example 1, except that the sodium alginate concentration was 2 wt% and the zinc chloride concentration was 0.5 wt%.

[0089] Example 8

[0090] The acid-responsive gel material was prepared according to the method of Example 1, except that the concentration of sodium alginate was 2 wt% and the concentration of tannic acid was 3 wt%.

[0091] Example 9

[0092] The acid-responsive gel material was prepared according to Example 1, except that the concentration of sodium alginate was 2 wt%, the concentration of tannic acid was 5 wt%, and the concentration of zinc chloride was 0.3 wt%.

[0093] Example 10

[0094] Acid-responsive gel materials were prepared according to the method of Example 1, except that the gel matrix material was replaced with carboxymethyl cellulose.

[0095] Example 11

[0096] Acid-responsive gel materials were prepared according to the method of Example 1, except that the gel matrix material was replaced with carboxymethyl chitosan.

[0097] Example 12

[0098] Acid-responsive gel materials were prepared according to the method of Example 1, except that the gel matrix material was replaced with gellan gum.

[0099] Example 13

[0100] Acid-responsive gel materials were prepared in accordance with the method of Example 1, except that polyphenolic compounds were replaced with polydopamine.

[0101] Example 14

[0102] Acid-responsive gel materials were prepared according to the method in Example 1, except that zinc chloride was replaced with manganese chloride.

[0103] Example 15

[0104] The acid-responsive gel material was prepared according to Example 1, except that the gel matrix material was replaced with carboxymethyl cellulose at a concentration of 1.5 wt%.

[0105] Example 16

[0106] The acid-responsive gel material was prepared according to Example 1, except that the gel matrix material was replaced with carboxymethyl cellulose at a concentration of 2 wt%.

[0107] Example 17

[0108] The acid-responsive gel material was prepared according to Example 1, except that the gel matrix material was replaced with carboxymethyl chitosan at a concentration of 1.5 wt%.

[0109] Example 18

[0110] The acid-responsive gel material was prepared according to Example 1, except that the gel matrix material was replaced with carboxymethyl chitosan at a concentration of 2 wt%.

[0111] Example 19

[0112] The acid-responsive gel material was prepared according to Example 1, except that the gel matrix material was replaced with gellan gum at a concentration of 1.5 wt%.

[0113] Example 20

[0114] The acid-responsive gel material was prepared according to Example 1, except that the gel matrix material was replaced with gellan gum at a concentration of 2 wt%.

[0115] Test Example 1

[0116] The gelation and adhesion properties of the acid-responsive gel materials obtained in Examples 1-20 were tested;

[0117] Detection method:

[0118] Specific testing procedures for gelation properties: In the in vitro gelation experiment, 1 mL of gel material was added to 10 mL of simulated gastric acid solution (pH = 1.2), and the gelation behavior in the acidic solution was observed. In the in vivo gelation experiment, 1 mL of gel material was administered to mice via gavage. Twenty minutes after gavage, the mice were euthanized by cervical dislocation, and the gastric tissue was dissected and extracted to observe the gelation behavior of the gel solution in the stomach.

[0119] Specific testing procedure for adhesion performance: Take 1 mL of each gel material and use a rheometer to measure the viscosity (mPa.s) of the gel under the conditions of 37℃, 1% strain, and 1Hz frequency.

[0120] The test results are shown in Table 1 and Figures 2-3 As stated, in which Figure 2 This is a diagram showing the gel state of the acid-responsive gel material obtained in Example 1 after mixing with a gastric acid simulation solution. Figure 3 This is a diagram showing the gelation process of the acid-responsive gel material obtained in Example 1 in the mouse stomach.

[0121] Table 1. Properties of the acid-responsive gel materials obtained in Examples 1-20

[0122] Gel formation gel gel gel gel gel gel gel gel gel gel Viscosity (mPa.s) 89 92 103 144 156 132 233 214 227 166 Example 11 12 13 14 15 16 17 18 19 20 Gel formation gel gel gel gel gel gel gel gel gel gel Viscosity (mPa.s) 202 302 95 103 278 457 489 673 578 682

[0123] As shown in Table 1, Examples 1-20 all solidified into gel structures under acidic conditions through acid response. Simultaneously, through... Figure 2 As can be seen (the left image shows the acid-responsive gel material, which has good fluidity; the right image shows the acid-responsive gelation after mixing the acid-responsive gel material with the gastric acid simulation solution), the gel material obtained in Example 1 can gel after mixing with the gastric acid simulation solution. Figure 3 As can be seen, the gel material obtained in Example 1 can gel in the mouse stomach. Rheological analysis of the viscosity of the gel materials in Examples 1-20 shows that the gel adhesion increases significantly with increasing sodium alginate concentration in the gel matrix material. Furthermore, the results of Examples 1, 2, and 3 indicate that the more metallophenolic network structures in the gel, the greater the gel viscosity.

