WO2023201575A1 - Injection type hydrogel, preparation method therefor, and use of injection type hydrogel as submucosal injection for endoscope adjuvant treatment - Google Patents
Injection type hydrogel, preparation method therefor, and use of injection type hydrogel as submucosal injection for endoscope adjuvant treatment Download PDFInfo
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- WO2023201575A1 WO2023201575A1 PCT/CN2022/087941 CN2022087941W WO2023201575A1 WO 2023201575 A1 WO2023201575 A1 WO 2023201575A1 CN 2022087941 W CN2022087941 W CN 2022087941W WO 2023201575 A1 WO2023201575 A1 WO 2023201575A1
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- WIPO (PCT)
- Prior art keywords
- injection
- carbomer
- solution
- good solvent
- sodium alginate
- Prior art date
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- 238000002347 injection Methods 0.000 title claims abstract description 146
- 239000007924 injection Substances 0.000 title claims abstract description 146
- 239000000017 hydrogel Substances 0.000 title claims abstract description 93
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 238000009098 adjuvant therapy Methods 0.000 title abstract 2
- 229920001661 Chitosan Polymers 0.000 claims abstract description 119
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 109
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 106
- 229960001631 carbomer Drugs 0.000 claims abstract description 106
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 103
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 103
- 239000000661 sodium alginate Substances 0.000 claims abstract description 103
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 103
- 239000002904 solvent Substances 0.000 claims abstract description 95
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 77
- 239000001110 calcium chloride Substances 0.000 claims abstract description 47
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 47
- 239000000243 solution Substances 0.000 claims description 179
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 121
- 239000003086 colorant Substances 0.000 claims description 57
- 229940049638 carbomer homopolymer type c Drugs 0.000 claims description 42
- 229940043234 carbomer-940 Drugs 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 238000004090 dissolution Methods 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 20
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 19
- 239000011575 calcium Substances 0.000 claims description 19
- 229910052791 calcium Inorganic materials 0.000 claims description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 15
- 239000011259 mixed solution Substances 0.000 claims description 15
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 13
- 230000008961 swelling Effects 0.000 claims description 11
- JMEVHYCNAPFOAB-UHFFFAOYSA-L 2-(3-hydroxy-5-sulfonato-1H-indol-2-yl)-3-oxoindole-5-sulfonate Chemical compound [O-]c1c([nH]c2ccc(cc12)S([O-])(=O)=O)C1=[NH+]c2ccc(cc2C1=O)S([O-])(=O)=O JMEVHYCNAPFOAB-UHFFFAOYSA-L 0.000 claims description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- 210000004877 mucosa Anatomy 0.000 claims description 9
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 7
- 229940085237 carbomer-980 Drugs 0.000 claims description 7
- 229960000907 methylthioninium chloride Drugs 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 6
- 239000008363 phosphate buffer Substances 0.000 claims description 5
- -1 carbomer 980 Chemical compound 0.000 claims description 4
- 210000003205 muscle Anatomy 0.000 claims description 4
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 claims description 3
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 claims description 3
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 claims description 3
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 claims description 3
- 229940075509 carbomer 1342 Drugs 0.000 claims description 3
- 229940031663 carbomer-974p Drugs 0.000 claims description 3
- 229960003699 evans blue Drugs 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- 229950003937 tolonium Drugs 0.000 claims description 3
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 claims description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- ZQBAKBUEJOMQEX-UHFFFAOYSA-N phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 claims 1
- 239000000499 gel Substances 0.000 abstract description 32
- 235000010410 calcium alginate Nutrition 0.000 abstract description 14
- 239000000648 calcium alginate Substances 0.000 abstract description 14
- 229960002681 calcium alginate Drugs 0.000 abstract description 14
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 abstract description 14
- 239000008215 water for injection Substances 0.000 description 74
- 238000003756 stirring Methods 0.000 description 36
- 230000000052 comparative effect Effects 0.000 description 22
- 239000000463 material Substances 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 7
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 229910001424 calcium ion Inorganic materials 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
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- 241000588724 Escherichia coli Species 0.000 description 2
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- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/722—Chitin, chitosan
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
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- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
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- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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Definitions
- the present invention relates to the technical field of injectable gels, and in particular to an injectable hydrogel, a preparation method thereof and the application of submucosal injection as an auxiliary treatment for endoscopy.
- Interventional endoscopy can detect and treat gastrointestinal polyps early to prevent their development into tumors and greatly reduce patient mortality.
- Endoscopic submucosal dissection is an important intervention method to prevent the progression of polyps to cancer. It requires the assistance of submucosal injection, which establishes a "cushion layer" between the surface mucosa and the submucosal muscle layer. ”, thereby avoiding perforation and damage to organs surrounding the lesion during minimally invasive surgery.
- This technology was developed in Japan in the early 1990s.
- physiological saline 0.0.9wt% sodium chloride
- physiological saline diffuses quickly in human tissues, and has the disadvantage of requiring multiple additional injections during the operation.
- Sodium alginate is one of the typical natural polysaccharides. Its aqueous solution and calcium ion solution can be cross-linked to form a hydrogel.
- the U.S. Food and Drug Administration (FDA) has certified it as a highly biocompatible biomaterial.
- FDA Food and Drug Administration
- calcium alginate hydrogel can be used clinically as an injectable gel instead of normal saline injection.
- a double-needle injection system must be used. The double-needle injection system is to place the sodium alginate aqueous solution and the calcium ion solidifying solution in different places. In the injection barrel, it is injected under the mucosa at the same time.
- the object of the present invention is to provide an injectable hydrogel and its preparation method and its application in preparing submucosal injection for endoscopic assisted treatment.
- the injectable hydrogel provided by the invention can be applied to a single-needle injection system and is simple to use.
- the present invention provides an injectable hydrogel, including the following components in parts by mass:
- the injectable hydrogel also includes a good solvent, and the good solvent is a good solvent for sodium alginate injection, a good solvent for chitosan derivative injection, a good solvent for calcium chloride injection, and a good solvent for carbomer injection. .
- the injectable hydrogel further includes 0.01 to 3 parts of colorant, and the good solvent also includes a good solvent for colorant injection.
- the colorant includes one or more of sodium indigo disulfonate, methylene blue, Evans blue, brilliant blue, trypan blue, and toluidine blue.
- the chitosan derivative includes one or more of chitosan quaternary ammonium salt, alkylated chitosan, carboxymethyl chitosan, and chitosan parahydroxybenzoate.
- the carbomer includes carbomer 940, carbomer 941, carbomer 980, carbomer 981, carbomer 971P, carbomer 71G, carbomer 934P, carbomer 1342, carbomer One or more of Carbomer 974P, Carbomer 956P, Carbomer 5984, Carbomer ETD2020 and Carbomer Ultrez10.
- the good solvent for sodium alginate injection includes one or more of water, sodium chloride solution and phosphate buffer; the mass percentage of the sodium chloride solution is 0.9wt%, and the phosphoric acid The pH value of the buffer solution is 5.5 to 7.5.
- the good solvent for injection of chitosan derivatives and the good solvent for injection of calcium chloride independently include water and/or ethanol.
- the good solvent for carbomer injection includes one or more of water, ethanol, propylene glycol and glycerin.
- the good solvent for colorant injection includes water and/or ethanol.
- the present invention provides a preparation method for the injectable hydrogel described in the above technical solution, which includes the following steps:
- Each component of the injectable hydrogel is mixed to obtain the injectable hydrogel.
- the mixing includes the following steps:
- the dropping speed is 0.1-0.15 mL/min.
- the mass concentration of the sodium alginate solution is 0.1-60g/L.
- the mass concentration of the chitosan derivative solution is 0.1-40g/L.
- the mass concentration of the calcium chloride solution is 0.1-50g/L.
- the mass concentration of the carbomer sol is 0.1-30g/L.
- the dissolution temperatures for preparing the sodium alginate solution and preparing the chitosan derivative solution are independently 20 to 90°C.
- the dissolution temperature for preparing the carbomer sol is 20-75°C
- the swelling temperature for preparing the carbomer sol is room temperature
- the swelling time for preparing the carbomer sol is 24 hours.
- the mixing includes the following steps:
- the calcium chloride-colorant solution was added dropwise to the mixed solution.
- the mass concentration of the colorant in the calcium chloride-colorant solution is 0.1-10gL.
- the present invention provides the use of the injectable hydrogel described in the above technical solution or the injectable hydrogel prepared by the preparation method described in the above technical solution as a submucosal injection.
- the submucosal injection is a submucosal injection for endoscopic-assisted treatment.
- the present invention provides the application of the injectable hydrogel described in the above technical solution or the injectable hydrogel prepared by the preparation method described in the above technical solution in endoscope-assisted treatment.
- the application is: before performing the endoscopic auxiliary treatment, a single-needle injection system is used to inject the injection hydrogel between the diseased surface mucosa and the submucosal muscle layer; the injection hydrogel is the above technical solution.
- the injectable hydrogel or the injectable hydrogel prepared by the preparation method described in the above technical solution.
- the invention provides an injectable hydrogel, which includes the following components by mass: 0.1 to 120 parts of sodium alginate, 0.01 to 20 parts of chitosan derivatives, 0.01 to 15 parts of calcium chloride, and 0.01 parts of carbomer ⁇ 9 parts; the injectable hydrogel also includes a good solvent, and the good solvent is a good solvent for sodium alginate injection, a good solvent for chitosan derivative injection, a good solvent for calcium chloride injection, and carbomer Good solvent for injection.
- the present invention introduces chitosan derivatives into the calcium alginate gel system.
- the addition of chitosan derivatives will neutralize part of the negative charges of sodium alginate and reduce the cross-linking density between sodium alginate and calcium ions; at the same time,
- the present invention introduces carbomer into the calcium alginate gel system.
- Carbomer as a high molecular polymer cross-linked with acrylic acid and propenyl sucrose, has no charge itself and is electrically neutral.
- carbomer has a diluting effect on the calcium alginate gel system, which can prevent sodium alginate and calcium ions from being cross-linked locally in a short period of time; on the other hand, chitosan derivatives have a diluting effect on the calcium alginate gel system.
- the present invention simultaneously introduces chitosan derivatives and carbomer into the calcium alginate gel system, so that the improved calcium alginate gel system can be applied to a single-needle injection system.
- the chitosan derivative in the calcium alginate gel system of the present invention not only has good biocompatibility, but also has excellent hygroscopic, moisturizing, antibacterial and hemostatic effects, and can treat organ perforation and damage caused by improper operation. Quickly stop bleeding in the damaged area to ensure a clear surgical field; at the same time, it inhibits the growth and reproduction of common bacteria and fungi such as Escherichia coli and Staphylococcus aureus, which is conducive to rapid postoperative wound healing.
- the injectable hydrogel provided by the present invention also includes 0.01 to 3 parts of colorant, and the good solvent also includes a good solvent for colorant injection.
- the present invention also introduces a colorant into the calcium alginate gel system. The presence of the colorant can achieve "visual marking" of polyp tissue, allowing doctors to more clearly observe the diseased mucosa during ESD surgery, ensuring that the disease can be removed quickly and accurately during the operation. polyp.
- Figure 1 shows the state of the injectable hydrogel prepared in Example 5 after being left standing at room temperature for 2 hours;
- Figure 2 shows the injectable state of the injectable hydrogel prepared in Example 5 after being left standing at room temperature for 2 hours.
- the invention provides an injectable hydrogel, which includes the following components in parts by mass:
- the injectable hydrogel also includes a good solvent, and the good solvent is a good solvent for sodium alginate injection, a good solvent for chitosan derivative injection, a good solvent for calcium chloride injection, and a good solvent for carbomer injection. .
