A gel preparation, a preparation method and application thereof, and a pharmaceutical gel preparation

Abstract

The present application relates to the technical field of pharmaceutical preparations, in particular to a gel preparation, a preparation method and application thereof, and a pharmaceutical gel preparation. The present application provides a gel preparation, which comprises a gel matrix, metal-coated polymer nanoparticles loaded in the gel matrix, and a pharmaceutically acceptable solvent; the mass ratio of the gel matrix, the metal coating in the metal-coated polymer nanoparticles, and the polymer nanoparticles in the metal-coated polymer nanoparticles is (1-10):(1-20):(1-10). The gel preparation can solve the problem of limited in-situ treatment methods for current peritoneal metastasis after tumor surgery and related diseases and inflammatory diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a gel formulation, its preparation method and application, and a pharmaceutical gel formulation. 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 comprehensive approach combining chemotherapy and surgery. Even after radical surgical resection, at least 50% of patients with advanced gastric cancer experience tumor recurrence or metastasis within 2-3 years post-surgery. Spontaneous dissemination of the primary gastric cancer lesion and surgically induced traumatic dissemination, resulting in free peritoneal cancer cells, form the pathological basis for peritoneal metastasis. During radical gastrectomy, the opening of lymphatic vessels in the surgical field, the shedding of cancer cells from the tumor margins, and bleeding due to tumor contamination can all potentially release cancer cells. Therefore, developing treatments that effectively and specifically target and kill exfoliated peritoneal tumor cells from gastric cancer and prevent their recurrence and metastasis is of significant clinical importance.

[0003] Exfoliated cancer cells and peritoneal metastases typically lack innervating blood vessels, and therapeutic drugs must directly contact the tumor to be effective, making conventional chemotherapy ineffective. Hyperthermia itself has a killing effect on tumor cells, and when combined with chemotherapy, it can produce a synergistic effect, inhibiting the repair of tumor cells damaged by chemotherapy drugs. Therefore, the current standard clinical treatment for inhibiting postoperative peritoneal metastases is intraperitoneal hyperthermic chemotherapy. However, intraperitoneal hyperthermic chemotherapy may have adverse reactions such as significant systemic toxicity, organ damage, abdominal pain, and perforation bleeding.

[0004] Gels are commonly used drug carriers, effectively increasing local drug concentrations, achieving local drug delivery, and reducing the toxic side effects of systemic administration. Simultaneously, gels possess sustained-release properties, allowing for a continuous and slow release of drugs, reducing the frequency and duration of administration. Currently, there are limited in situ treatment methods available both domestically and internationally for preventing postoperative peritoneal metastasis and gastric tumors and other digestive tract diseases. Therefore, developing a safe, effective, and convenient gel for the in situ treatment of postoperative peritoneal metastasis and gastric tumors has significant clinical importance. Summary of the Invention

[0005] The purpose of this invention is to provide a gel preparation, its preparation method and application, and a pharmaceutical gel preparation that can solve the problem of limited in situ treatment methods for postoperative peritoneal metastasis of tumors and related diseases and inflammatory diseases.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a gel formulation comprising a gel matrix, polymeric nanoparticles coated with a metal coating and loaded in the gel matrix, and a pharmaceutically acceptable solvent;

[0008] The mass ratio of the gel matrix, the metal coating in the metal-coated polymer nanoparticles, and the polymer nanoparticles in the metal-coated polymer nanoparticles is (1-10):(1-20):(1-10).

[0009] Preferably, the gel matrix comprises one or more of alginate and its derivatives, cellulose and its derivatives, chitosan and its derivatives, and polysaccharide gum.

[0010] Preferably, the alginate and its derivatives include one or more of sodium alginate, potassium alginate, calcium alginate, lithium alginate, sodium oxidized alginate, potassium oxidized alginate, calcium oxidized alginate and lithium oxidized alginate.

[0011] The cellulose and its derivatives include 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.

[0012] The chitosan and its derivatives include one or more of chitosan lactate, chitosan quaternary ammonium salt, chitosan hydrochloride, chitosan nitrate, chitosan sulfate, chitosan acetate, hydroxypropyl chitosan, and carboxymethyl chitosan;

[0013] The polysaccharide gum includes one or more of gelatin, gellan gum, pectin, konjac gum, carrageenan, guar gum, locust bean gum, xanthan gum, and gum arabic.

[0014] Preferably, the material of the metal coating includes polyphenols and cationic substances;

[0015] The polyphenols include one or more of the following: tannic acid, gallic acid, propyl gallate, epigallocatechin, epigallocatechin gallate, epicatechin gallate, tanshinone, proanthocyanidins, theaflavins, alginic acid, ellagic acid, flavonoids, phenolic acids, polyphenol amides, and polydopamine.

[0016] Preferably, the polymeric nanoparticles comprise phospholipids and / or polymers;

[0017] The phospholipids include one or more of 1,2-distearylphosphatidylethanolamine, 1,2-dipalmitoyl-sn-3-phosphatidylethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-tetradecanoylphosphatidylethanolamine, and distearylphosphatidylserine.

[0018] Preferably, the polymer comprises one or more of the following: polyethylene glycol monomethyl ether-polylactic acid glycolate copolymer, polyethylene glycol monomethyl ether-polylactic acid glycolate-polylysine block copolymer, polyethylene glycol-polyL-aspartic acid derivative block copolymer, polyethylene glycol-polylactic acid-polyethylene glycol block copolymer, polylactic acid-polyethylene glycol-polylactic acid block copolymer, polyethylene glycol-polyDL-lactic acid block copolymer, polyglycolic acid-lactide-polyethylene glycol-polyglycolic acid block copolymer, polyethylene glycol-polyglycolic acid-lactide-polyethylene glycol block copolymer, polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, polyethylene oxide, polydimethylsiloxane, methacrylate, polyacrylic acid, poly(N-isopropylacrylamide), poly(methyl methacrylate-co-ethyl acrylate), polyphosphazene, polyurethane, and polyamino acids.

[0019] The present invention also provides a method for preparing the gel formulation described in the above technical solution, comprising the following steps:

[0020] After emulsifying, removing the organic phase, and drying the polymer material, it is mixed with a pharmaceutically acceptable solvent to obtain a polymer nanoparticle suspension.

[0021] After mixing the polymer nanoparticle suspension and the metal coating material, the pH is adjusted to alkaline to obtain a polymer nanoparticle solution coated with a metal coating.

[0022] The polymer nanoparticle solution coated with the metal coating is mixed with the gel matrix material to obtain the gel formulation.

[0023] The present invention also provides the application of the gel formulation described in the above technical solution or the gel formulation prepared by the preparation method described in the above technical solution in the preparation of drug gel formulations, wherein the drug gel formulations include antitumor drug gel formulations, anti-inflammatory drug gel formulations, radiotherapy drug gel formulations or photoacoustic therapy drug gel formulations.