[0124] Under acidic conditions, all gels can solidify through an acid response to form a gel structure. Rheological testing of the viscosity in Examples 10-14 shows that the viscosity varies with different gel matrix materials, with gellan gum exhibiting a higher viscosity and carboxymethyl cellulose a relatively lower viscosity. Compared to Example 1, which underwent performance testing, Examples 13 and 14 indicate that the type of polyphenol has no significant effect on gel viscosity, while different cationic components may have some influence. Examples 10, 15, and 16 show that the gel viscosity increases significantly with increasing carboxymethyl cellulose concentration in the gel matrix material. Examples 11, 17, and 18 show that the gel viscosity increases significantly with increasing carboxymethyl chitosan concentration in the gel matrix material. Examples 12, 19, and 20 show that the gel viscosity increases significantly with increasing gellan gum concentration in the gel matrix material.

[0125] Example 21

[0126] Weigh 5 wt% tannic acid and 0.5 wt% zinc chloride and dissolve them in 1 mL of water for injection. Adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution and stir until homogeneous to obtain a metallophenolic network solution. Then, add 2 wt% sodium alginate to the metallophenolic network solution and stir thoroughly to induce swelling, obtaining the acid-responsive gel material. Finally, add 0.1 wt% oxaliplatin to the above acid-responsive gel material and dissolve completely to obtain an oxaliplatin-loaded acid-responsive gel formulation.

[0127] Example 22

[0128] 5 wt% tannic acid and 0.25 wt% zinc chloride were dissolved in 1 mL of water for injection. The pH of the solution was then adjusted to 7.4 with 1 mol / L sodium hydroxide solution, and the mixture was stirred until homogeneous to obtain a metallophenolic network solution. Then, 1.5 wt% sodium alginate was added to the metallophenolic network solution, and the mixture was stirred thoroughly to induce swelling, thus obtaining the acid-responsive gel material. Finally, 1.2 wt% erlotinib was added to the acid-responsive gel material, and after complete dissolution, an erlotinib-loaded acid-responsive gel formulation was obtained.

[0129] Example 23

[0130] 1 wt% tannic acid and 0.1 wt% zinc chloride were dissolved in 1 mL of enzyme-free water. The pH of the solution was then adjusted to 7.4 with 1 mol / L enzyme-free sodium hydroxide solution. The mixture was stirred until homogeneous to obtain a metallophenolic network solution. 1 wt% sodium alginate was then added to the metallophenolic network solution, and the mixture was stirred thoroughly to induce swelling, thus obtaining the acid-responsive gel material. Finally, 3 wt% SiPD-L1 was added to the acid-responsive gel material, and after complete dissolution, a SiPD-L1-loaded acid-responsive gel formulation was obtained.

[0131] Example 24

[0132] 2.5 wt% tannic acid and 0.25 wt% zinc chloride were dissolved in 1 mL of water for injection. The pH of the solution was then adjusted to 7.4 with 1 mol / L sodium hydroxide solution, and the mixture was stirred until homogeneous to obtain a metallophenolic network solution. Then, 1.5 wt% sodium alginate was added to the metallophenolic network solution, and the mixture was stirred thoroughly to induce swelling, thus obtaining the acid-responsive gel material. Finally, 3.2 wt% dexamethasone was added to the acid-responsive gel material, and after complete dissolution, a dexamethasone-loaded acid-responsive gel formulation was obtained.

[0133] Example 25

[0134] 2.5 wt% tannic acid and 0.5 wt% zinc chloride were dissolved in 1 mL of water for injection. The pH of the solution was then adjusted to 7.4 with 1 mol / L sodium hydroxide solution, and the mixture was stirred until homogeneous to obtain a metallophenolic network solution. Then, 1.5 wt% sodium alginate was added to the metallophenolic network solution, and the mixture was stirred thoroughly to induce swelling, thus obtaining the acid-responsive gel material. Finally, 0.1 wt% oxaliplatin was added to the acid-responsive gel material, and after complete dissolution, an oxaliplatin-loaded acid-responsive gel formulation was obtained.

[0135] Example 26

[0136] Weigh 1.25wt% tannic acid and 0.25wt% copper chloride and dissolve them in 1mL of water for injection. Then, adjust the pH of the solution to 7.4 with 1mol / L sodium hydroxide solution and stir to mix evenly to obtain a metal phenolic network solution. Then, add 2wt% sodium alginate to the metal phenolic network solution and stir thoroughly to swell to obtain the acid-responsive gel material.