- the injectable hydrogel provided by the present invention includes 0.1 to 120 parts of sodium alginate, preferably 0.7 to 70 parts, and more preferably 5 to 20 parts.
- the injectable hydrogel provided by the present invention includes 0.01 to 20 parts of chitosan derivatives, preferably 0.01 to 10 parts, and more preferably 0.2 to 2.5 parts.
- the chitosan derivative preferably includes one or more of chitosan quaternary ammonium salt, alkylated chitosan, carboxymethyl chitosan, and chitosan parahydroxybenzoate. , more preferably chitosan quaternary ammonium salt and/or carboxymethyl chitosan.
- the injectable hydrogel provided by the present invention includes 0.01 to 15 parts of calcium chloride, preferably 0.01 to 6 parts, and more preferably 0.5 to 3 parts.
- the injectable hydrogel provided by the present invention includes 0.01 to 9 parts of carbomer, preferably 0.01 to 3.6 parts, and more preferably 0.2 to 1.5 parts.
- the carbomer includes carbomer 940, carbomer 941, carbomer 980, carbomer 981, carbomer 971P, carbomer 71G, carbomer 934P, carbomer 1342 , one or more of carbomer 974P, carbomer 956P, carbomer 5984, carbomer ETD2020 and carbomer Ultrez10, more preferably carbomer 940, carbomer 980 and carbomer 5984 one or more of them.
- the injectable hydrogel preferably further includes 0.01 to 3 parts of colorant, preferably 0.01 to 0.9 parts, and more preferably 0.02 to 0.15 parts.
- the colorant preferably includes one or more of sodium indigo disulfonate, methylene blue, Evans blue, brilliant blue, trypan blue, and toluidine blue.
- sodium indigo disulfonate and/or methylene blue preferably includes one or more of sodium indigo disulfonate, methylene blue, Evans blue, brilliant blue, trypan blue, and toluidine blue.
- the injectable hydrogel provided by the present invention also includes a good solvent.
- the good solvent is a good solvent for sodium alginate injection, a good solvent for chitosan derivative injection, a good solvent for calcium chloride injection, and a good solvent for carbomer injection.
- the good solvent for sodium alginate injection preferably includes one or more of water, sodium chloride solution and phosphate buffer, and is more preferably water.
- the mass percentage of the sodium chloride solution is preferably 0.9 wt%.
- the pH value of the phosphate buffer is preferably 5.5 to 7.5.
- the good solvent for injection of chitosan derivatives preferably includes water and/or ethanol, more preferably water.
- the good solvent for calcium chloride injection preferably includes water and/or ethanol, more preferably water.
- the good solvent for carbomer injection preferably includes one or more of water, ethanol, propylene glycol and glycerin, and is more preferably water.
- the good solvent also includes a good solvent for colorant injection.
- the good solvent for colorant injection preferably includes water and/or ethanol, more preferably water.
- the injectable hydrogel is preferably stored away from light at 0 to 35°C.
- the present invention provides a preparation method for the injectable hydrogel described in the above technical solution, which includes the following steps:
- Each component of the injectable hydrogel is mixed to obtain the injectable hydrogel.
- the mixing includes the following steps:
- the calcium chloride solution was added dropwise to the mixed solution.
- sodium alginate is dissolved (hereinafter referred to as the first dissolution) in a good solvent for sodium alginate injection to obtain a sodium alginate solution.
- the dissolution temperature for preparing the sodium alginate solution is preferably 20 to 90°C, preferably 30 to 80°C, and more preferably 40 to 65°C.
- the first dissolution is preferably performed under water bath conditions.
- the first dissolution is preferably performed under stirring conditions.
- the mass concentration of the sodium alginate solution is preferably 0.1 to 60 g/L, more preferably 0.1 to 35 g/L, and even more preferably 5 to 10 g/L.
- the chitosan derivative is dissolved (hereinafter referred to as the second dissolution) in a good solvent for chitosan derivative injection to obtain a chitosan derivative solution.
- the dissolution temperature for preparing the chitosan derivative solution is preferably 20 to 90°C, preferably 30 to 80°C, and more preferably 40 to 65°C.
- the second dissolution is preferably carried out under water bath conditions.
- the second dissolution is preferably performed under stirring conditions.
- the mass concentration of the chitosan derivative solution is preferably 0.1 to 40 g/L, more preferably 0.1 to 20 g/L, and even more preferably 2 to 5 g/L.
- calcium chloride is dissolved (hereinafter referred to as the third dissolution) in a good solvent for calcium chloride injection to obtain a calcium chloride solution.
- the dissolution temperature for preparing the calcium chloride solution is preferably room temperature.
- the third dissolution is preferably performed under stirring conditions.
- the mass concentration of the calcium chloride solution is preferably 0.1 to 50 g/L, more preferably 0.1 to 20 g/L, and even more preferably 5 to 10 g/L.
- carbomer is dissolved (hereinafter referred to as the fourth dissolution) in a good solvent for carbomer injection and then swollen to obtain carbomer sol.
- the dissolution temperature for preparing the carbomer sol is preferably 20 to 75°C, more preferably 30 to 70°C, and further preferably 40 to 65°C.
- the fourth dissolution is preferably performed under water bath conditions.
- the fourth dissolution is preferably performed under stirring conditions.
- the swelling temperature for preparing the carbomer sol is preferably room temperature, and the swelling time for preparing the carbomer sol is preferably 24 hours.
- the mass concentration of the carbomer sol is preferably 0.1 to 30 g/L, more preferably 0.1 to 12 g/L, and even more preferably 2 to 5 g/L.
- the present invention mixes the sodium alginate solution, the chitosan derivative solution and the carbomer sol to obtain a mixed solution.
- the present invention adds the calcium chloride solution dropwise to the mixed solution.
- the dropping speed is preferably 0.1 to 0.15 mL/min, specifically preferably 01 mL/min or 0.15 mL/min.
- the dropwise addition is preferably performed under stirring conditions.
- the mixing includes the following steps:
- the mixing preferably includes the following steps:
- the calcium chloride-colorant solution was added dropwise to the mixed solution.
- the mixed raw materials preferably also include a colorant and a good solvent for colorant injection, and the sodium alginate solution, chitosan derivative solution, carbomer sol, mixed solution and dripping protection
- a colorant and a good solvent for colorant injection preferably also include a colorant and a good solvent for colorant injection, and the sodium alginate solution, chitosan derivative solution, carbomer sol, mixed solution and dripping protection
- the scope is the same as the above-mentioned technical solution without colorant and good solvent for colorant injection, and will not be repeated here.
- calcium chloride and coloring agent are dissolved (hereinafter referred to as the fifth dissolution) in a good solvent for calcium chloride injection and a good solvent for coloring agent injection, to obtain a calcium chloride-coloring agent solution; .
- the protection scope of the fifth dissolution and the third dissolution are the same.
- the mass concentration of the colorant is preferably 0.1 to 10 g/L, more preferably 0.1 to 3 g/L, and even more preferably 0.2 to 0.5 g/L.
- the mass concentration of calcium chloride in the calcium chloride-colorant solution is the same as the above technical solution.
- the present invention provides the use of the injectable hydrogel described in the above technical solution or the injectable hydrogel prepared by the preparation method described in the above technical solution as a submucosal injection.
- the submucosal injection is preferably a submucosal injection for endoscopic-assisted treatment.
- the present invention provides the application of the injectable hydrogel described in the above technical solution or the injectable hydrogel prepared by the preparation method described in the above technical solution in endoscope-assisted treatment.
- the application is preferably: before performing the endoscopic auxiliary treatment, a single-needle injection system is used to inject the injection hydrogel between the diseased surface mucosa and the submucosal muscle layer; the injection hydrogel is The injectable hydrogel described in the above technical solution or the injectable hydrogel prepared by the preparation method described in the above technical solution.
- the injectable hydrogel consists of four types: sodium alginate solution, chitosan derivative solution, calcium chloride-colorant solution, and carbomer 940 sol.
- the components are composed according to the volume ratio of 10:1:1:1;
- the injectable hydrogel consists of four types: sodium alginate solution, chitosan derivative solution, calcium chloride-colorant solution, and carbomer 940 sol.
- the components are composed according to the volume ratio of 10:5:1:3;
- the injectable hydrogel consists of four components: sodium alginate solution, chitosan derivative solution, calcium chloride solution, and carbomer 940 sol.
- the volume ratio is 10:1:3:1;
- Carbomer 940 sol is obtained. ;
- the injectable hydrogel consists of four components: sodium alginate solution, chitosan derivative solution, calcium chloride solution, and carbomer 940 sol.
- the volume ratio is 20:5:1:3;
- Carbomer 940 sol is obtained. ;
- the injectable hydrogel consists of four components: sodium alginate solution, chitosan derivative solution, calcium chloride solution, and carbomer 940 sol according to volume. It is composed of ratio 20:1:3:1;
- the preparation method is basically the same as that of Example 3. The difference is that in Comparative Example 1, no carbomer 940 sol and chitosan derivative solution were added. In Comparative Example 1, the sodium alginate solution and calcium chloride solution were added. The volume ratio is the same as in Example 1.
- the preparation method is basically the same as that of Example 3. The difference is that in Comparative Example 2, no carbomer 940 sol is added. In Comparative Example 2, the sodium alginate solution, chitosan derivative solution, and calcium chloride solution are the same. The volume ratio is the same as in Example 1.
- the preparation method is basically the same as that of Example 3. The difference is that in Comparative Example 3, the carbomer 940 sol is replaced by a hyaluronic acid aqueous solution of the same mass concentration.
- the hyaluronic acid aqueous solution is made by dissolving hyaluronic acid in Solution formed in water for injection.
- the preparation method is basically the same as that of Example 3. The difference is that in Comparative Example 4, the carbomer 940 sol is replaced with a gelatin aqueous solution of the same mass concentration.
- the gelatin aqueous solution is formed by dissolving gelatin in water for injection. solution.
- the preparation method is basically the same as that of Example 3, except that the injectable hydrogel used for endoscopic auxiliary treatment in Comparative Example 5 is prepared according to the following steps;
- the preparation method is basically the same as that of Example 3, except that the injectable hydrogel used for endoscopic auxiliary treatment in Comparative Example 6 is prepared according to the following steps;
- the preparation method is basically the same as that of Example 3, except that in Comparative Example 7, the carbomer 940 sol is prepared according to the following method:
- Carbopol 940 Under sterile conditions, dissolve Carbopol 940 in water for injection at room temperature, and stir evenly to obtain Carbopol 940 sol.
- Examples 3 to 8 and Comparative Examples 1 to 7 are prepared, they are placed in a single-needle injection system with an injection volume of 2 mL. They are allowed to stand for 30 minutes before injection. After the injection is completed, they are injected into the pig colon outside the body. Tissue subcutaneously and submucosally, record the injection thrust (unit N) exerted on the injection system during injection. Note: When the injection thrust exceeds 65N, the injection cannot be completed.
- Examples 3 to 8 and Comparative Examples 1 to 7 are prepared, they are placed in a single-needle injection system and injected into the subcutaneous mucosa of the pig colon tissue in vitro.
- the injection volume is 2 mL. After the injection is completed, let it stand for 2 hours and then measure. The height of submucosal support of the gel pad.
- Escherichia coli was used to test the surface antibacterial activity of the injection gel.
- 1 mL of the injection gel obtained in Examples 3 to 8 and Comparative Examples 1 to 7 were co-cultured with 1 mL of bacterial liquid with a concentration of 10 5 CFU/mL, and a blank was set.
- For the control group after incubating for 24 hours, take the bacterial liquid of each group into a 96-well plate, measure its absorbance with a microplate reader (wavelength 600 nm), and calculate the antibacterial rate AR.