[0024] The present invention also provides a pharmaceutical gel formulation, comprising a gel formulation and a pharmaceutical active ingredient;

[0025] The gel formulation is the gel formulation described in the above technical solution or the gel formulation prepared by the preparation method described in the above technical solution.

[0026] Preferably, the mass ratio of the gel formulation to the active pharmaceutical ingredient is (0-150):(0-10), and the mass of both the gel formulation and the active pharmaceutical ingredient is not 0.

[0027] The active pharmaceutical ingredient includes one or more of the following: chemotherapy drugs, targeted drugs, local anesthetics, nucleic acid drugs, and anti-inflammatory drugs.

[0028] This invention provides a gel formulation comprising a gel matrix, polymeric nanoparticles coated with a metal coating and loaded in the gel matrix, and a pharmaceutically acceptable solvent; the mass ratio of the gel matrix, the metal coating in the metal-coated polymeric nanoparticles, and the polymeric nanoparticles in the metal-coated polymeric nanoparticles is (1-10):(1-20):(1-10). The gel formulation of this invention has pH-sensitive properties and can load various therapeutic active ingredients. In the acidic microenvironment of postoperative peritoneal inflammation and tumors, the metal coating on the surface of the metal-coated polymeric nanoparticles degrades, releasing metal cations, which cross-link with the gel matrix in the gel solution, thereby gelling to form a local gel drug reservoir, solving the problem of limited in situ treatment methods for current tumor peritoneal metastasis and related diseases and inflammatory diseases. Simultaneously, the gel formulation is a flowing liquid state, convenient for spraying, injection, and oral administration; it can locally solidify into a gel in an acidic microenvironment; and after loading the active pharmaceutical ingredient, the gel formulation can protect the active pharmaceutical ingredient, forming an in situ gel drug reservoir at the tumor site, providing a long-lasting sustained-release effect. Attached Figure Description

[0029] Figure 1 This is a schematic diagram of the preparation process of the gel formulation described in this invention;

[0030] Figure 2 The images shown are TEM and SEM images of the metal-coated nanoparticles in the metal-coated nanoparticle gel solution described in Example 7.

[0031] Figure 3 The image shows the gelation of the metal-coated nanoparticle gel solution described in Example 1 after mixing with a tumor acidic microenvironment simulation solution (pH = 6.6).

[0032] Figure 4 The nanoparticle gel solution coated with a metal coating as described in Example 1 can gel in the stomach of a mouse;

[0033] Figure 5 This is a graph showing the change in tumor size over time as monitored by in vivo imaging fluorescence signals in Example 21.

[0034] Figure 6 This is a graph showing the change in tumor size over time as monitored by gastric ultrasound in Example 22.

[0035] Figure 7 This is a graph showing the change in tumor size over time as monitored by in vivo imaging fluorescence signals in Example 23.

[0036] Figure 8 Example 24: Mechanical withdrawal reflex threshold measurement curve for postoperative incision pain model;

[0037] Figure 9 This is a graph showing the change in tumor size over time as monitored by in vivo imaging fluorescence signals in Example 25.

[0038] Figure 10 The results of Masson staining of the adhesion tissue in test example 4;

[0039] Figure 11 CT images and semi-quantitative statistical graphs showing the effect of Example 26 in inhibiting chronic sinusitis;

[0040] Figure 12 This is a graph showing the change in tumor size over time as monitored by in vivo imaging fluorescence signals in Example 27.

[0041] Figure 13 This is a survival curve of the tumor-recurrent mice in Example 28.

[0042] Figure 14 This is a graph of inflammatory markers in the radiotherapy protection model of Example 29. Detailed Implementation

[0043] This invention provides a gel formulation comprising a gel matrix, polymeric nanoparticles coated with a metal coating and loaded in the gel matrix, and a pharmaceutically acceptable solvent;

[0044] The mass ratio of the gel matrix, the metal coating in the metal-coated polymer nanoparticles, and the polymer nanoparticles in the metal-coated polymer nanoparticles is (1-10):(1-20):(1-10).

[0045] In this invention, the mass ratio of the gel matrix, the metal coating in the metal-coated polymer nanoparticles, and the polymer nanoparticles in the metal-coated polymer nanoparticles is (1-10):(1-20):(1-10), preferably (2-5):(2-15):(2-3), and more preferably (2-5):(2.2-11):(2-3).

[0046] In this invention, the gel matrix preferably comprises one or more of alginate and its derivatives, cellulose and its derivatives, chitosan and its derivatives, and polysaccharide gum; the alginate and its derivatives preferably comprise one or more of sodium alginate, potassium alginate, calcium alginate, lithium alginate, sodium oxidized alginate, potassium oxidized alginate, calcium oxidized alginate, and lithium oxidized alginate, more preferably sodium alginate; the cellulose and its derivatives preferably comprise 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. The chitosan matrix comprises one or more of the following, more preferably carboxymethyl cellulose; the chitosan and its derivatives preferably comprise one or more of the following: chitosan lactate, chitosan quaternary ammonium salt, chitosan hydrochloride, chitosan nitrate, chitosan sulfate, chitosan acetate, hydroxypropyl chitosan, and carboxymethyl chitosan, more preferably carboxymethyl chitosan; the polysaccharide gum preferably comprises one or more of the following: gelatin, gellan gum, pectin, konjac gum, carrageenan, guar gum, locust bean gum, xanthan gum, and gum arabic, more preferably gellan gum; when the gel matrix comprises two or more of the above-mentioned specific selections, the present invention does not impose any special limitation on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio.

[0047] In this invention, the gel matrix is ​​used to load pharmaceutically active ingredients.

[0048] In this invention, the material of the metal coating preferably includes polyphenols and cationic substances. In this invention, the mass ratio of the polyphenols to the cationic substances is preferably (1-10):1, more preferably (5-10):1, and even more preferably 10:1; the polyphenols preferably include one or more of tannic acid, gallic acid, propyl gallate, epigallocatechin gallate, epigallocatechin gallate, epicatechin gallate, salvianolic acid, proanthocyanidins, theaflavins, alginic acid, ellagic acid, flavonoids, phenolic acids, polyphenol amides, and polydopamine, more preferably tannic acid; the cationic substances... The ionic substances preferably include one or more of sodium phosphate, calcium salt, manganese salt, zinc salt, iron salt, aluminum salt, copper salt, silver 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; and the iron salt preferably includes ferric chloride. More preferably, manganese chloride, sodium phosphate, or calcium chloride is used. When the material of the metal coating is two or more of the above-mentioned specific selections, the present invention does not impose any special limitation on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio.

[0049] In this invention, the metal coating material can be bonded to the surface of nanoparticles constructed from polymer materials under alkaline conditions to form a metal coating, and degrades to release metal cations under acidic conditions, which then combine with the gel matrix material to solidify into a gel.