[0137] Performance testing

[0138] Test Example 2

[0139] Test the performance of the acid-responsive gel formulation prepared in Example 21;

[0140] Establishment of an in situ gastric cancer model: Ten-week-old female C57 mice were anesthetized by intraperitoneal injection of sodium pentobarbital. Gastric tissue was isolated from the mice, and 2*10 cells were subserosaly inoculated at the greater curvature of the stomach. 6 Five mouse gastric cancer cells (MFC) were randomly divided into three groups of five mice each: A) PBS group: 0.2 mL of PBS was administered by gavage on days 0, 4, 8, and 12 for a total of four times; B) Oxaliplatin free drug group: 0.2 mL of oxaliplatin injection (1 mg / mL) was administered by gavage on days 0, 4, 8, and 12 for a total of four times; C) Oxaliplatin gel group: 0.2 mL of oxaliplatin-loaded responsive gel (1 mg / mL) was administered by gavage on days 0, 4, 8, and 12 for a total of four times.

[0141] Figure 4 To monitor tumor size using gastric ultrasound and to detect in situ growth of the mouse stomach using ultrasound, the area circled in the box in the figure represents the mouse stomach tissue, and the areas marked with numbers in the box represent the locations of the mouse tumor tissue.

[0142] Figure 5 Image showing the growth of a tumor in the stomach as monitored by ultrasound.

[0143] from Figures 4-5 The results showed that, compared with the PBS group and the oxaliplatin free drug group, the oxaliplatin gel group was able to kill tumor cells for a longer period of time and had a more significant tumor-suppressing effect (p<0.05).

[0144] Test Example 3

[0145] Test the performance of the acid-responsive gel formulation prepared in Example 22

[0146] Establishment of an in situ gastric cancer model: Ten-week-old female C57 mice were anesthetized by intraperitoneal injection of sodium pentobarbital. Gastric tissue was isolated from the mice, and 2*10 cells were subserosaly inoculated at the greater curvature of the stomach. 6Five mouse gastric cancer cells (MFC) were randomly divided into three groups of five mice each: A) PBS group: 0.2 mL of PBS was administered by gavage on days 7, 10, 13, and 16 for a total of four times; B) Erlotinib free drug group: 0.8 mg / mL of erlotinib injection was administered by gavage on days 7, 10, 13, and 16 for a total of four times; C) Erlotinib gel group: 0.8 mg / mL of erlotinib acid-loaded responsive gel was administered by gavage on days 7, 10, 13, and 16 for a total of four times.

[0147] Tumor size can be monitored using gastric ultrasound. Figure 6 Statistical results of ultrasound measurements showed that, compared with the PBS group and the erlotinib free drug group, the erlotinib gel group was able to kill tumor cells for a longer period of time and had a more significant tumor-suppressing effect (p<0.05).

[0148] Test Example 4

[0149] Test the performance of the acid-responsive gel formulation prepared in Example 21;

[0150] Establishment of a gastric cancer peritoneal metastasis model: Ten-week-old female C57 mice were anesthetized by intraperitoneal injection of sodium pentobarbital, and 2*10 cm abscesses were implanted in the peritoneum. 6 Five mouse gastric cancer cells (MFC-luc) labeled with luciferase were randomly divided into three groups of five mice each: A) PBS group: 0.2 mL of PBS was injected intraperitoneally on days 7, 10, 13, and 16 for a total of four times; B) Oxaliplatin free drug group: 0.2 mL of oxaliplatin injection (1 mg / mL) was injected intraperitoneally on days 7, 10, 13, and 16 for a total of four times; C) Oxaliplatin gel group: 0.2 mL of oxaliplatin-loaded responsive gel (1 mg / mL) was injected intraperitoneally on days 7, 10, 13, and 16 for a total of four times.

[0151] Tumor size can be monitored using in vivo imaging in small animals. Figure 7 Statistical results of fluorescence signals showed that, compared with the PBS group and the oxaliplatin free drug group, the oxaliplatin gel group could kill tumor cells for a long time and had a more significant inhibitory effect on peritoneal metastases of gastric cancer (p<0.05).