- Equation 1 The formula for calculating the antibacterial rate is as shown in Equation 1:
- AR represents the antibacterial rate.
- the absorbance value of the blank control group is the absorbance value at 600nm of the blank control group (bacterial culture medium without injection gel);
- the absorbance value of the experimental group is the absorbance value of the experimental group with bacterial culture liquid added at 600nm. Absorbance values.
- the test results are shown in Table 10.
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Abstract
The present invention relates to the technical field of injection gels, and in particular to an injection type hydrogel, a preparation method therefor, and use of the injection type hydrogel as a submucosal injection for endoscope adjuvant treatment. The injection type hydrogel provided by the present invention comprises the following components in parts by mass: 0.1-120 parts of sodium alginate, 0.01-20 parts of chitosan derivative, 0.01-15 parts of calcium chloride, and 0.01-9 parts of carbomer. The injection type hydrogel further comprises a good solvent. The good solvent is a good solvent for sodium alginate injection, a good solvent for chitosan derivative injection, a good solvent for calcium chloride injection, and a good solvent for carbomer injection. According to the present invention, the chitosan derivative and the carbomer are simultaneously introduced into a calcium alginate gel system, such that the improved calcium alginate gel system can be applied to a single-needle injection system.
Description
本发明涉及注射凝胶技术领域，特别涉及一种注射型水凝胶及其制备方法和作为内窥镜辅助治疗的粘膜下注射液的应用。The present invention relates to the technical field of injectable gels, and in particular to an injectable hydrogel, a preparation method thereof and the application of submucosal injection as an auxiliary treatment for endoscopy.
介入性内窥镜检查可以对消化道息肉病变做到早发现、早治疗，以预防其向肿瘤方向发展，大大降低了患者的死亡率。Interventional endoscopy can detect and treat gastrointestinal polyps early to prevent their development into tumors and greatly reduce patient mortality.
内窥镜黏膜下剥离术(Endoscopic submucosal dissection，ESD)是阻止息肉向癌症发展的重要干预手段，其需要粘膜下注射液的辅助，即在表面黏膜和黏膜下肌层之间建立一个“垫层”，从而避免微创手术过程中对病变周围器官产生穿孔和损伤。该技术上世纪90年代初在日本发展起来，截止目前，临床上主要使用生理盐水(0.9wt％氯化钠)作为ESD术的辅助注射液。但生理盐水在人体组织中扩散快，存在手术过程中需多次补充注射的弊端。Endoscopic submucosal dissection (ESD) is an important intervention method to prevent the progression of polyps to cancer. It requires the assistance of submucosal injection, which establishes a "cushion layer" between the surface mucosa and the submucosal muscle layer. ”, thereby avoiding perforation and damage to organs surrounding the lesion during minimally invasive surgery. This technology was developed in Japan in the early 1990s. Up to now, physiological saline (0.9wt% sodium chloride) is mainly used clinically as an auxiliary injection for ESD surgery. However, physiological saline diffuses quickly in human tissues, and has the disadvantage of requiring multiple additional injections during the operation.
海藻酸钠是典型的天然多糖之一，其水溶液与钙离子溶液交联可形成水凝胶，美国食品药品监督管理局(FDA)认证其是具有高度生物相容性的生物材料。研究表明，海藻酸钙水凝胶可作为注射凝胶代替生理盐水注射液在临床上使用。但是，当利用海藻酸钙水凝胶作为注射凝胶在临床上使用时，必须采用双针头注射体系，所述双针头注射体系就是分别将海藻酸钠水溶液与钙离子固化液分别置于不同的注射筒中，同时注射到黏膜下，海藻酸钠与钙离子接触后两者快速交联固化在黏膜下形成“垫层”。双针头注射体系的缺点：(1)术前，必须同时准备两种溶液(海藻酸钠水溶液、钙离子固化液)，并置于双针头不同的注射通道中；(2)双针头注射体系是双通道，还需保证两种溶液同时注射，结构复杂，控制精密，使用成本较高。Sodium alginate is one of the typical natural polysaccharides. Its aqueous solution and calcium ion solution can be cross-linked to form a hydrogel. The U.S. Food and Drug Administration (FDA) has certified it as a highly biocompatible biomaterial. Studies have shown that calcium alginate hydrogel can be used clinically as an injectable gel instead of normal saline injection. However, when calcium alginate hydrogel is used clinically as an injection gel, a double-needle injection system must be used. The double-needle injection system is to place the sodium alginate aqueous solution and the calcium ion solidifying solution in different places. In the injection barrel, it is injected under the mucosa at the same time. After sodium alginate and calcium ions come into contact, the two quickly cross-link and solidify under the mucosa to form a "cushion". Disadvantages of the double-needle injection system: (1) Before surgery, two solutions (sodium alginate aqueous solution and calcium ion solidifying solution) must be prepared at the same time and placed in different injection channels of the double-needle; (2) The double-needle injection system is With dual channels, it is necessary to ensure that two solutions are injected at the same time. The structure is complex, the control is precise, and the use cost is high.
发明内容Contents of the invention
本发明的目的在于提供一种注射型水凝胶及其制备方法和在制备内窥镜辅助治疗的粘膜下注射液中的应用。本发明提供的注射型水凝胶能够应用于单针头注射体系，使用简单。The object of the present invention is to provide an injectable hydrogel and its preparation method and its application in preparing submucosal injection for endoscopic assisted treatment. The injectable hydrogel provided by the invention can be applied to a single-needle injection system and is simple to use.
为了解决上述技术问题，本发明采用的技术方案是：本发明提供一种注射型水凝胶，包括以下质量份数的组分：In order to solve the above technical problems, the technical solution adopted by the present invention is: the present invention provides an injectable hydrogel, including the following components in parts by mass:
海藻酸钠0.1～120份，壳聚糖衍生物0.01～20份，氯化钙0.01～15份，卡波 姆0.01～9份；0.1 to 120 parts of sodium alginate, 0.01 to 20 parts of chitosan derivatives, 0.01 to 15 parts of calcium chloride, 0.01 to 9 parts of carbomer;
所述注射型水凝胶还包括良溶剂，所述良溶剂为海藻酸钠注射用良溶剂、壳聚糖衍生物注射用良溶剂、氯化钙注射用良溶剂和卡波姆注射用良溶剂。The injectable hydrogel also includes a good solvent, and the good solvent is a good solvent for sodium alginate injection, a good solvent for chitosan derivative injection, a good solvent for calcium chloride injection, and a good solvent for carbomer injection. .
优选的，所述注射型水凝胶还包括0.01～3份着色剂，所述良溶剂还包括着色剂注射用良溶剂。Preferably, the injectable hydrogel further includes 0.01 to 3 parts of colorant, and the good solvent also includes a good solvent for colorant injection.
优选的，所述着色剂包括靛蓝二磺酸钠、亚甲基蓝、埃文斯蓝、亮蓝、台盼蓝、甲苯胺蓝中的一种或多种。Preferably, the colorant includes one or more of sodium indigo disulfonate, methylene blue, Evans blue, brilliant blue, trypan blue, and toluidine blue.
优选的，所述壳聚糖衍生物包括壳聚糖季铵盐、烷基化壳聚糖、羧甲基壳聚糖、对羟基苯甲酸壳聚糖酯中的一种或多种。Preferably, the chitosan derivative includes one or more of chitosan quaternary ammonium salt, alkylated chitosan, carboxymethyl chitosan, and chitosan parahydroxybenzoate.
优选的，所述卡波姆包括卡波姆940、卡波姆941、卡波姆980、卡波姆981、卡波姆971P、卡波姆71G、卡波姆934P、卡波姆1342、卡波姆974P、卡波姆956P、卡波姆5984、卡波姆ETD2020和卡波姆Ultrez10中的一种或多种。Preferably, the carbomer includes carbomer 940, carbomer 941, carbomer 980, carbomer 981, carbomer 971P, carbomer 71G, carbomer 934P, carbomer 1342, carbomer One or more of Carbomer 974P, Carbomer 956P, Carbomer 5984, Carbomer ETD2020 and Carbomer Ultrez10.
优选的，所述海藻酸钠注射用良溶剂包括水、氯化钠溶液和磷酸缓冲液中的一种或多种；所述氯化钠溶液的质量百分含量为0.9wt％，所述磷酸缓冲液的pH值为5.5～7.5。Preferably, the good solvent for sodium alginate injection includes one or more of water, sodium chloride solution and phosphate buffer; the mass percentage of the sodium chloride solution is 0.9wt%, and the phosphoric acid The pH value of the buffer solution is 5.5 to 7.5.
优选的，所述壳聚糖衍生物注射用良溶剂和所述氯化钙注射用良溶剂独立地包括水和/或乙醇。Preferably, the good solvent for injection of chitosan derivatives and the good solvent for injection of calcium chloride independently include water and/or ethanol.
优选的，所述卡波姆注射用良溶剂包括水、乙醇、丙二醇和甘油中的一种或多种。Preferably, the good solvent for carbomer injection includes one or more of water, ethanol, propylene glycol and glycerin.
优选的，所述着色剂注射用良溶剂包括水和/或乙醇。Preferably, the good solvent for colorant injection includes water and/or ethanol.
本发明提供了上述技术方案所述的注射型水凝胶的制备方法，包括以下步骤：The present invention provides a preparation method for the injectable hydrogel described in the above technical solution, which includes the following steps:
将所述注射水凝胶的各组分混合，得到所述注射型水凝胶。Each component of the injectable hydrogel is mixed to obtain the injectable hydrogel.
优选的，所述注射水凝胶的组分不包括着色剂时，所述混合包括以下步骤：Preferably, when the components of the injectable hydrogel do not include colorants, the mixing includes the following steps:
在无菌条件下，将海藻酸钠溶解于海藻酸钠注射用良溶剂中，得到海藻酸钠溶液；Under sterile conditions, dissolve sodium alginate in a good solvent for sodium alginate injection to obtain a sodium alginate solution;
在无菌条件下，将壳聚糖衍生物溶解于壳聚糖衍生物注射用良溶剂中，得到壳聚糖衍生物溶液；Under sterile conditions, dissolve the chitosan derivative in a good solvent for chitosan derivative injection to obtain a chitosan derivative solution;
在无菌条件下，将氯化钙溶解于氯化钙注射用良溶剂中，得到氯化钙溶液，Under sterile conditions, dissolve calcium chloride in a good solvent for calcium chloride injection to obtain a calcium chloride solution.
在无菌条件下，将卡波姆溶解于卡波姆注射用良溶剂中后进行溶胀，得到卡波姆溶胶，Under sterile conditions, dissolve carbomer in a good solvent for carbomer injection and then swell to obtain carbomer sol.
将所述海藻酸钠溶液、所述壳聚糖衍生物溶液和所述卡波姆溶胶混合得到混合溶液；Mix the sodium alginate solution, the chitosan derivative solution and the carbomer sol to obtain a mixed solution;
优选的，所述滴加的速度为0.1～0.15mL/min。Preferably, the dropping speed is 0.1-0.15 mL/min.
优选的，所述海藻酸钠溶液的质量浓度为0.1～60g/L。Preferably, the mass concentration of the sodium alginate solution is 0.1-60g/L.
优选的，所述壳聚糖衍生物溶液的质量浓度为0.1～40g/L。Preferably, the mass concentration of the chitosan derivative solution is 0.1-40g/L.
优选的，所述氯化钙溶液的质量浓度为0.1～50g/L。Preferably, the mass concentration of the calcium chloride solution is 0.1-50g/L.
优选的，所述卡波姆溶胶的质量浓度为0.1～30g/L。Preferably, the mass concentration of the carbomer sol is 0.1-30g/L.