[0050] In this invention, the polymeric nanoparticles preferably comprise phospholipids and / or polymers; the phospholipids preferably comprise one or more of 1,2-distearylphosphatidylethanolamine, 1,2-dipalmitoyl-sn-3-phosphatidylethanolamine, 1,2-dioleoyl-sn-glycerol-3-phosphoethanolamine, 1,2-tetradecanoylphosphatidylethanolamine, and distearylphosphatidylserine, more preferably 1,2-distearylphosphatidylethanolamine; the polymers preferably comprise polyethylene glycol monomethyl ether-polylactic acid glycolate copolymer, polyethylene glycol monomethyl ether-polylactic acid glycolate-polylysine block copolymer, polyethylene glycol-polyL-aspartic acid derivative block copolymer, polyethylene glycol-polylactic acid-polyethylene glycol block copolymer, polylactic acid-polyethylene glycol- The polymer nanoparticles are selected from one or more of the following: polylactic acid block copolymers, polyethylene glycol-poly(DL-lactic acid) block copolymers, poly(lactic-co-glycolic acid)-poly(lactic-co-glycolic acid) block copolymers, polyethylene glycol-poly(lactic-co-glycolic acid)-poly(lactic-co-glycolic acid) block copolymers, polycaprolactone-poly(lactic-co-glycolic acid)-polycaprolactone block copolymers, polyethylene oxide, polydimethylsiloxane, methacrylate, polyacrylic acid, poly(N-isopropylacrylamide), poly(methyl methacrylate)-co-ethyl acrylate, polyphosphazene, polyurethane, and polyamino acids, more preferably polyethylene glycol monomethyl ether-polylactic-co-hydroxyacetic acid-polylysine block copolymers. When the polymer nanoparticles are two or more of the above-mentioned specific selections, the present invention does not impose any special limitation on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio.

[0051] In this invention, the polymer nanoparticles are drug delivery carrier materials.

[0052] In this invention, there is no particular limitation on the type of pharmaceutically acceptable 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. When the pharmaceutically acceptable solvent is two or more of the above-mentioned specific selections, there is no particular limitation on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio.

[0053] In this invention, the preferred ratio of the polymer nanoparticles to the pharmaceutically acceptable solvent is (1-20) mg:1 mL, more preferably (5-15) mg:1 mL, and most preferably 10 mg:1 mL.

[0054] The present invention also provides a method for preparing the gel formulation described in the above technical solution, comprising the following steps:

[0055] After emulsifying, removing the organic phase, and drying the polymer material, it is mixed with a pharmaceutically acceptable solvent to obtain a polymer nanoparticle suspension.

[0056] After mixing the polymer nanoparticle suspension and the metal coating material, the pH is adjusted to alkaline to obtain a polymer nanoparticle solution coated with a metal coating.

[0057] The polymer nanoparticle solution coated with the metal coating is mixed with the gel matrix material to obtain the gel formulation.

[0058] In this invention, unless otherwise specified, all raw materials used in the preparation are commercially available products well known to those skilled in the art.

[0059] This invention involves emulsifying, removing the organic phase, and drying a polymer material sequentially, followed by mixing with a pharmaceutically acceptable solvent to obtain a polymer nanoparticle suspension.

[0060] In this invention, the emulsification process preferably includes mixing the polymer material and dichloromethane, adding a portion of the emulsifier for ultrasonic emulsification, and then adding the remaining emulsifier for ultrasonic emulsification. This invention does not impose any special limitations on the type and amount of the emulsifier or the specific emulsification conditions; any process well-known to those skilled in the art can be used. In an embodiment of this invention, the emulsification process specifically involves mixing 0.01g of the polymer material and 500μL of dichloromethane at a mass ratio of 1:100, adding 50μL of a 0.1% poloxamer 188 aqueous solution for ultrasonic emulsification, and then adding 5mL of a 0.1% poloxamer 188 aqueous solution for ultrasonic emulsification.

[0061] In this invention, the process of removing the organic phase is preferably vacuum removal at room temperature; this invention does not impose any special limitations on the conditions for vacuum removal, and conditions well known to those skilled in the art can be used.

[0062] The present invention does not impose any special limitations on the freeze-drying process; any process well known to those skilled in the art can be used.

[0063] After obtaining the polymer nanoparticle suspension, the present invention mixes the polymer nanoparticle suspension with the metal coating material and adjusts the pH to alkaline to obtain a polymer nanoparticle solution coated with metal coating.

[0064] The present invention does not impose any special limitations on the mixing process; any process known to those skilled in the art can be used.

[0065] The present invention does not impose any special limitations on the process of adjusting the pH to alkaline. A process well known to those skilled in the art can be used, and it is ensured that the adjusted pH is within the range of 7 to 8.

[0066] After pH adjustment, the present invention preferably includes stirring. The present invention does not have any special limitations on the stirring process, and any process known to those skilled in the art can be used.

[0067] After obtaining the polymer nanoparticle solution coated with a metal coating, the present invention mixes the polymer nanoparticle solution coated with a metal coating with a gel matrix material to obtain the gel formulation.

[0068] In this invention, the mixing is preferably carried out under stirring conditions. This invention does not impose any special limitations on the stirring conditions, and conditions well known to those skilled in the art can be used.

[0069] The present invention also provides the application of the gel formulation described in the above technical solution or the gel formulation prepared by the preparation method described in the above technical solution in the preparation of drug gel formulations, wherein the drug gel formulation preferably includes antitumor drug gel formulations, anti-inflammatory drug gel formulations, radiotherapy drug gel formulations or photoacoustic therapy drug gel formulations.

[0070] The present invention also provides a pharmaceutical gel formulation, comprising a gel formulation and a pharmaceutical active ingredient;

[0071] The gel formulation is the gel formulation described in the above technical solution or the gel formulation prepared by the preparation method described in the above technical solution.

[0072] In this invention, the mass ratio of the gel preparation to the active pharmaceutical ingredient is preferably (0-150):(0-10), more preferably (10-150):(1-10), and most preferably (31-115):(1-3).

[0073] In this invention, the active pharmaceutical ingredient preferably includes one or more of the following: chemotherapy drugs, targeted drugs, local anesthetics, nucleic acid drugs, and anti-inflammatory drugs; the chemotherapy drugs preferably include cyclophosphamide, docetaxel, 10-hydroxycamptothecin, camptothecin, cisplatin, carboplatin, cycloplatin, carmustine, nimustine, rubitecan, 9-aminocamptothecin, vincristine, capecitabine, desmethylcantharidin, epirubicin, doxorubicin, daunorubicin, doxorubicin, oxaliplatin, gemcitabine, etc. Pemetrexed, temozolomide, teniposide, etoposide, vindesine, vinflunine, vinorelbine, cytarabine, methotrexate, tegafur, mitomycin, mitoxantrone, topotecan, irinotecan, arsenic trioxide, and 5-fluorouracil, more preferably oxaliplatin, cyclophosphamide, docetaxel, or doxorubicin; the targeted drug preferably includes trastuzumab, ramucirumab, nivolumab, pembrolizumab, anlotinib, apatinib, bevacizumab, gefitinib, The anesthetic is preferably one or more of erlotinib and cetuximab, more preferably gefitinib and / or erlotinib; the local anesthetic preferably includes one or more of ropivacaine, procaine, chloroprocaine, mepivacaine, tetracaine, lidocaine, bupivacaine, levobupivacaine, benzocaine, and dacronin, more preferably lidocaine and / or ropivacaine; the nucleic acid drug preferably includes miRNA, lncRNA, siRNA, circRNA, saRNA, and piRNA. One or more of the RNAs, more preferably including miRNA and / or siRNA; the anti-inflammatory drug preferably includes one or more of aspirin, sodium salicylate, magnesium salicylate, magnesium salicylate choline, disalicylate, diflunisal, ibuprofen, phenoxyibuprofen, ketoibuprofen, indomethacin, flurbibuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, diclofenac sodium, fenprofen, ketorolac, tetraclofenamic acid, sulindac, tometidine, and dexamethasone, more preferably dexamethasone. When the active pharmaceutical ingredient is two or more of the above-mentioned specific selections, the present invention does not have any special limitation on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio.