[0152] Test Example 5

[0153] Test the properties of the acid-responsive gel material prepared in Example 1;

[0154] Construction of an abdominal adhesion model: 12-week-old female C57 mice were anesthetized by intraperitoneal injection of sodium pentobarbital. A 2cm incision was made along the linea alba to expose the cecum. The cecum was then gently wiped with sterile surgical gauze until petechial bleeding was observed on the cecal surface, thereby inducing surface damage to the cecum. Subsequently, the abdominal wall was scraped with a scalpel to form an area of ​​1*1cm. 2 For peritoneal injury, the damaged cecum and abdominal wall were positioned opposite each other. Mice were randomly divided into two groups of five each: PBS group (100 μL PBS solution sprayed onto the injury site); Example 1 group (100 μL acid-responsive gel solution sprayed onto the injury site); Example 11 group (100 μL acid-responsive gel solution sprayed onto the injury site); Example 12 group (100 μL acid-responsive gel solution sprayed onto the injury site); Example 13 group (100 μL acid-responsive gel solution sprayed onto the injury site); Example 14 group (100 μL acid-responsive gel solution sprayed onto the injury site); Example 15 group (100 μL acid-responsive gel solution sprayed onto the injury site). The abdominal wall and skin of the mice were then sutured layer by layer. On the 14th day postoperatively, the animals were dissected to observe the abdominal adhesions, and the adhesion tissue was collected for histological staining.

[0155] Figure 8 Masson staining results showed that, compared with the PBS control group, the acid-responsive gel treatment group could effectively inhibit postoperative tissue adhesion to a certain extent, and there was less new adhesion between intestinal tissue and abdominal wall tissue.

[0156] Test Example 6

[0157] Test the performance of the acid-responsive gel formulation prepared in Example 23;

[0158] Establishment of an in situ gastric cancer model: Ten-week-old female C57 mice were anesthetized by intraperitoneal injection of sodium pentobarbital. Gastric tissue was isolated from the mice, and 2*10 cells were subserosaly inoculated at the greater curvature of the stomach. 6 Five mouse gastric cancer cells (MFC) were randomly divided into three groups of five mice each: A) PBS group: 0.2 mL of PBS was administered by gavage on days 7, 10, 13, and 16 for a total of four times; B) free siPD-L1 group: 0.2 mL of siPD-L1 injection was administered by gavage on days 7, 10, 13, and 16 for a total of four times; C) siPD-L1 gel group: 0.2 mL of 5 nM erlotinib-loaded responsive gel was administered by gavage on days 7, 10, 13, and 16 for a total of four times.

[0159] Tumor size can be monitored using gastric ultrasound. Figure 9 Statistical results of ultrasound measurements showed that, compared with the PBS group and the siPD-L1 free drug group, the siPD-L1 gel group could kill tumor cells for a long time and had a more significant tumor-suppressing effect (p<0.05).

[0160] Test Example 7

[0161] Test the performance of the acid-responsive gel formulation prepared in Example 24;

[0162] Establishment of a rat model of chronic sinusitis: Twenty SD rats, weighing 250–350 g, were randomly divided into five groups: A) blank control group (n=4), B) chronic sinusitis group (n=4), C) Rhinocort group (n=4), D) dexamethasone free drug group (n=4), and E) dexamethasone gel group (n=4). Groups B, C, D, and E underwent subcutaneous injection of 1 mL of 2.5% ovalbumin (OVA) and 0.4% aluminum hydroxide on days 0 and 7 for sensitization. From day 12, 20 μL of 6% OVA solution was administered into each nostril via nasal drops for one week. From day 19, 20 μL of 6% OVA solution was administered into each nostril three times a week for four weeks. From weeks 5 to 12, 20 μL of 6% OVA solution was administered into each nostril three times a week, followed by 10 μL of 20 ng Staphylococcus aureus superantigen (SEB) solution 10 minutes later. During weeks 13 and 14, groups A and B received 20 μL of PBS nasal drops three times a week; group C received 20 μL of Rhinocort nasal drops three times a week; group D received 20 μL of free dexamethasone nasal drops three times a week; and group E received 200 μL of dexamethasone gel injected into the sinus cavity once. All laboratory animals were sacrificed in week 15.

[0163] Depend on Figure 10 As can be seen, compared with group B (chronic sinusitis group), groups E (dexamethasone gel group), D (dexamethasone free drug group), and C (Rhinocort group) significantly inhibited and improved infection and inflammatory response, and reduced sinus ostium mucosal edema (p<0.05). Group E (dexamethasone gel group) showed better treatment effect than groups D (dexamethasone free drug group) and C (Rhinocort group), but there was no statistically significant difference compared with group A (blank control group) (p>0.05).