优选的，制备所述海藻酸钠溶液和制备所述壳聚糖衍生物溶液的溶解温度独立地为20～90℃。Preferably, the dissolution temperatures for preparing the sodium alginate solution and preparing the chitosan derivative solution are independently 20 to 90°C.
优选的，制备所述卡波姆溶胶的溶解温度为20～75℃，制备所述卡波姆溶胶的溶胀温度为室温，制备所述卡波姆溶胶的溶胀时间为24h。Preferably, the dissolution temperature for preparing the carbomer sol is 20-75°C, the swelling temperature for preparing the carbomer sol is room temperature, and the swelling time for preparing the carbomer sol is 24 hours.
优选的，所述注射水凝胶的组分包括着色剂时，所述混合包括以下步骤：Preferably, when the components of the injectable hydrogel include a colorant, the mixing includes the following steps:
在无菌条件下，将海藻酸钠溶解于海藻酸钠注射用良溶剂中，得到海藻酸钠溶液；Under sterile conditions, dissolve sodium alginate in a good solvent for sodium alginate injection to obtain a sodium alginate solution;
在无菌条件下，将壳聚糖衍生物溶解于壳聚糖衍生物注射用良溶剂中，得到壳聚糖衍生物溶液；Under sterile conditions, dissolve the chitosan derivative in a good solvent for chitosan derivative injection to obtain a chitosan derivative solution;
在无菌条件下，将氯化钙、着色剂溶解于氯化钙注射用良溶剂和着色剂注射用良溶剂中，得到氯化钙-着色剂溶液，Under sterile conditions, dissolve calcium chloride and colorant in a good solvent for calcium chloride injection and a good solvent for colorant injection to obtain a calcium chloride-colorant solution,
在无菌条件下，将卡波姆溶解于卡波姆注射用良溶剂中后进行溶胀，得到卡波姆溶胶，Under sterile conditions, dissolve carbomer in a good solvent for carbomer injection and then swell to obtain carbomer sol.
将所述海藻酸钠溶液、所述壳聚糖衍生物溶液和所述卡波姆溶胶混合得到混合溶液；Mix the sodium alginate solution, the chitosan derivative solution and the carbomer sol to obtain a mixed solution;
向所述混合溶液中滴加所述氯化钙-着色剂溶液。The calcium chloride-colorant solution was added dropwise to the mixed solution.
优选的，所述氯化钙-着色剂溶液中，所述着色剂的质量浓度为0.1～10gL。Preferably, the mass concentration of the colorant in the calcium chloride-colorant solution is 0.1-10gL.
本发明提供了上述技术方案所述的注射型水凝胶或上述技术方案所述的制备方法制备得到的注射型水凝胶作为粘膜下注射液的应用。The present invention provides the use of the injectable hydrogel described in the above technical solution or the injectable hydrogel prepared by the preparation method described in the above technical solution as a submucosal injection.
优选的，所述粘膜下注射液为内窥镜辅助治疗的粘膜下注射液。Preferably, the submucosal injection is a submucosal injection for endoscopic-assisted treatment.
本发明提供了上述技术方案所述的注射型水凝胶或上述技术方案所述的制备方法制备得到的注射型水凝胶在内窥镜辅助治疗中的应用。The present invention provides the application of the injectable hydrogel described in the above technical solution or the injectable hydrogel prepared by the preparation method described in the above technical solution in endoscope-assisted treatment.
优选的，所述应用为：进行所述内窥镜辅助治疗之前，采用单针头注射体系将注射水凝胶注入病变表面黏膜和黏膜下肌层之间；所述注射水凝胶为上述 技术方案所述的注射型水凝胶或上述技术方案所述的制备方法制备得到的注射型水凝胶。Preferably, the application is: before performing the endoscopic auxiliary treatment, a single-needle injection system is used to inject the injection hydrogel between the diseased surface mucosa and the submucosal muscle layer; the injection hydrogel is the above technical solution. The injectable hydrogel or the injectable hydrogel prepared by the preparation method described in the above technical solution.
本发明提供一种注射型水凝胶，包括以下质量份数的组分：海藻酸钠0.1～120份，壳聚糖衍生物0.01～20份，氯化钙0.01～15份，卡波姆0.01～9份；所述注射型水凝胶还包括良溶剂，所述良溶剂为海藻酸钠注射用良溶剂、壳聚糖衍生物注射用良溶剂、氯化钙注射用良溶剂和卡波姆注射用良溶剂。本发明在海藻酸钙凝胶体系中引入壳聚糖衍生物，壳聚糖衍生物的加入会中和部分海藻酸钠的负电荷，降低了海藻酸钠与钙离子的交联密度；同时，本发明在海藻酸钙凝胶体系中引入卡波姆，卡波姆作为丙烯酸与丙烯基蔗糖交联的高分子聚合物，本身不带有电荷，呈电中性。一方面，卡波姆对海藻酸钙凝胶体系具有稀释的作用，可以防止海藻酸钠与钙离子在短时间内局部过快交联；另一方面，壳聚糖衍生物在海藻酸钙凝胶体系中呈碱性，能够中和卡波姆在海藻酸钙凝胶体系的酸度，使得卡波姆进一步溶胀，卡波姆的分子链弥散伸展、呈现极大的膨胀状态，对海藻酸钙凝胶体系形成增稠作用，对提高注射凝胶在黏膜下的支撑高度和支撑时间具有较好的作用。由此，本发明在海藻酸钙凝胶体系中同时引入了壳聚糖衍生物和卡波姆，使得改进后的海藻酸钙凝胶体系可以应用于单针头注射体系。The invention provides an injectable hydrogel, which includes the following components by mass: 0.1 to 120 parts of sodium alginate, 0.01 to 20 parts of chitosan derivatives, 0.01 to 15 parts of calcium chloride, and 0.01 parts of carbomer ~9 parts; the injectable hydrogel also includes a good solvent, and the good solvent is a good solvent for sodium alginate injection, a good solvent for chitosan derivative injection, a good solvent for calcium chloride injection, and carbomer Good solvent for injection. The present invention introduces chitosan derivatives into the calcium alginate gel system. The addition of chitosan derivatives will neutralize part of the negative charges of sodium alginate and reduce the cross-linking density between sodium alginate and calcium ions; at the same time, The present invention introduces carbomer into the calcium alginate gel system. Carbomer, as a high molecular polymer cross-linked with acrylic acid and propenyl sucrose, has no charge itself and is electrically neutral. On the one hand, carbomer has a diluting effect on the calcium alginate gel system, which can prevent sodium alginate and calcium ions from being cross-linked locally in a short period of time; on the other hand, chitosan derivatives have a diluting effect on the calcium alginate gel system. It is alkaline in the gel system and can neutralize the acidity of carbomer in the calcium alginate gel system, causing the carbomer to further swell. The molecular chains of carbomer spread out and expand, showing a state of great expansion, which is harmful to calcium alginate. The gel system forms a thickening effect, which has a good effect on improving the support height and support time of the injected gel under the mucosa. Therefore, the present invention simultaneously introduces chitosan derivatives and carbomer into the calcium alginate gel system, so that the improved calcium alginate gel system can be applied to a single-needle injection system.
同时，本发明海藻酸钙凝胶体系中的壳聚糖衍生物不仅具有较好的生物相容性，还具有优良的吸湿、保湿、抗菌、止血作用，可以对因操作不当导致的器官穿孔和损坏部位进行快速止血，以保证手术视野清晰；同时抑制大肠杆菌、金黄色葡萄球菌等常见细菌和真菌的生长和繁殖，有利于术后伤口的快速愈合。At the same time, the chitosan derivative in the calcium alginate gel system of the present invention not only has good biocompatibility, but also has excellent hygroscopic, moisturizing, antibacterial and hemostatic effects, and can treat organ perforation and damage caused by improper operation. Quickly stop bleeding in the damaged area to ensure a clear surgical field; at the same time, it inhibits the growth and reproduction of common bacteria and fungi such as Escherichia coli and Staphylococcus aureus, which is conducive to rapid postoperative wound healing.
进一步的，本发明提供的注射型水凝胶还包括0.01～3份着色剂，所述良溶剂还包括着色剂注射用良溶剂。本发明还在海藻酸钙凝胶体系中引入着色剂，着色剂的存在可对息肉组织实现“可视化标记”，使得医生在ESD术中更清晰地观察病变粘膜，确保手术快速、准确地切除病变息肉。Furthermore, the injectable hydrogel provided by the present invention also includes 0.01 to 3 parts of colorant, and the good solvent also includes a good solvent for colorant injection. The present invention also introduces a colorant into the calcium alginate gel system. The presence of the colorant can achieve "visual marking" of polyp tissue, allowing doctors to more clearly observe the diseased mucosa during ESD surgery, ensuring that the disease can be removed quickly and accurately during the operation. polyp.
说明书附图Instructions with pictures
图1为实施例5制备得到的注射型水凝胶在室温下静置2h后的状态；Figure 1 shows the state of the injectable hydrogel prepared in Example 5 after being left standing at room temperature for 2 hours;
图2为实施例5制备得到的注射型水凝胶在室温下静置2h后可注射的状态。Figure 2 shows the injectable state of the injectable hydrogel prepared in Example 5 after being left standing at room temperature for 2 hours.
本发明提供了一种注射型水凝胶，包括以下质量份数的组分：The invention provides an injectable hydrogel, which includes the following components in parts by mass:
海藻酸钠0.1～120份，壳聚糖衍生物0.01～20份，氯化钙0.01～15份，卡波 姆0.01～9份；0.1 to 120 parts of sodium alginate, 0.01 to 20 parts of chitosan derivatives, 0.01 to 15 parts of calcium chloride, 0.01 to 9 parts of carbomer;
所述注射型水凝胶还包括良溶剂，所述良溶剂为海藻酸钠注射用良溶剂、壳聚糖衍生物注射用良溶剂、氯化钙注射用良溶剂和卡波姆注射用良溶剂。The injectable hydrogel also includes a good solvent, and the good solvent is a good solvent for sodium alginate injection, a good solvent for chitosan derivative injection, a good solvent for calcium chloride injection, and a good solvent for carbomer injection. .
在本发明中，若无特殊说明，所用原料均为本领域技术人员熟知的市售产品。In the present invention, unless otherwise specified, the raw materials used are commercially available products well known to those skilled in the art.
本发明提供的注射型水凝胶包括0.1～120份的海藻酸钠，优选为0.7～70份，更优选为5～20份。The injectable hydrogel provided by the present invention includes 0.1 to 120 parts of sodium alginate, preferably 0.7 to 70 parts, and more preferably 5 to 20 parts.
本发明提供的注射型水凝胶包括0.01～20份的壳聚糖衍生物，优选为0.01～10份，更优选为0.2～2.5份。The injectable hydrogel provided by the present invention includes 0.01 to 20 parts of chitosan derivatives, preferably 0.01 to 10 parts, and more preferably 0.2 to 2.5 parts.
在本发明中，所述壳聚糖衍生物优选包括壳聚糖季铵盐、烷基化壳聚糖、羧甲基壳聚糖、对羟基苯甲酸壳聚糖酯中的一种或多种，更优选为壳聚糖季铵盐和/或羧甲基壳聚糖。In the present invention, the chitosan derivative preferably includes one or more of chitosan quaternary ammonium salt, alkylated chitosan, carboxymethyl chitosan, and chitosan parahydroxybenzoate. , more preferably chitosan quaternary ammonium salt and/or carboxymethyl chitosan.
本发明提供的注射型水凝胶包括0.01～15份的氯化钙，优选为0.01～6份，更优选为0.5～3份。The injectable hydrogel provided by the present invention includes 0.01 to 15 parts of calcium chloride, preferably 0.01 to 6 parts, and more preferably 0.5 to 3 parts.