[0074] In this invention, the preparation method of the drug gel formulation preferably includes the following steps:

[0075] The gel formulation and the active pharmaceutical ingredient are mixed to obtain the pharmaceutical gel formulation;

[0076] Alternatively, the active pharmaceutical ingredient, polymer material and dichloromethane can be mixed and dissolved, then emulsified, the organic phase removed and dried sequentially, and then mixed with a pharmaceutically acceptable solvent to obtain a drug-loaded polymer nanoparticle suspension.

[0077] After mixing the drug-loaded polymer nanoparticle suspension and the metal coating material, the pH is adjusted to alkaline to obtain a drug-loaded polymer nanoparticle solution coated with a metal coating.

[0078] The drug-loaded polymer nanoparticle solution coated with the metal coating is mixed with the gel matrix material to obtain the drug gel formulation.

[0079] In this invention, the drug gel formulation is preferably targeted at the treatment of postoperative peritoneal metastasis and gastric tumors. This invention involves spraying a gel solution postoperatively. Based on the acidic microenvironment of the postoperative peritoneum and tumor, the metal coating on the surface of the polymer nanoparticles in the gel solution degrades, releasing free cations. These cations combine with sodium alginate in the gel matrix to form an in-situ gel, thereby sustaining the release of chemotherapeutic drugs and exerting a local anti-tumor effect.

[0080] In this invention, the drug gel preparation is preferably applied to the acidic microenvironment of the body by oral administration, infusion, intraperitoneal spray, local injection or topical application.

[0081] When the drug gel formulation is administered orally and comes into direct contact with the tumor in a local acidic microenvironment, the drug gel formulation is preferably applied to oral tumors, nasopharyngeal tumors, or gastrointestinal tumors; the gastrointestinal tumors preferably include esophageal tumors, gastric tumors, or intestinal tumors.

[0082] When the drug gel preparation is applied via intraperitoneal spray to isolate the postoperative incision site and abdominal tissue, the drug gel preparation is preferably used for postoperative anti-adhesion treatment.

[0083] In this invention, the drug gel formulation preferably achieves synergistic treatment (radiotherapy, photoacoustic therapy) by loading different therapeutic drugs or treatment methods.

[0084] The following detailed description of the gel formulations, their preparation methods, and applications provided by the present invention, along with pharmaceutical gel formulations, is provided in conjunction with specific examples. However, these descriptions should not be construed as limiting the scope of protection of the present invention.

[0085] Example 1

[0086] At a mass ratio of 1:100, 0.01 g of 1,2-distearate phosphatidylethanolamine was dissolved in 500 μL of dichloromethane. Then, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Finally, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting polymer nanoparticles were dissolved in 1 mL of water for injection to obtain a polymer nanoparticle suspension.

[0087] Add 0.01 g of tannic acid and 0.001 g of manganese chloride to the polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a nanoparticle solution coated with a metal coating.

[0088] 0.01 g of sodium alginate was added to the solution of nanoparticles coated with metal coating and stirred thoroughly to induce swelling, thereby obtaining a gel solution of nanoparticles coated with metal coating.

[0089] Example 2

[0090] Referring to Example 1, the difference is that 0.01g of tannic acid is replaced with 0.025g of tannic acid; and 0.001g of manganese chloride is replaced with 0.0025g of manganese chloride.

[0091] Example 3

[0092] Referring to Example 1, the difference is that 0.01g of tannic acid is replaced with 0.05g of tannic acid; and 0.001g of manganese chloride is replaced with 0.005g of manganese chloride.

[0093] Example 4

[0094] At a mass ratio of 1:100, 0.01 g of 1,2-distearate phosphatidylethanolamine was dissolved in 500 μL of dichloromethane. Then, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Finally, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting polymer nanoparticles were dissolved in 1 mL of water for injection to obtain a polymer nanoparticle suspension.

[0095] Add 0.01 g of sodium phosphate and 0.001 g of calcium chloride to the polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a nanoparticle solution coated with a metal coating.

[0096] 0.01 g of sodium alginate was added to the solution of nanoparticles coated with metal coating and stirred thoroughly to induce swelling, thereby obtaining a gel solution of nanoparticles coated with metal coating.

[0097] Example 5

[0098] Referring to Example 4, the difference is that 0.01g of sodium phosphate is replaced with 0.025g of sodium phosphate; and 0.001g of calcium chloride is replaced with 0.0025g of calcium chloride.

[0099] Example 6

[0100] Referring to Example 4, the difference is that 0.01g of sodium phosphate is replaced with 0.05g of sodium phosphate; and 0.001g of calcium chloride is replaced with 0.005g of calcium chloride.

[0101] Test Example 1

[0102] The formation of precipitates (after mixing with the metal coating) and the final gel solutions were observed during the preparation process of Examples 1-6. The specific observation results are shown in Table 1:

[0103] Table 1 shows the formation of precipitates and the final gel solutions obtained during the preparation process described in Examples 1-6.

[0104]

[0105]

[0106] As shown in Table 1, there was no obvious solid precipitation or stratification in the metal coating preparation process of Examples 1 to 6. At the same time, the gels prepared in the end were all in solution state, which is beneficial for later application.

[0107] Example 7

[0108] At a mass ratio of 1:100, 0.01 g of polyethylene glycol monomethyl ether-polylactic acid glycolic acid-polylysine block copolymer (mPEG-PLGA-PLL) was dissolved in 500 μL of dichloromethane. Then, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Finally, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting polymer nanoparticles were dissolved in 1 mL of water for injection to obtain a polymer nanoparticle suspension.

[0109] Add 0.01 g of tannic acid and 0.001 g of manganese chloride to the polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a nanoparticle solution coated with a metal coating.

[0110] 0.01 g of sodium alginate was added to the solution of nanoparticles coated with metal coating and stirred thoroughly to induce swelling, thereby obtaining a gel solution of nanoparticles coated with metal coating.