[0164] Test Example 8

[0165] Test the performance of the acid-responsive gel formulation prepared in Example 25;

[0166] Establishment of a subcutaneous subcutaneous tumor recurrence model of gastric cancer: 10-week-old female C57 mice were subcutaneously inoculated with 2*10 spores in the right axilla. 6 Luciferase-labeled mouse gastric cancer cells (MFC-luc) were used until the tumor volume reached 150 mm. 3Afterwards, most of the tumor tissue was removed, leaving approximately 1% of the tumor tissue. The successfully modeled mice were then randomly divided into three groups of five mice each: A) PBS group: 0.2 mL of PBS was injected subcutaneously at the incision site, administered six times on postoperative days 0, 3, 6, 9, 12, and 15; B) Oxaliplatin free drug group: 0.2 mL of oxaliplatin injection (1 mg / mL) was injected subcutaneously at the incision site, administered six times on postoperative days 0, 3, 6, 9, 12, and 15; C) Oxaliplatin gel group: 0.2 mL of oxaliplatin-loaded responsive gel (1 mg / mL) was injected subcutaneously at the incision site, administered six times on postoperative days 0, 3, 6, 9, 12, and 15.

[0167] Depend on Figure 11 Statistics on the survival of mice after tumor recurrence showed that, compared with the PBS group, the oxaliplatin gel group could effectively prolong the survival period of mice.

[0168] Test Example 9

[0169] Test the properties of the acid-responsive gel material prepared in Example 26;

[0170] Cervical radiotherapy with vaginal protection model: Ten-week-old female Balb / c mice were randomly divided into three groups of five mice each: A) negative control group (0.2 mL saline injected vaginally); B) positive control group (0.2 mL saline injected vaginally); C) gel group (0.2 mL gel solution injected vaginally). On days 0, 1, 2, and 3 after the initial treatment, groups B and C received 8 Gy cervical radiotherapy. After radiotherapy, vaginal mucosal tissue was collected from the mice to observe local cellular damage and inflammation.

[0171] By detecting inflammatory markers in the vaginal mucosa tissue of mice Figure 12 The results showed that, compared with the negative control group in group A, the inflammatory markers in the positive control group in group B were significantly increased, while the gel group in group C could reduce the inflammatory markers and play a certain role in radiotherapy protection.

[0172] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. An acid-responsive gel material, characterized in that, The raw materials for preparation are: Gel matrix materials, polyphenolic compounds, metal salts, pH adjusters, and solvents; The polyphenolic compound is tannic acid; the mass of the polyphenolic compound is 1-5% of the mass of the acid-responsive gel material; The gel matrix material is one or more of sodium alginate, carboxymethyl cellulose, carboxymethyl chitosan and gellan gum; the mass of the gel matrix material is 1 to 2% of the mass of the acid-responsive gel material. The metal salt is one or more of manganese salt, zinc salt, and copper salt; the mass of the metal salt is 0.1-0.5% of the mass of the acid-responsive gel material. The acid-responsive gel material is in a flowing liquid state; The steps of the method for preparing the acid-responsive gel material are as follows: After mixing polyphenolic compounds, metal salts and solvents, a pH adjuster is added to adjust the pH of the system to >7, thus obtaining a metal-phenolic network solution. The metal phenolic network solution and the gel matrix material are mixed and swollen to obtain the acid-responsive gel material.

2. The method for preparing the acid-responsive gel material according to claim 1, characterized in that, The steps are as follows: After mixing polyphenolic compounds, metal salts and solvents, a pH adjuster is added to adjust the pH of the system to >7, thus obtaining a metal-phenolic network solution. The metal phenolic network solution and the gel matrix material are mixed and swollen to obtain the acid-responsive gel material.

3. An acid-responsive gel formulation, characterized in that, Includes gel materials, active pharmaceutical ingredients, and solvents; The gel material is the acid-responsive gel material according to claim 1 or the acid-responsive gel material prepared by the preparation method according to claim 2; The active pharmaceutical ingredient is one or more of chemotherapy drugs, targeted drugs, anti-inflammatory drugs, and nucleic acid drugs; The chemotherapy drug is oxaliplatin; the targeted drug is one or more of anlotinib, apatinib, gefitinib, and erlotinib; and the nucleic acid drug is siRNA.

4. The acid-responsive gel formulation according to claim 3, characterized in that, The mass of the active pharmaceutical ingredient is not less than 0.1% of the mass of the acid-responsive gel formulation.

5. The method for preparing the acid-responsive gel formulation according to claim 3 or 4, characterized in that, Includes the following steps: The gel material, the active pharmaceutical ingredient, and the solvent are mixed to obtain the acid-responsive gel formulation.

6. The use of the acid-responsive gel formulation according to claim 3 or 4 or the acid-responsive gel formulation prepared by the preparation method according to claim 5 in the preparation of a drug.

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