本发明提供的注射型水凝胶包括0.01～9份的卡波姆，优选为0.01～3.6份，更优选为0.2～1.5份。The injectable hydrogel provided by the present invention includes 0.01 to 9 parts of carbomer, preferably 0.01 to 3.6 parts, and more preferably 0.2 to 1.5 parts.
在本发明中，所述卡波姆包括卡波姆940、卡波姆941、卡波姆980、卡波姆981、卡波姆971P、卡波姆71G、卡波姆934P、卡波姆1342、卡波姆974P、卡波姆956P、卡波姆5984、卡波姆ETD2020和卡波姆Ultrez10中的一种或多种，更优选为卡波姆940、卡波姆980和卡波姆5984中的一种或多种。In the present invention, the carbomer includes carbomer 940, carbomer 941, carbomer 980, carbomer 981, carbomer 971P, carbomer 71G, carbomer 934P, carbomer 1342 , one or more of carbomer 974P, carbomer 956P, carbomer 5984, carbomer ETD2020 and carbomer Ultrez10, more preferably carbomer 940, carbomer 980 and carbomer 5984 one or more of them.
在本发明中，所述注射型水凝胶优选还包括0.01～3份着色剂，优选为0.01～0.9份，更优选为0.02～0.15份。In the present invention, the injectable hydrogel preferably further includes 0.01 to 3 parts of colorant, preferably 0.01 to 0.9 parts, and more preferably 0.02 to 0.15 parts.
在本发明中，所述着色剂优选包括靛蓝二磺酸钠、亚甲基蓝、埃文斯蓝、亮蓝、台盼蓝、甲苯胺蓝中的一种或多种。靛蓝二磺酸钠和/或亚甲基蓝。In the present invention, the colorant preferably includes one or more of sodium indigo disulfonate, methylene blue, Evans blue, brilliant blue, trypan blue, and toluidine blue. Sodium indigo disulfonate and/or methylene blue.
本发明提供的注射型水凝胶还包括良溶剂。The injectable hydrogel provided by the present invention also includes a good solvent.
在本发明中，所述良溶剂为海藻酸钠注射用良溶剂、壳聚糖衍生物注射用良溶剂、氯化钙注射用良溶剂和卡波姆注射用良溶剂。In the present invention, the good solvent is a good solvent for sodium alginate injection, a good solvent for chitosan derivative injection, a good solvent for calcium chloride injection, and a good solvent for carbomer injection.
在本发明中，所述海藻酸钠注射用良溶剂优选包括水、氯化钠溶液和磷酸缓冲液中的一种或多种，更优选为水。In the present invention, the good solvent for sodium alginate injection preferably includes one or more of water, sodium chloride solution and phosphate buffer, and is more preferably water.
在本发明中，所述氯化钠溶液的质量百分含量优选为0.9wt％。In the present invention, the mass percentage of the sodium chloride solution is preferably 0.9 wt%.
在本发明中，所述磷酸缓冲液的pH值优选为5.5～7.5。In the present invention, the pH value of the phosphate buffer is preferably 5.5 to 7.5.
在本发明中，所述壳聚糖衍生物注射用良溶剂优选包括水和/或乙醇，更优选为水。In the present invention, the good solvent for injection of chitosan derivatives preferably includes water and/or ethanol, more preferably water.
在本发明中，所述氯化钙注射用良溶剂优选包括水和/或乙醇，更优选为水。In the present invention, the good solvent for calcium chloride injection preferably includes water and/or ethanol, more preferably water.
在本发明中，所述卡波姆注射用良溶剂优选包括水、乙醇、丙二醇和甘油中的一种或多种，更优选为水。In the present invention, the good solvent for carbomer injection preferably includes one or more of water, ethanol, propylene glycol and glycerin, and is more preferably water.
在本发明中，所述良溶剂还包括着色剂注射用良溶剂。In the present invention, the good solvent also includes a good solvent for colorant injection.
在本发明中，所述着色剂注射用良溶剂优选包括水和/或乙醇，更优选为水。In the present invention, the good solvent for colorant injection preferably includes water and/or ethanol, more preferably water.
在本发明中，所述注射型水凝胶优选在避光且0～35℃条件下保存。In the present invention, the injectable hydrogel is preferably stored away from light at 0 to 35°C.
本发明提供了上述技术方案所述的注射型水凝胶的制备方法，包括以下步骤：The present invention provides a preparation method for the injectable hydrogel described in the above technical solution, which includes the following steps:
将所述注射水凝胶的各组分混合，得到所述注射型水凝胶。Each component of the injectable hydrogel is mixed to obtain the injectable hydrogel.
在本发明中，所述注射水凝胶的组分不包括着色剂时，所述混合包括以下步骤：In the present invention, when the components of the injectable hydrogel do not include colorants, the mixing includes the following steps:
在无菌条件下，将海藻酸钠溶解于海藻酸钠注射用良溶剂中，得到海藻酸钠溶液；Under sterile conditions, dissolve sodium alginate in a good solvent for sodium alginate injection to obtain a sodium alginate solution;
在无菌条件下，将壳聚糖衍生物溶解于壳聚糖衍生物注射用良溶剂中，得到壳聚糖衍生物溶液；Under sterile conditions, dissolve the chitosan derivative in a good solvent for chitosan derivative injection to obtain a chitosan derivative solution;
在无菌条件下，将氯化钙溶解于氯化钙注射用良溶剂中，得到氯化钙溶液，Under sterile conditions, dissolve calcium chloride in a good solvent for calcium chloride injection to obtain a calcium chloride solution.
在无菌条件下，将卡波姆溶解于卡波姆注射用良溶剂中后进行溶胀，得到卡波姆溶胶，Under sterile conditions, dissolve carbomer in a good solvent for carbomer injection and then swell to obtain carbomer sol.
将所述海藻酸钠溶液、所述壳聚糖衍生物溶液和所述卡波姆溶胶混合得到混合溶液；Mix the sodium alginate solution, the chitosan derivative solution and the carbomer sol to obtain a mixed solution;
向所述混合溶液中滴加所述氯化钙溶液。The calcium chloride solution was added dropwise to the mixed solution.
本发明在无菌条件下，将海藻酸钠溶解(以下称为第一溶解)于海藻酸钠注射用良溶剂中，得到海藻酸钠溶液。In the present invention, under aseptic conditions, sodium alginate is dissolved (hereinafter referred to as the first dissolution) in a good solvent for sodium alginate injection to obtain a sodium alginate solution.
在本发明中，制备所述海藻酸钠溶液的溶解温度优选为20～90℃，优选为30～80℃，更优选为40～65℃。In the present invention, the dissolution temperature for preparing the sodium alginate solution is preferably 20 to 90°C, preferably 30 to 80°C, and more preferably 40 to 65°C.
在本发明中，所述第一溶解优选在水浴条件下进行。In the present invention, the first dissolution is preferably performed under water bath conditions.
在本发明中，所述第一溶解优选在搅拌条件下进行。In the present invention, the first dissolution is preferably performed under stirring conditions.
在本发明中，所述海藻酸钠溶液的质量浓度优选为0.1～60g/L，更优选为0.1～35g/L，进一步优选为5～10g/L。In the present invention, the mass concentration of the sodium alginate solution is preferably 0.1 to 60 g/L, more preferably 0.1 to 35 g/L, and even more preferably 5 to 10 g/L.
本发明在无菌条件下，将壳聚糖衍生物溶解(以下称为第二溶解)于壳聚糖衍生物注射用良溶剂中，得到壳聚糖衍生物溶液。In the present invention, under aseptic conditions, the chitosan derivative is dissolved (hereinafter referred to as the second dissolution) in a good solvent for chitosan derivative injection to obtain a chitosan derivative solution.
在本发明中，制备所述壳聚糖衍生物溶液的溶解温度优选为20～90℃，优选为30～80℃，更优选为40～65℃。In the present invention, the dissolution temperature for preparing the chitosan derivative solution is preferably 20 to 90°C, preferably 30 to 80°C, and more preferably 40 to 65°C.
在本发明中，所述第二溶解优选在水浴条件下进行。In the present invention, the second dissolution is preferably carried out under water bath conditions.
在本发明中，所述第二溶解优选在搅拌条件下进行。In the present invention, the second dissolution is preferably performed under stirring conditions.
在本发明中，所述壳聚糖衍生物溶液的质量浓度优选为0.1～40g/L，更优选为0.1～20g/L，进一步优选为2～5g/L。In the present invention, the mass concentration of the chitosan derivative solution is preferably 0.1 to 40 g/L, more preferably 0.1 to 20 g/L, and even more preferably 2 to 5 g/L.
本发明在无菌条件下，将氯化钙溶解(以下称为第三溶解)于氯化钙注射用良溶剂中，得到氯化钙溶液。In the present invention, under aseptic conditions, calcium chloride is dissolved (hereinafter referred to as the third dissolution) in a good solvent for calcium chloride injection to obtain a calcium chloride solution.
在本发明中，制备所述氯化钙溶液的溶解温度优选为室温。In the present invention, the dissolution temperature for preparing the calcium chloride solution is preferably room temperature.
在本发明中，所述第三溶解优选在搅拌条件下进行。In the present invention, the third dissolution is preferably performed under stirring conditions.
在本发明中，所述氯化钙溶液的质量浓度优选为0.1～50g/L，更优选为0.1～20g/L，进一步优选为5～10g/L。In the present invention, the mass concentration of the calcium chloride solution is preferably 0.1 to 50 g/L, more preferably 0.1 to 20 g/L, and even more preferably 5 to 10 g/L.
本发明在无菌条件下，将卡波姆溶解(以下称为第四溶解)于卡波姆注射用良溶剂中后进行溶胀，得到卡波姆溶胶，In the present invention, under aseptic conditions, carbomer is dissolved (hereinafter referred to as the fourth dissolution) in a good solvent for carbomer injection and then swollen to obtain carbomer sol.
在本发明中，制备所述卡波姆溶胶的溶解温度优选为20～75℃，更优选为30～70℃，进一步优选为40～65℃。In the present invention, the dissolution temperature for preparing the carbomer sol is preferably 20 to 75°C, more preferably 30 to 70°C, and further preferably 40 to 65°C.
在本发明中，所述第四溶解优选在水浴条件下进行。In the present invention, the fourth dissolution is preferably performed under water bath conditions.
在本发明中，所述第四溶解优选在搅拌条件下进行。In the present invention, the fourth dissolution is preferably performed under stirring conditions.
在本发明中，制备所述卡波姆溶胶的溶胀温度优选为室温，制备所述卡波姆溶胶的溶胀时间优选为24h。In the present invention, the swelling temperature for preparing the carbomer sol is preferably room temperature, and the swelling time for preparing the carbomer sol is preferably 24 hours.
在本发明中，所述卡波姆溶胶的质量浓度优选为0.1～30g/L，更优选为0.1～12g/L，进一步优选为2～5g/L。In the present invention, the mass concentration of the carbomer sol is preferably 0.1 to 30 g/L, more preferably 0.1 to 12 g/L, and even more preferably 2 to 5 g/L.
得到海藻酸钠溶液、壳聚糖衍生物溶液和卡波姆溶胶后，本发明将所述海藻酸钠溶液、所述壳聚糖衍生物溶液和所述卡波姆溶胶混合得到混合溶液。After obtaining the sodium alginate solution, the chitosan derivative solution and the carbomer sol, the present invention mixes the sodium alginate solution, the chitosan derivative solution and the carbomer sol to obtain a mixed solution.
得到氯化钙溶液和混合溶液后，本发明向所述混合溶液中滴加所述氯化钙溶液。After obtaining the calcium chloride solution and the mixed solution, the present invention adds the calcium chloride solution dropwise to the mixed solution.