[0111] The metal-coated nanoparticles in the gel solution were observed using transmission electron microscopy (TEM), and the distribution of the metal-coated nanoparticles in the gel was observed using scanning electron microscopy (SEM). The test results are as follows: Figure 2 As shown, from left to right are TEM and SEM images; Figure 2It can be seen that the nanoparticles coated with the metal coating have a distinct core-shell structure, indicating that the metal coating has successfully coated the polymer nanoparticles; and the nanoparticles coated with the metal coating are uniformly distributed in the gel, wherein the black arrows represent the polymer nanoparticles coated with the metal coating.

[0112] Example 8

[0113] Referring to Example 1, the difference is that 0.01g of sodium alginate was replaced with 0.025g of sodium alginate.

[0114] Example 9

[0115] Referring to Example 1, the difference is that 0.01g of sodium alginate is replaced with 0.05g of sodium alginate.

[0116] Example 10

[0117] Referring to Example 7, the difference is that 0.01g of sodium alginate is replaced with 0.025g of sodium alginate.

[0118] Example 11

[0119] Referring to Example 7, the difference is that 0.01g of sodium alginate is replaced with 0.05g of sodium alginate.

[0120] Test Example 2

[0121] Acid-responsive gelling and adhesion properties of the metal-coated nanoparticle gel solutions prepared in Examples 1-11:

[0122] Acid-responsive gelation performance test: In vitro gelation experiment: 1 mL of the metal-coated nanoparticle gel solution prepared in Examples 1-11 was added to 10 mL of a tumor acidic microenvironment simulation solution (pH=6.6), and the gelation behavior in the acidic solution was observed. In vivo gelation experiment: 1 mL of the metal-coated nanoparticle gel solution prepared in Examples 1-11 was administered to mice by gavage. 20 min 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.

[0123] Adhesion performance test: Take 1 mL of the nanoparticle gel solution coated with metal-loaded coating prepared in Examples 1 to 11, and use a rheometer to detect the viscosity (mPa·s) of the gel at a temperature of 37℃, a strain of 1%, and a frequency of 1Hz.

[0124] The test results are shown in Table 2 and Figures 3-4 As shown, where Figure 3The images show the gelation process of the metal-coated nanoparticle gel solution described in Example 1 after mixing with a simulated acidic tumor microenvironment solution (pH = 6.6). (From left to right, the images show the physical sample of the metal-coated nanoparticle gel solution described in Example 1 and the acid-response gelation process after mixing the metal-coated nanoparticle gel solution described in Example 1 with the simulated acidic tumor microenvironment solution.) Figure 4 The nanoparticle gel solution coated with a metal coating described in Example 1 can gel in the stomach of mice (the arrows in the figure indicate the gel formed in response to pH in the mouse stomach):

[0125] Table 2. Acid-responsive gelling and adhesion properties of the metal-coated nanoparticle gel solutions prepared in Examples 1-11

[0126]

[0127] As shown in Table 2, the metal-coated nanoparticle gel solutions prepared in Examples 1-11 can all solidify into gel structures under acidic conditions through acid response; Figure 3 It is known that the nanoparticle gel solution coated with a metal layer as described in Example 1 can gel after being mixed with a tumor acidic microenvironment simulation solution (pH = 6.6); Figure 4 It is evident that the metal-coated nanoparticle gel solution described in Example 1 can gel in the mouse stomach. Rheological analysis of the viscosity of the metal-coated nanoparticle gel solutions described in Examples 1-11 shows that the gel adhesion performance significantly increases with increasing concentration of sodium alginate, the gel matrix material. A viscosity comparison between Examples 1 and 8 shows that the preparation of nanoparticles using the polymers 1,2-distearate phosphatidylethanolamine and polyethylene glycol monomethyl ether-polylactic acid glycolic acid-polylysine block copolymer has little effect on gel viscosity. A viscosity comparison between Examples 1-3 or Examples 4-6 shows that the gel adhesion performance significantly increases with increasing content of the metal coating material.

[0128] Example 12

[0129] Referring to Example 1, the difference is that the gel matrix material is replaced with carboxymethyl cellulose.

[0130] Example 13

[0131] Referring to Example 1, the difference is that the gel matrix material is replaced with carboxymethyl chitosan.

[0132] Example 14

[0133] Referring to Example 1, the difference is that the gel matrix material is replaced with gellan gum.

[0134] Example 15

[0135] Refer to Example 4, except that the gel matrix material is replaced with carboxymethyl cellulose.

[0136] Example 16

[0137] Refer to Example 4, except that the gel matrix material is replaced with carboxymethyl chitosan.

[0138] Example 17

[0139] Refer to Example 4, except that the gel matrix material is replaced with gellan gum.

[0140] Example 18

[0141] Refer to Example 7, except that the gel matrix material is replaced with carboxymethyl cellulose.

[0142] Example 19

[0143] Referring to Example 7, the difference is that the gel matrix material is replaced with carboxymethyl chitosan.

[0144] Example 20

[0145] Refer to Example 7, except that the gel matrix material is replaced with gellan gum.

[0146] Test Example 3

[0147] Acid-responsive gelling and adhesion properties of the metal-coated nanoparticle gel solutions prepared in Examples 12-20:

[0148] Acid-responsive gelation performance test: In vitro gelation experiment was conducted by adding 1 mL of the metal-coated nanoparticle gel solution prepared in Examples 12-20 to 10 mL of tumor acidic microenvironment simulation solution (pH=6.6) and observing the gelation behavior of the gel in the acidic solution.

[0149] Adhesion performance test: Take 1 mL of the nanoparticle gel solution coated with metal coating prepared in Examples 12-20 and use a rheometer to detect the viscosity (mPa·s) of the gel at a temperature of 37℃, a strain of 1%, and a frequency of 1Hz.

[0150] The test results are shown in Table 3:

[0151] Table 3. Acid-responsive gelling and adhesion properties of the metal-coated nanoparticle gel solutions prepared in Examples 12-20

[0152]

[0153] As shown in Table 3, the nanoparticle gel solutions with metal-loaded coatings prepared in Examples 12-20 can all solidify into gel structures through acid response under acidic conditions. By rheological testing of the viscosity of the nanoparticle gel solutions with metal-loaded coatings in Examples 12-20, it can be seen that different gel matrix materials have different gel adhesion properties, with gellan gel having a larger viscosity and carboxymethyl cellulose having a relatively smaller viscosity.

[0154] Example 21

[0155] At a mass ratio of 1:100, 0.01 g of 1,2-distearate phosphatidylethanolamine was dissolved in 500 μL of dichloromethane. Then, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Finally, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting polymer nanoparticles were dissolved in 1 mL of water for injection to obtain a polymer nanoparticle suspension.

[0156] Add 0.025 g of tannic acid and 0.0025 g of manganese chloride to the polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a nanoparticle solution coated with a metal coating.