在本发明中，所述滴加的速度优选为0.1～0.15mL/min，具体优选为01mL/min或0.15mL/min。In the present invention, the dropping speed is preferably 0.1 to 0.15 mL/min, specifically preferably 01 mL/min or 0.15 mL/min.
在本发明中，所述滴加优选在搅拌的条件下进行。In the present invention, the dropwise addition is preferably performed under stirring conditions.
在本发明中，所述注射水凝胶的组分优选包括着色剂时，所述混合包括以下步骤：In the present invention, when the components of the injectable hydrogel preferably include a colorant, the mixing includes the following steps:
在本发明中，所述混合的原料优选还包括着色剂和着色剂注射用良溶剂时，所述混合优选包括以下步骤：In the present invention, when the mixed raw materials preferably further include a colorant and a good solvent for colorant injection, the mixing preferably includes the following steps:
在无菌条件下，将海藻酸钠溶解于海藻酸钠注射用良溶剂中，得到海藻酸钠溶液；Under sterile conditions, dissolve sodium alginate in a good solvent for sodium alginate injection to obtain a sodium alginate solution;
在无菌条件下，将壳聚糖衍生物溶解于壳聚糖衍生物注射用良溶剂中，得到壳聚糖衍生物溶液；Under sterile conditions, dissolve the chitosan derivative in a good solvent for chitosan derivative injection to obtain a chitosan derivative solution;
在无菌条件下，将氯化钙、着色剂溶解于氯化钙注射用良溶剂和着色剂注射用良溶剂中，得到氯化钙-着色剂溶液；Under sterile conditions, dissolve calcium chloride and colorant in a good solvent for calcium chloride injection and a good solvent for colorant injection to obtain a calcium chloride-colorant solution;
在无菌条件下，将卡波姆溶解于卡波姆注射用良溶剂中后进行溶胀，得到卡波姆溶胶；Under sterile conditions, dissolve carbomer in a good solvent for carbomer injection and then swell to obtain carbomer sol;
将所述海藻酸钠溶液、所述壳聚糖衍生物溶液和所述卡波姆溶胶混合得到混合溶液；Mix the sodium alginate solution, the chitosan derivative solution and the carbomer sol to obtain a mixed solution;
向所述混合溶液中滴加所述氯化钙-着色剂溶液。The calcium chloride-colorant solution was added dropwise to the mixed solution.
在本发明中，所述混合的原料优选还包括着色剂和着色剂注射用良溶剂时，所述海藻酸钠溶液、壳聚糖衍生物溶液、卡波姆溶胶、混合溶液和滴加的保护范围与上述无着色剂和着色剂注射用良溶剂时的技术方案相同，在此不再一一赘述。In the present invention, the mixed raw materials preferably also include a colorant and a good solvent for colorant injection, and the sodium alginate solution, chitosan derivative solution, carbomer sol, mixed solution and dripping protection The scope is the same as the above-mentioned technical solution without colorant and good solvent for colorant injection, and will not be repeated here.
本发明在无菌条件下，将氯化钙、着色剂溶解(以下称为第五溶解)于氯化钙注射用良溶剂和着色剂注射用良溶剂中，得到氯化钙-着色剂溶液；。In the present invention, under aseptic conditions, calcium chloride and coloring agent are dissolved (hereinafter referred to as the fifth dissolution) in a good solvent for calcium chloride injection and a good solvent for coloring agent injection, to obtain a calcium chloride-coloring agent solution; .
在本发明中，所述第五溶解和所述第三溶解的保护范围相同。In the present invention, the protection scope of the fifth dissolution and the third dissolution are the same.
在本发明中，所述氯化钙-着色剂溶液中，所述着色剂的质量浓度优选为0.1～10gL，更优选为0.1～3g/L，进一步优选为0.2～0.5g/L。In the present invention, in the calcium chloride-colorant solution, the mass concentration of the colorant is preferably 0.1 to 10 g/L, more preferably 0.1 to 3 g/L, and even more preferably 0.2 to 0.5 g/L.
在本发明中，所述氯化钙-着色剂溶液中，所述氯化钙的质量浓度与上述技术方案相同。In the present invention, the mass concentration of calcium chloride in the calcium chloride-colorant solution is the same as the above technical solution.
本发明提供了上述技术方案所述的注射型水凝胶或上述技术方案所述的制备方法制备得到的注射型水凝胶作为粘膜下注射液的应用。The present invention provides the use of the injectable hydrogel described in the above technical solution or the injectable hydrogel prepared by the preparation method described in the above technical solution as a submucosal injection.
在本发明中，所述粘膜下注射液优选为内窥镜辅助治疗的粘膜下注射液。In the present invention, the submucosal injection is preferably a submucosal injection for endoscopic-assisted treatment.
本发明提供了上述技术方案所述的注射型水凝胶或上述技术方案所述的制备方法制备得到的注射型水凝胶在内窥镜辅助治疗中的应用。The present invention provides the application of the injectable hydrogel described in the above technical solution or the injectable hydrogel prepared by the preparation method described in the above technical solution in endoscope-assisted treatment.
在本发明中，所述应用优选为：进行所述内窥镜辅助治疗之前，采用单针头注射体系将注射水凝胶注入病变表面黏膜和黏膜下肌层之间；所述注射水凝胶为上述技术方案所述的注射型水凝胶或上述技术方案所述的制备方法制备得到的注射型水凝胶。In the present invention, the application is preferably: before performing the endoscopic auxiliary treatment, a single-needle injection system is used to inject the injection hydrogel between the diseased surface mucosa and the submucosal muscle layer; the injection hydrogel is The injectable hydrogel described in the above technical solution or the injectable hydrogel prepared by the preparation method described in the above technical solution.
下面结合实施例对本发明提供的耐高温硬质复合涂层及其制备方法和涂层刀具进行详细地描述，但不能将它们理解为对本发明保护范围的限定。The high-temperature resistant hard composite coating provided by the present invention, its preparation method and coated cutting tools are described in detail below with reference to examples, but they should not be understood as limiting the scope of the present invention.
实施例1Example 1
(1)配制海藻酸钠溶液(1) Prepare sodium alginate solution
在无菌条件下，室温下，将海藻酸钠加入到注射用水中，在45℃水浴条件下使其搅拌溶解，最后补加注射用水定容，即得到海藻酸钠溶液。海藻酸钠溶液中海藻酸钠和注射用水的用量如表1所示。Under sterile conditions, at room temperature, add sodium alginate to water for injection, stir and dissolve it in a 45°C water bath, and finally add water for injection to adjust the volume to obtain a sodium alginate solution. The dosage of sodium alginate and water for injection in the sodium alginate solution is shown in Table 1.
表1 实施例1中海藻酸钠溶液配方Table 1 Sodium alginate solution formula in Example 1
|
物料 |
11 | 22 | 33 | 44 | 55 |
| 海藻酸钠Sodium alginate | 0.9g0.9g | 3.6g3.6g | 13.1g13.1g | 21.4g21.4g | 28.7g28.7g |
| 注射用水Water for Injection | 500ml500ml | 495ml495ml | 485ml485ml | 480ml480ml | 470ml470ml |
| 评价evaluate | 较优Better | 优秀excellent | 较优Better | 适中Moderate | 适中Moderate |
注：优秀：溶液均一、透明、无气泡，流动性优；较优：溶液均一、透明、无气泡，流动性次之(浓稠或偏稀)；适中：溶液均一、无气泡，流动性次之(浓稠或偏稀)。(下同)。Note: Excellent: the solution is uniform, transparent, no bubbles, and has excellent fluidity; Better: the solution is uniform, transparent, and bubble-free, and the fluidity is second best (thick or dilute); Moderate: the solution is uniform, bubble-free, and the fluidity is second best Which (thick or thin). (The same below).
(2)配制壳聚糖衍生物溶液(2) Prepare chitosan derivative solution
在无菌条件下，将壳聚糖季铵盐加入注射用水中，在50℃水浴条件下使其搅拌溶解，最后补加注射用水定容，即得到壳聚糖衍生物溶液。壳聚糖衍生物溶液中壳聚糖季铵盐和注射用水的用量如表2所示。Under sterile conditions, add chitosan quaternary ammonium salt to water for injection, stir and dissolve it in a 50°C water bath, and finally add water for injection to adjust the volume to obtain a chitosan derivative solution. The dosage of chitosan quaternary ammonium salt and water for injection in the chitosan derivative solution is shown in Table 2.
表2 实施例1中壳聚糖季铵盐溶液配方Table 2 Chitosan quaternary ammonium salt solution formula in Example 1
|
物料 |
11 | 22 | 33 | 44 | 55 |
| 壳聚糖季铵盐Chitosan quaternary ammonium salt | 9.7g9.7g | 4.1g4.1g | 0.8g0.8g | 0.2g0.2g | 0.04g0.04g |
| 注射用水Water for Injection | 240ml240ml | 245ml245ml | 250ml250ml | 250ml250ml | 250ml250ml |
| 评价evaluate | 适中Moderate | 较优better | 优秀excellent | 较优better | 适中Moderate |
(3)配制氯化钙溶液(3) Prepare calcium chloride solution
在无菌条件下，将氯化钙、靛蓝二磺酸钠加入到注射用水中，室温下搅拌溶解完全，即得到氯化钙-着色剂溶液；氯化钙-着色剂溶液中氯化钙、靛蓝 二磺酸钠和注射用水的用量如表3所示。Under sterile conditions, add calcium chloride and sodium indigo disulfonate to water for injection, stir and dissolve completely at room temperature, and obtain calcium chloride-colorant solution; in calcium chloride-colorant solution, calcium chloride, The dosage of sodium indigo disulfonate and water for injection is shown in Table 3.
表3 实施例1中氯化钙-着色剂溶液配方Table 3 Calcium chloride-colorant solution formula in Example 1
|
物料 |
11 | 22 | 33 | 44 | 55 |
| 氯化钙calcium chloride | 11.2g11.2g | 4.3g4.3g | 1.8g1.8g | 0.2g0.2g | 0.04g0.04g |
| 靛蓝二磺酸钠Sodium Indigo Disulfonate | 1.9g1.9g | 0.440.44 | 0.076g0.076g | 1.8g1.8g | 0.38g0.38g |
| 注射用水Water for Injection | 240ml240ml | 245ml245ml | 250ml250ml | 250ml250ml | 250ml250ml |
| 评价evaluate | 适中Moderate | 较优better | 优秀excellent | 较优better | 适中Moderate |
(4)配制卡波姆溶胶(4) Preparation of carbomer sol
在无菌条件下，将卡波姆在40℃水浴条件下搅拌溶解于注射用水中，最后补加注射用水定容，然后室温下充分溶胀24h，即得到卡波姆溶胶。卡波姆溶胶中卡波姆的种类和注射用水的用量如表4～6所示。Under sterile conditions, stir and dissolve carbomer in water for injection at 40°C in a water bath. Finally, add water for injection to make the volume, and then fully swell at room temperature for 24 hours to obtain carbomer sol. The types of carbomer in carbomer sol and the dosage of water for injection are shown in Tables 4 to 6.