[0157] 0.025g of sodium alginate was added to the solution of nanoparticles coated with the metal coating and stirred thoroughly until swollen to obtain a gel formulation solution.

[0158] Add 0.001 g of oxaliplatin to the above gel formulation solution to obtain oxaliplatin-loaded gel.

[0159] 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 gel (1 mg / mL) was injected intraperitoneally on days 7, 10, 13, and 16 for a total of four times.

[0160] Monitoring abdominal tumor size using in vivo imaging in small animals Figure 5 This is a graph showing the change in tumor size over time as monitored by in vivo imaging fluorescence signals, from Example 21. Figure 5It can be seen that, compared with the PBS group, the oxaliplatin gel group can kill tumor cells for a longer period of time and has a more significant tumor-inhibiting effect (p<0.05).

[0161] Example 22

[0162] At a mass ratio of 1:100, 0.01 g of 1,2-distearate phosphatidylethanolamine was dissolved in 500 μL of dichloromethane. Then, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Finally, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting polymer nanoparticles were dissolved in 1 mL of water for injection to obtain a polymer nanoparticle suspension.

[0163] Add 0.05 g of tannic acid and 0.005 g of manganese chloride to the polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a nanoparticle solution coated with a metal coating.

[0164] 0.05 g of sodium alginate was added to the solution of nanoparticles coated with the metal coating and stirred thoroughly until swollen to obtain a gel formulation solution;

[0165] Add 0.001 g of oxaliplatin to the above gel formulation solution to obtain oxaliplatin-loaded gel.

[0166] Establishment of a gastric cancer in situ tumor model: Ten-week-old female C57 mice were anesthetized by intraperitoneal injection of sodium pentobarbital. Gastric tissue was dissected after abdominal dissection, and 2*10 mg / L gastric carcinoma was injected subserosally at the lesser curvature of the stomach. 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 was administered by gavage at a dose of 1 mg / mL on days 7, 10, 13, and 16 for a total of four times; C) Oxaliplatin gel group: 0.2 mL of oxaliplatin-loaded gel was administered by gavage at a dose of 1 mg / mL on days 7, 10, 13, and 16 for a total of four times.

[0167] Tumor size was monitored using gastric ultrasound, among which Figure 6 This is a graph showing the change in tumor size over time as monitored by gastric ultrasound in Example 22. Figure 6 It can be seen that, compared with the PBS group and the oxaliplatin free drug group, the oxaliplatin gel group can kill tumor cells for a long time and has a more obvious tumor-suppressing effect (p<0.05).

[0168] Example 23

[0169] At a mass ratio of 1:100, 0.01 g of 1,2-distearate phosphatidylethanolamine was dissolved in 500 μL of dichloromethane. Then, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Finally, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting polymer nanoparticles were dissolved in 1 mL of water for injection to obtain a polymer nanoparticle suspension.

[0170] Add 0.025 g of tannic acid and 0.005 g of manganese chloride to the polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a nanoparticle solution coated with a metal coating.

[0171] 0.025g of sodium alginate was added to the solution of nanoparticles coated with the metal coating and stirred thoroughly until swollen to obtain a gel formulation solution.

[0172] 0.0012 g of gefitinib was added to the above gel formulation solution to obtain gefitinib-loaded gel.

[0173] 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) Gefitinib free drug group: 0.2 mL of gefitinib injection solution (1.2 mg / mL) was injected intraperitoneally on days 7, 10, 13, and 16 for a total of four times; C) Gefitinib gel group: 0.2 mL of gefitinib gel (1.2 mg / mL) was injected intraperitoneally on days 7, 10, 13, and 16 for a total of four times.

[0174] Tumor size was monitored using in vivo imaging in small animals, among which Figure 7 This is a graph showing the change in tumor size over time using in vivo imaging fluorescence signal monitoring, as described in Example 23. Figure 7 It can be seen that, compared with the PBS group and the gefitinib free drug group, the gefitinib gel group can kill tumor cells for a long time and has a more obvious tumor-suppressing effect (p<0.05).

[0175] Example 24

[0176] At a mass ratio of 1:100, 0.01 g of 1,2-distearate phosphatidylethanolamine was dissolved in 500 μL of dichloromethane. Then, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Finally, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting polymer nanoparticles were dissolved in 1 mL of water for injection to obtain a polymer nanoparticle suspension.

[0177] Add 0.01 g of tannic acid and 0.001 g of manganese chloride to the polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a nanoparticle solution coated with a metal coating.

[0178] 0.01 g of sodium alginate was added to the solution of nanoparticles coated with the metal coating and stirred thoroughly until swollen to obtain a gel formulation solution.

[0179] Add 0.02g of lidocaine to the above gel formulation solution to obtain lidocaine-loaded gel.

[0180] Male SD rats weighing 200–250 g were randomly divided into two groups of six rats each: A) PBS group: 0.25 mL PBS was injected near the incision site; B) Lidocaine free drug group: 0.25 mL lidocaine was injected near the incision site; C) Lidocaine gel group: 0.25 mL lidocaine was injected near the incision site. The mechanical withdrawal reflex threshold of each group was measured 2 hours before surgery as the baseline value.

[0181] Preparation of the incisional pain model: Rats were anesthetized by intraperitoneal injection of 4 mg / 100g of 2 wt% sodium pentobarbital solution. After the rats lost consciousness, a 1 cm incision was made from 0.5 cm proximal to the toe using the Brennan method. The skin was cut open, and the plantar muscle was lifted with ophthalmic forceps and longitudinally cut, while maintaining the integrity of the muscle's origin, insertion, and attachment. After applying pressure to stop bleeding, the skin was sutured with two fine needles, and the corresponding drugs were injected next to the incision. The entire surgical procedure took about 10 minutes and was performed by the same person. After postoperative wound disinfection with povidone-iodine, the rats were placed in a quiet, warm environment away from strong light.

[0182] Mechanical withdrawal reflex threshold determination: By detecting the mechanical stimulation threshold of rat paws at different time points, the degree of rats' tolerance to mechanically mediated pain was reflected. The higher the mechanical stimulation tolerance threshold, the lower the pain sensitivity. Rats were placed in a transparent plexiglass box with a bottom of 0.5cm*0.5cm mesh and allowed to acclimatize for 30 minutes. Calibrated Von Frey filaments (2g, 4g, 6g, 8g, 10g, 15g, 26g bending force) were vertically inserted into the paws of adjacent mice until the filaments bent. Each filament bending stimulation lasted for 1 second, and stimulation was performed five times with an interval of more than 1 minute. The stimulation force was increased from 2g to 26g. Three or more obvious pain behaviors, such as licking or withdrawing the paw, were considered effective pain responses. The previous weight was recorded as the mechanical pain threshold. The mechanical stimulation pain threshold was measured at 4h, 8h, 24h, 36h, 48h, 60h, and 72h after postoperative drug administration until the drug effect disappeared. The specific steps were as described above.