表4 实施例1中卡波姆940溶液配方Table 4 Carbomer 940 solution formula in Example 1
|
物料 |
11 | 22 | 33 | 44 | 55 |
| 卡波姆940carbomer 940 | 2.10g2.10g | 0.31g0.31g | 0.80g0.80g | 0.2g0.2g | 6.6g6.6g |
| 注射用水Water for Injection | 250ml250ml | 245ml245ml | 250ml250ml | 250ml250ml | 250ml250ml |
| 评价evaluate | 适中Moderate | 较优Better | 优秀excellent | 较优Better | 适中Moderate |
表5 实施例1中卡波姆980溶液配方Table 5 Carbomer 980 solution formula in Example 1
|
物料 |
11 | 22 | 33 | 44 | 55 |
| 卡波姆980carbomer 980 | 4.1g4.1g | 2.3g2.3g | 0.77g0.77g | 0.22g0.22g | 0.64g0.64g |
| 注射用水Water for Injection | 245ml245ml | 247ml247ml | 250ml250ml | 250ml250ml | 250ml250ml |
| 评价evaluate | 适中Moderate | 较优better | 优秀excellent | 较优better | 优秀excellent |
表6 实施例1中卡波姆5984溶液配方Table 6 Carbomer 5984 solution formula in Example 1
|
物料 |
11 | 22 | 33 | 44 | 55 |
| 卡波姆5984carbomer 5984 | 5.5g5.5g | 2.6g2.6g | 0.63g0.63g | 0.11g0.11g | 0.84g0.84g |
| 注射用水Water for Injection | 245ml245ml | 247ml247ml | 250ml250ml | 250ml250ml | 250ml250ml |
| 评价evaluate | 适中Moderate | 较优Better | 较优better | 较优better | 较优better |
实施例2Example 2
(1)配制海藻酸钠溶液(1) Prepare sodium alginate solution
室温下，将1.8g海藻酸钠溶解在注射用水中，最后继续补加注射用水并将系统体积定容至250mL，在不同水浴条件下使其搅拌溶解，即得到海 藻酸钠溶液；水浴温度如表7所示。Dissolve 1.8g sodium alginate in water for injection at room temperature. Finally, continue to add water for injection and adjust the system volume to 250 mL. Stir and dissolve it under different water bath conditions to obtain a sodium alginate solution; the water bath temperature is as follows: As shown in Table 7.
表7 实施例2中制备海藻酸钠溶液的水浴温度Table 7 Water bath temperature for preparing sodium alginate solution in Example 2
|
物料 |
11 | 22 | 33 | 44 | 55 |
| 水浴温度water bath temperature | 25℃25℃ | 34℃34℃ | 50℃50℃ | 73℃73℃ | 88℃88℃ |
| 状况situation | 适中Moderate | 较优Better | 优秀excellent | 较优better | 适中Moderate |
(2)配制壳聚糖衍生物溶液(2) Prepare chitosan derivative solution
在无菌条件下，将0.8g壳聚糖季铵盐加入到注射用水中，水浴条件下使其搅拌溶解，最后补加注射用水并将系统体积定容至250mL，即得到壳聚糖衍生物溶液；水浴温度如表8所示。Under sterile conditions, add 0.8g of chitosan quaternary ammonium salt to water for injection, stir and dissolve it under water bath conditions, and finally add water for injection and adjust the system volume to 250 mL to obtain the chitosan derivative Solution; water bath temperature is shown in Table 8.
表8 实施例2中制备壳聚糖衍生物溶液的水浴温度Table 8 Water bath temperature for preparing chitosan derivative solution in Example 2
|
物料 |
11 | 22 | 33 | 44 | 55 |
| 水浴温度water bath temperature | 25℃25℃ | 34℃34℃ | 50℃50℃ | 73℃73℃ | 88℃88℃ |
| 状况situation | 适中Moderate | 较优better | 优秀excellent | 较优Better | 适中Moderate |
(3)配制卡波姆溶胶(3) Preparation of carbomer sol
在无菌条件下，将0.85g卡波姆980在室温下溶解于注射用水中，最后补加注射用水并将系统体积定容至250mL，然后室温下充分溶胀24h后，即得到卡波姆溶胶；水浴温度如表7所示。Under sterile conditions, dissolve 0.85g carbomer 980 in water for injection at room temperature. Finally, add water for injection and adjust the system volume to 250 mL. Then, after fully swelling at room temperature for 24 hours, the carbomer sol is obtained. ;The water bath temperature is shown in Table 7.
表9 实施例2中制备卡波姆溶胶的水浴温度Table 9 Water bath temperature for preparing carbomer sol in Example 2
|
物料 |
11 | 22 | 33 | 44 |
| 水浴温度water bath temperature | 25℃25℃ | 34℃34℃ | 50℃50℃ | 73℃73℃ |
| 状况situation | 适中Moderate | 较优Better | 优秀excellent | 适中Moderate |
实施例3Example 3
配制1.001L用于内窥镜辅助治疗的注射型水凝胶，注射型水凝胶由海藻酸钠溶液、壳聚糖衍生物溶液、氯化钙-着色剂溶液、卡波姆940溶胶四种组分按照体积比10:1:1:1组成；Prepare 1.001L of injectable hydrogel for endoscopic auxiliary treatment. The injectable hydrogel consists of four types: sodium alginate solution, chitosan derivative solution, calcium chloride-colorant solution, and carbomer 940 sol. The components are composed according to the volume ratio of 10:1:1:1;
(1)配制海藻酸钠溶液(1) Prepare sodium alginate solution
室温下，将3.85g海藻酸钠溶解在注射用水中，最后继续补加注射用水并将系统体积定容至770mL，在60℃水浴条件下使其搅拌溶解，即得到海藻酸钠溶液；Dissolve 3.85g sodium alginate in water for injection at room temperature. Finally, continue to add water for injection and adjust the system volume to 770 mL. Stir and dissolve it in a 60°C water bath to obtain a sodium alginate solution;
(2)配制壳聚糖衍生物溶液(2) Prepare chitosan derivative solution
在无菌条件下，将154mg壳聚糖季铵盐加入到适量注射用水中，50℃ 水浴条件下使其搅拌溶解，最后补加注射用水并将系统体积定容至77mL，即得到壳聚糖衍生物溶液Under sterile conditions, add 154 mg of chitosan quaternary ammonium salt to an appropriate amount of water for injection, stir and dissolve it in a 50°C water bath, and finally add water for injection and adjust the system volume to 77 mL to obtain chitosan derivative solution
(3)配制氯化钙-着色剂溶液(3) Prepare calcium chloride-colorant solution
在无菌条件下，将385mg氯化钙、15.4mg靛蓝二磺酸钠加入到适量注射用水中，室温下搅拌溶解完全，然后补加注射用水并将系统体积定容至77mL，即得到氯化钙溶液；Under sterile conditions, add 385 mg calcium chloride and 15.4 mg sodium indigo disulfonate to an appropriate amount of water for injection, stir and dissolve completely at room temperature, then add water for injection and adjust the system volume to 77 mL to obtain chlorination calcium solution;
(4)配制卡波姆940溶胶(4) Preparation of carbomer 940 sol
在无菌条件下，将154mg卡波姆940在室温下溶解于适量注射用水中，最后补加注射用水并将系统体积定容至77mL，然后室温下充分溶胀24h后，即得到卡波姆940溶胶；Under sterile conditions, dissolve 154 mg of Carbomer 940 in an appropriate amount of water for injection at room temperature. Finally, add water for injection and adjust the system volume to 77 mL, and then fully swell at room temperature for 24 hours to obtain Carbomer 940. sol;
(5)按照体积比，先将壳聚糖衍生物溶液与海藻酸钠溶液混合均匀，再加入卡波姆940溶胶并混合均匀，然后以0.1mL/min的速度向体系中滴加氯化钙溶液，边滴加边迅速搅拌均匀，即得，避光保存在4℃下备用。(5) According to the volume ratio, first mix the chitosan derivative solution and the sodium alginate solution evenly, then add carbomer 940 sol and mix evenly, then add calcium chloride dropwise into the system at a speed of 0.1mL/min. The solution is added dropwise and stirred quickly to obtain the solution. Store it away from light at 4°C for later use.
实施例4Example 4
配制0.996L用于内窥镜辅助治疗的注射型水凝胶，注射型水凝胶由海藻酸钠溶液、壳聚糖衍生物溶液、氯化钙-着色剂溶液、卡波姆940溶胶四种组分按照体积比10:5:1:3组成；Prepare 0.996L of injectable hydrogel for endoscopic auxiliary treatment. The injectable hydrogel consists of four types: sodium alginate solution, chitosan derivative solution, calcium chloride-colorant solution, and carbomer 940 sol. The components are composed according to the volume ratio of 10:5:1:3;
(1)配制海藻酸钠溶液(1) Prepare sodium alginate solution
室温下，将5.26g海藻酸钠溶解在注射用水中，最后继续补加注射用水并将系统体积定容至526mL，在60℃水浴条件下使其搅拌溶解，即得到海藻酸钠溶液；Dissolve 5.26g sodium alginate in water for injection at room temperature. Finally, continue to add water for injection and adjust the system volume to 526 mL. Stir and dissolve it in a 60°C water bath to obtain a sodium alginate solution;
(2)配制壳聚糖衍生物溶液(2) Prepare chitosan derivative solution
在无菌条件下，将1.315g羧甲基壳聚糖加入注射用水中，60℃水浴条件下使其搅拌溶解，最后补加注射用水并将系统体积定容至263mL，即得到壳聚糖衍生物溶液Under sterile conditions, add 1.315g carboxymethyl chitosan to water for injection, stir and dissolve it in a 60°C water bath, and finally add water for injection and adjust the system volume to 263 mL to obtain chitosan derivatives solution
(3)配制氯化钙-着色剂溶液(3) Prepare calcium chloride-colorant solution
在无菌条件下，将526mg氯化钙、126.3mg亚甲基蓝加入到注射用水中，室温下搅拌溶解完全，然后补加注射用水并将系统体积定容至52.6mL，即得到氯化钙溶液；Under sterile conditions, add 526 mg calcium chloride and 126.3 mg methylene blue to water for injection, stir and dissolve completely at room temperature, then add water for injection and adjust the system volume to 52.6 mL to obtain a calcium chloride solution;
(4)配制卡波姆940溶胶(4) Preparation of carbomer 940 sol
在无菌条件下，将790mg卡波姆940在室温下溶解于注射用水中，最后补 加注射用水并将系统体积定容至158mL，然后室温下充分溶胀24h后，即得到卡波姆940溶胶；Under sterile conditions, dissolve 790 mg of Carbomer 940 in water for injection at room temperature. Finally, add water for injection and adjust the system volume to 158 mL. Then, after fully swelling at room temperature for 24 hours, Carbomer 940 sol is obtained. ;
(5)按照体积比，先将壳聚糖衍生物溶液与海藻酸钠溶液混合均匀，再加入卡波姆940溶胶并混合均匀，然后以0.1mL/min的速度向体系中滴加氯化钙溶液，边滴加边迅速搅拌均匀，即得，避光保存在8℃下备用。(5) According to the volume ratio, first mix the chitosan derivative solution and the sodium alginate solution evenly, then add carbomer 940 sol and mix evenly, then add calcium chloride dropwise into the system at a speed of 0.1mL/min. The solution is added dropwise and stirred quickly to obtain the solution. Store it away from light at 8°C for later use.