[0183] Figure 8 The mechanical withdrawal reflex threshold measurement curve for the postoperative incision pain model in Example 24 is obtained from... Figure 8 It is known that the lidocaine free drug group has a short duration of action, losing its analgesic effect in about one day, while the lidocaine gel group can significantly inhibit postoperative incision pain compared to the PBS group and the lidocaine free drug group.

[0184] Example 25

[0185] At a mass ratio of 1:100, 0.01 g of 1,2-distearate phosphatidylethanolamine was dissolved in 500 μL of dichloromethane. Then, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Finally, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting polymer nanoparticles were dissolved in 1 mL of water for injection to obtain a polymer nanoparticle suspension.

[0186] Add 0.01 g of tannic acid and 0.001 g of manganese chloride to the polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a nanoparticle solution coated with a metal coating.

[0187] 0.025g of sodium alginate was added to the solution of nanoparticles coated with the metal coating and stirred thoroughly until swollen to obtain a gel formulation solution.

[0188] 0.003 g of si PD-L1 was added to the above gel formulation solution to obtain si PD-L1 loaded gel.

[0189] 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) free siPD-L1 group: 0.2 mL of siPD-L1 injection solution was injected intraperitoneally on days 7, 10, 13, and 16 for a total of four times; C) siPD-L1 gel group: 0.2 mL of siPD-L1-loaded gel was injected intraperitoneally on days 7, 10, 13, and 16 for a total of four times.

[0190] Tumor size was monitored using in vivo imaging in small animals, among which Figure 9 This is a graph showing the change in tumor size over time using in vivo imaging fluorescence signal monitoring, as described in Example 25. Figure 9 It can be seen that, compared with the PBS group and the siPD-L1 free drug group, the siPD-L1 gel group can kill tumor cells for a long time and has a more obvious tumor-suppressing effect (p<0.05).

[0191] Test Example 4

[0192] The metal-coated nanoparticle gel solutions prepared in Examples 1, 4, and 12–17 were used to construct a peritoneal adhesion model: 12-week-old female C57 mice were anesthetized with sodium pentobarbital via intraperitoneal injection. A 2 cm 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 cecal surface damage. Subsequently, the abdominal wall was scraped with a scalpel to form an area of ​​1 x 1 cm. 2 For peritoneal injury, the damaged cecum and abdominal wall were placed opposite each other. Mice were randomly divided into 8 groups of 3 mice each: PBS group: 100 μL PBS solution was sprayed onto the injury site; Example 1 group: 100 μL gel solution was sprayed onto the injury site; Example 4 group: 100 μL gel solution was sprayed onto the injury site; Example 14 group: 100 μL gel solution was sprayed onto the injury site; Example 15 group: 100 μL gel solution was sprayed onto the injury site; Example 16 group: 100 μL gel solution was sprayed onto the injury site; Example 17 group: 100 μL gel solution was sprayed onto the injury site; Example 18 group: 100 μL gel solution was sprayed onto the injury site; Example 19 group: 100 μL gel solution was sprayed onto the injury site. The abdominal wall and skin of the mice were then sutured layer by layer. On the 14th day after surgery, the animals were dissected to observe the abdominal adhesions, and the adhesion tissue was collected for histological staining.

[0193] Figure 10 The results of Masson staining experiments on adhesion tissue were obtained from... Figure 10It can be seen that, compared with the PBS group, there was a large amount of newly formed connective fibrous tissue in the intestine and abdominal wall tissues, while the gel preparation treatment group could inhibit postoperative tissue adhesion to a certain extent and had less newly formed tissue.

[0194] Example 26

[0195] At a mass ratio of 1:100, 0.01 g of 1,2-distearate phosphatidylethanolamine was dissolved in 500 μL of dichloromethane. Then, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Finally, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting polymer nanoparticles were dissolved in 1 mL of water for injection to obtain a polymer nanoparticle suspension.

[0196] Add 0.05 g of tannic acid and 0.005 g of manganese chloride to the polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a nanoparticle solution coated with a metal coating.

[0197] 0.02 g of sodium alginate was added to the solution of nanoparticles coated with the metal coating and stirred thoroughly until swollen to obtain a gel formulation solution.

[0198] 0.002 g of dexamethasone was added to the above gel formulation solution to obtain dexamethasone-loaded gel.

[0199] Establishment of a rat model of chronic sinusitis: Sixteen SD rats, weighing 250-350g, were randomly divided into four groups: A, blank control group (n=4); B, chronic sinusitis group (n=4); C, dexamethasone free drug group (n=4); and D, dexamethasone gel group (n=4). In groups B, C, and D, sensitization was achieved by subcutaneous injection of 1 mL of 2.5% ovalbumin (OVA) and 0.4% aluminum hydroxide on days 0 and 7. From day 12, 20 μL of 6% OVA solution was administered into each nostril 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 13-14, groups A and B received 20 μL of PBS nasal drops three times a week; group C received 20 μL of free dexamethasone nasal drops three times a week; and group D received 200 μL of dexamethasone gel intrasinus injection once. All experimental animals were sacrificed at week 15.

[0200] Depend on Figure 11As can be seen, compared with group B (chronic sinusitis group), groups D (dexamethasone gel group) and C (dexamethasone free drug group) significantly inhibited and improved infection and inflammatory response, and reduced sinus ostium mucosal edema (p<0.05). Group D (dexamethasone gel group) showed better treatment effect than group C (dexamethasone free drug group), but there was no statistically significant difference compared with group A (blank control group) (p>0.05).

[0201] Example 27

[0202] At a mass ratio of 2:100, 0.015 g of 1,2-distearylphosphatidylethanolamine was dissolved in 500 μL of dichloromethane, followed by the addition of 0.001 g of oxaliplatin, which was then fully dissolved. Next, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Then, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting oxaliplatin-loaded polymer nanoparticles were dissolved in 1 mL of water for injection to obtain an oxaliplatin-loaded polymer nanoparticle suspension.

[0203] Add 0.025 g of tannic acid and 0.0025 g of manganese chloride to the oxaliplatin-loaded polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a metal-coated oxaliplatin-loaded nanoparticle solution.

[0204] 0.02 g of sodium alginate was added to the oxaliplatin-loaded nanoparticle solution coated with the metal coating and stirred thoroughly to induce swelling, thereby obtaining an oxaliplatin-loaded gel formulation.

[0205] 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 gel (1 mg / mL) was injected intraperitoneally on days 7, 10, 13, and 16 for a total of four times.

[0206] Monitoring abdominal tumor size using in vivo imaging in small animals Figure 12 This is a graph showing the change in tumor size over time using in vivo imaging fluorescence signal monitoring, as described in Example 27. Figure 12It can be seen that, compared with the PBS group, the oxaliplatin gel group can kill tumor cells for a longer period of time and has a more significant tumor-inhibiting effect (p<0.05).

[0207] Example 28

[0208] At a mass ratio of 1:100, 0.01 g of 1,2-distearate phosphatidylethanolamine was dissolved in 500 μL of dichloromethane. Then, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Finally, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting polymer nanoparticles were dissolved in 1 mL of water for injection to obtain a polymer nanoparticle suspension.

[0209] Add 0.025 g of tannic acid and 0.0025 g of manganese chloride to the polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a nanoparticle solution coated with a metal coating.

[0210] 0.02 g of sodium alginate was added to the solution of nanoparticles coated with the metal coating and stirred thoroughly until swollen to obtain a gel formulation solution.

[0211] Add 0.001 g of oxaliplatin to the above gel formulation solution to obtain oxaliplatin-loaded gel.

[0212] 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. 3 Afterwards, 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 gel (1 mg / mL) was injected subcutaneously at the incision site, administered six times on postoperative days 0, 3, 6, 9, 12, and 15.

[0213] By observing the survival of mice with tumor recurrence, Figure 13 This is a survival curve of mice with tumor recurrence in Example 28, from... Figure 13 It can be seen that, compared with the PBS group, the oxaliplatin gel group can effectively prolong the survival period of mice.

[0214] Example 29

[0215] At a mass ratio of 1:100, 0.01 g of 1,2-distearate phosphatidylethanolamine was dissolved in 500 μL of dichloromethane. Then, 50 μL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified. Finally, 5 mL of a 0.1% poloxamer 188 aqueous solution was added and ultrasonically emulsified again. The organic phase was then removed under vacuum at room temperature, followed by lyophilization. The resulting polymer nanoparticles were dissolved in 1 mL of water for injection to obtain a polymer nanoparticle suspension.

[0216] Add 0.025 g of tannic acid and 0.002 g of zinc chloride to the polymer nanoparticle suspension, then adjust the pH of the solution to 7.4 with 1 mol / L sodium hydroxide solution, and stir at room temperature for 20 min to obtain a nanoparticle solution coated with a metal coating.

[0217] 0.02 g of sodium alginate was added to the solution of nanoparticles coated with the metal coating and stirred thoroughly until swollen to obtain a gel formulation solution.

[0218] 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: vaginal injection of 0.2 ml saline; B) positive control group: vaginal injection of 0.2 ml saline; C) gel group: vaginal injection of the above-mentioned gel preparation solution. On days 0, 1, 2, and 3 after the above treatment, groups B and C received 8 Gy cervical radiotherapy. After radiotherapy, vaginal mucosal tissue was collected from the mice to observe local cellular tissue damage and inflammation.

[0219] Figure 14 To detect inflammatory markers in the vaginal mucosa of mice, by Figure 14 It can be seen that, compared with the negative control group in group A, the inflammatory markers in the positive control group in group B increased significantly, and the gel group in group C could reduce the inflammatory markers to a certain extent, thus playing a protective role against radiotherapy.

[0220] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A gel formulation, characterized in that, It includes a gel matrix, polymeric nanoparticles coated with a metal coating loaded in the gel matrix, and a pharmaceutically acceptable solvent; The mass ratio of the gel matrix, the metal coating in the metal-coated polymer nanoparticles, and the polymer nanoparticles in the metal-coated polymer nanoparticles is (1~10):(1~20):(1~10); The gel matrix includes one or more of alginate and its derivatives, cellulose and its derivatives, chitosan and its derivatives, and polysaccharide gums; The materials of the metal coating include polyphenols and cationic substances; The polyphenol is tannic acid; The cationic substance is manganese chloride; The alginate and its derivatives are one or more of sodium alginate, potassium alginate, calcium alginate, lithium alginate, sodium oxidized alginate, potassium oxidized alginate, calcium oxidized alginate and lithium oxidized alginate. The cellulose and its derivatives are 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. The chitosan and its derivatives are one or more of chitosan lactate, chitosan quaternary ammonium salt, chitosan hydrochloride, chitosan nitrate, chitosan sulfate, chitosan acetate, hydroxypropyl chitosan, and carboxymethyl chitosan; The polysaccharide gum is one or more of gelatin, gellan gum, pectin, konjac gum, carrageenan, guar gum, locust bean gum, xanthan gum, and gum arabic.

2. The gel formulation as described in claim 1, characterized in that, The polymeric nanoparticles include phospholipids and / or polymers; The phospholipids include one or more of 1,2-distearylphosphatidylethanolamine, 1,2-dipalmitoyl-sn-3-phosphatidylethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-tetradecanoylphosphatidylethanolamine, and distearylphosphatidylserine.

3. The gel formulation as described in claim 2, characterized in that, The polymers include one or more of the following: polyethylene glycol monomethyl ether-polylactic acid glycolate copolymer, polyethylene glycol monomethyl ether-polylactic acid glycolate-polylysine block copolymer, polyethylene glycol-poly-L-aspartic acid derivative block copolymer, polyethylene glycol-polylactic acid-polyethylene glycol block copolymer, polylactic acid-polyethylene glycol-polylactic acid block copolymer, polyethylene glycol-polyDL-lactic acid block copolymer, polyglycolic acid-lactide-polyethylene glycol-polyglycolic acid block copolymer, polyethylene glycol-polyglycolic acid-lactide-polyethylene glycol block copolymer, polycaprolactone-polyethylene glycol-polycaprolactone block copolymer, polyethylene oxide, polydimethylsiloxane, methacrylate, polyacrylic acid, poly(N-isopropylacrylamide), poly(methyl methacrylate-co-ethyl acrylate), polyphosphazene, polyurethane, and polyamino acids.

4. The method for preparing the gel formulation according to any one of claims 1 to 3, characterized in that, Includes the following steps: After emulsifying, removing the organic phase, and drying the polymer material, it is mixed with a pharmaceutically acceptable solvent to obtain a polymer nanoparticle suspension. After mixing the polymer nanoparticle suspension and the metal coating material, the pH is adjusted to alkaline to obtain a polymer nanoparticle solution coated with a metal coating. The polymer nanoparticle solution coated with the metal coating is mixed with the gel matrix material to obtain the gel formulation.

5. The use of the gel formulation according to any one of claims 1 to 3 or the gel formulation prepared by the preparation method according to claim 4 in the preparation of pharmaceutical gel formulations, characterized in that, The drug gel formulation includes antitumor drug gel formulations, anti-inflammatory drug gel formulations, or phototherapy drug gel formulations.

6. A pharmaceutical gel formulation, characterized in that, Including gel formulations and active pharmaceutical ingredients; The gel formulation is the gel formulation according to any one of claims 1 to 3 or the gel formulation prepared by the preparation method according to claim 4.

7. The pharmaceutical gel formulation as described in claim 6, characterized in that, The mass ratio of the gel formulation to the active pharmaceutical ingredient is (0~150):(0~10), and the mass of both the gel formulation and the active pharmaceutical ingredient is not 0. The active pharmaceutical ingredient includes one or more of the following: chemotherapy drugs, targeted drugs, local anesthetics, nucleic acid drugs, and anti-inflammatory drugs.

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