实施例5Example 5
配制1.0004L用于内窥镜辅助治疗的注射型水凝胶，注射型水凝胶由海藻酸钠溶液、壳聚糖衍生物溶液、氯化钙溶液、卡波姆940溶胶四种组分按照体积比10:1:3:1组成；Prepare 1.0004L of injectable hydrogel for endoscopic auxiliary treatment. The injectable hydrogel consists of four components: sodium alginate solution, chitosan derivative solution, calcium chloride solution, and carbomer 940 sol. The volume ratio is 10:1:3:1;
(1)配制海藻酸钠溶液(1) Prepare sodium alginate solution
室温下，将3.3g海藻酸钠溶解在注射用水中，最后继续补加注射用水并将系统体积定容至667mL，在60℃水浴条件下使其搅拌溶解，即得到海藻酸钠溶液；Dissolve 3.3g sodium alginate in water for injection at room temperature. Finally, continue to add water for injection and adjust the system volume to 667 mL. Stir and dissolve it in a 60°C water bath to obtain a sodium alginate solution;
(2)配制壳聚糖衍生物溶液(2) Prepare chitosan derivative solution
在无菌条件下，将133.4mg壳聚糖季铵盐加入到注射用水中，50℃水浴条件下使其搅拌溶解，最后补加注射用水并将系统体积定容至66.7mL，即得到壳聚糖衍生物溶液Under sterile conditions, add 133.4 mg of chitosan quaternary ammonium salt to water for injection, stir and dissolve it in a 50°C water bath, and finally add water for injection and adjust the system volume to 66.7 mL to obtain chitosan Sugar derivative solution
(3)配制氯化钙溶液(3) Prepare calcium chloride solution
在无菌条件下，将1g氯化钙、40mg靛蓝二磺酸钠加入到注射用水中，室温下搅拌溶解完全，然后补加注射用水并将系统体积定容至200mL，即得到氯化钙溶液；Under sterile conditions, add 1g calcium chloride and 40mg sodium indigo disulfonate to water for injection, stir and dissolve completely at room temperature, then add water for injection and adjust the system volume to 200mL to obtain a calcium chloride solution ;
(4)配制卡波姆940溶胶(4) Preparation of carbomer 940 sol
在无菌条件下，将133.4mg卡波姆940在室温下溶解于注射用水中，最后补加注射用水并将系统体积定容至66.7mL，然后室温下充分溶胀24h后，即得到卡波姆940溶胶；Under sterile conditions, dissolve 133.4 mg of Carbomer 940 in water for injection at room temperature. Finally, add water for injection and adjust the system volume to 66.7 mL. Then, fully swell at room temperature for 24 hours to obtain carbomer. 940 sol;
(5)按照体积比，先将壳聚糖衍生物溶液与海藻酸钠溶液混合均匀，再加入卡波姆940溶胶并混合均匀，然后以0.1mL/min的速度向体系中滴加氯化钙溶液，边滴加边迅速搅拌均匀，即得，避光保存在5℃下备用，实施例3所获注射凝胶在室温下静置2h后的物理状态和可注射情况如图1、图2所示。(5) According to the volume ratio, first mix the chitosan derivative solution and the sodium alginate solution evenly, then add carbomer 940 sol and mix evenly, then add calcium chloride dropwise into the system at a speed of 0.1mL/min. The solution is obtained by stirring rapidly while adding it dropwise. Store it away from light at 5°C for later use. The physical state and injectability of the injection gel obtained in Example 3 after being left at room temperature for 2 hours are shown in Figures 1 and 2. shown.
实施例6Example 6
配制1L用于内窥镜辅助治疗的注射型水凝胶，注射型水凝胶由海藻酸钠溶液、壳聚糖衍生物溶液、氯化钙溶液、卡波姆940溶胶四种组分按照体积比20:5:3:3组成；Prepare 1L of injectable hydrogel for endoscopic auxiliary treatment. The injectable hydrogel consists of four components: sodium alginate solution, chitosan derivative solution, calcium chloride solution, and carbomer 940 sol according to volume. It is composed of ratio 20:5:3:3;
(1)配制海藻酸钠溶液(1) Prepare sodium alginate solution
室温下，将6.45g海藻酸钠溶解在注射用水中，最后继续补加注射用水并将系统体积定容至645mL，在60℃水浴条件下使其搅拌溶解，即得到海藻酸钠溶液；Dissolve 6.45g sodium alginate in water for injection at room temperature. Finally, continue to add water for injection and adjust the system volume to 645mL. Stir and dissolve it in a 60°C water bath to obtain a sodium alginate solution;
(2)配制壳聚糖衍生物溶液(2) Prepare chitosan derivative solution
在无菌条件下，将805mg羧甲基壳聚糖加入到注射用水中，50℃水浴条件下使其搅拌溶解，最后补加注射用水并将系统体积定容至161mL，即得到壳聚糖衍生物溶液Under sterile conditions, add 805 mg of carboxymethyl chitosan to water for injection, stir and dissolve it in a 50°C water bath, and finally add water for injection and adjust the system volume to 161 mL to obtain chitosan derivatives solution
(3)配制氯化钙溶液(3) Prepare calcium chloride solution
在无菌条件下，将970mg氯化钙、48.5mg亚甲基蓝加入到注射用水中，室温下搅拌溶解完全，然后补加注射用水并将系统体积定容至97mL，即得到氯化钙溶液；Under sterile conditions, add 970 mg calcium chloride and 48.5 mg methylene blue to water for injection, stir and dissolve completely at room temperature, then add water for injection and adjust the system volume to 97 mL to obtain a calcium chloride solution;
(4)配制卡波姆940溶胶(4) Preparation of carbomer 940 sol
在无菌条件下，将485mg卡波姆940在室温下溶解于注射用水中，最后补加注射用水并将系统体积定容至97mL，然后室温下充分溶胀24h后，即得到卡波姆940溶胶；Under sterile conditions, dissolve 485 mg of Carbomer 940 in water for injection at room temperature. Finally, add water for injection and adjust the system volume to 97 mL. Then, after fully swelling at room temperature for 24 hours, Carbomer 940 sol is obtained. ;
(5)按照体积比，先将壳聚糖衍生物溶液与海藻酸钠溶液混合均匀，再加入卡波姆940溶胶并混合均匀，然后以0.1mL/min的速度向体系中滴加氯化钙溶液，边滴加边迅速搅拌均匀，即得，避光保存在4℃下备用。(5) According to the volume ratio, first mix the chitosan derivative solution and the sodium alginate solution evenly, then add carbomer 940 sol and mix evenly, then add calcium chloride dropwise into the system at a speed of 0.1mL/min. The solution is added dropwise and stirred quickly to obtain the solution. Store it away from light at 4°C for later use.
实施例7Example 7
配制0.999L用于内窥镜辅助治疗的注射型水凝胶，注射型水凝胶由海藻酸钠溶液、壳聚糖衍生物溶液、氯化钙溶液、卡波姆940溶胶四种组分按照体积比20:5:1:3组成；Prepare 0.999L of injectable hydrogel for endoscopic auxiliary treatment. The injectable hydrogel consists of four components: sodium alginate solution, chitosan derivative solution, calcium chloride solution, and carbomer 940 sol. The volume ratio is 20:5:1:3;
(1)配制海藻酸钠溶液(1) Prepare sodium alginate solution
室温下，将3.45g海藻酸钠溶解在注射用水中，最后继续补加注射用水并将系统体积定容至690mL，在60℃水浴条件下使其搅拌溶解，即得到海藻酸钠溶液；Dissolve 3.45g sodium alginate in water for injection at room temperature. Finally, continue to add water for injection and adjust the system volume to 690 mL. Stir and dissolve it in a 60°C water bath to obtain a sodium alginate solution;
(2)配制壳聚糖衍生物溶液(2) Prepare chitosan derivative solution
在无菌条件下，将344mg壳聚糖季铵盐加入到注射用水中，60℃水浴条件下使其搅拌溶解，最后补加注射用水并将系统体积定容至172mL，即得到壳聚糖衍生物溶液；Under sterile conditions, add 344 mg of chitosan quaternary ammonium salt to water for injection, stir and dissolve it in a 60°C water bath, and finally add water for injection and adjust the system volume to 172 mL to obtain chitosan derivatives solution;
(3)配制氯化钙溶液(3) Prepare calcium chloride solution
在无菌条件下，将170mg氯化钙、6.8mg靛蓝二磺酸钠加入到注射用水中，室温下搅拌溶解完全，然后补加注射用水并将系统体积定容至34mL，即得到氯化钙溶液；Under sterile conditions, add 170 mg calcium chloride and 6.8 mg sodium indigo disulfonate to water for injection, stir and dissolve completely at room temperature, then add water for injection and adjust the system volume to 34 mL to obtain calcium chloride solution;
(4)配制卡波姆940溶胶(4) Preparation of carbomer 940 sol
在无菌条件下，将206mg卡波姆940在室温下溶解于注射用水中，最后补加注射用水并将系统体积定容至103mL，然后室温下充分溶胀24h后，即得到卡波姆940溶胶；Under sterile conditions, dissolve 206 mg of Carbomer 940 in water for injection at room temperature. Finally, add water for injection and adjust the system volume to 103 mL. Then, after fully swelling at room temperature for 24 hours, Carbomer 940 sol is obtained. ;
(5)按照体积比，先将壳聚糖衍生物溶液与海藻酸钠溶液混合均匀，再加入卡波姆940溶胶并混合均匀，然后以0.15mL/min的速度向体系中滴加氯化钙溶液，边滴加边迅速搅拌均匀，即得，避光保存在5℃下备用。(5) According to the volume ratio, first mix the chitosan derivative solution and the sodium alginate solution evenly, then add carbomer 940 sol and mix evenly, then add calcium chloride dropwise into the system at a speed of 0.15mL/min. The solution is added dropwise and stirred quickly to obtain the solution. Store it away from light at 5°C for later use.
实施例8Example 8
配制1L用于内窥镜辅助治疗的注射型水凝胶，注射型水凝胶由海藻酸钠溶液、壳聚糖衍生物溶液、氯化钙溶液、卡波姆940溶胶四种组分按照体积比20:1:3:1组成；Prepare 1L of injectable hydrogel for endoscopic auxiliary treatment. The injectable hydrogel consists of four components: sodium alginate solution, chitosan derivative solution, calcium chloride solution, and carbomer 940 sol according to volume. It is composed of ratio 20:1:3:1;
(1)配制海藻酸钠溶液(1) Prepare sodium alginate solution
室温下，将8g海藻酸钠，溶解在注射用水中，最后继续补加注射用水并将系统体积定容至800mL，在60℃水浴条件下使其搅拌溶解，即得到海藻酸钠溶液；Dissolve 8g of sodium alginate in water for injection at room temperature. Finally, continue to add water for injection and adjust the system volume to 800mL. Stir and dissolve it in a 60°C water bath to obtain a sodium alginate solution;
(2)配制壳聚糖衍生物溶液(2) Prepare chitosan derivative solution
在无菌条件下，将200mg壳聚糖季铵盐加入到注射用水中，60℃水浴条件下使其搅拌溶解，最后补加注射用水并将系统体积定容至40mL，即得到壳聚糖衍生物溶液Under sterile conditions, add 200 mg of chitosan quaternary ammonium salt to water for injection, stir and dissolve it in a 60°C water bath, and finally add water for injection and adjust the system volume to 40 mL to obtain chitosan derivatives solution
(3)配制氯化钙溶液(3) Prepare calcium chloride solution
在无菌条件下，将1.2g氯化钙、60mg亚甲基蓝加入到注射用水中，室温下搅拌溶解完全，然后补加注射用水并将系统体积定容至120mL，即得到氯化钙溶液；Under sterile conditions, add 1.2g calcium chloride and 60mg methylene blue to water for injection, stir and dissolve completely at room temperature, then add water for injection and adjust the system volume to 120mL to obtain a calcium chloride solution;
(4)配制卡波姆940溶胶(4) Preparation of carbomer 940 sol
在无菌条件下，将200mg卡波姆940在室温下溶解于注射用水中，最后补加注射用水并将系统体积定容至40mL，然后充分溶胀24h后，即得到卡波姆940溶胶；Under sterile conditions, dissolve 200 mg of Carbomer 940 in water for injection at room temperature. Finally, add water for injection and adjust the system volume to 40 mL. After fully swelling for 24 hours, Carbomer 940 sol is obtained;
(5)按照体积比，先将壳聚糖衍生物溶液与海藻酸钠溶液混合均匀，再加入卡波姆940溶胶并混合均匀，然后以0.15mL/min的速度向体系中滴加氯化钙溶液，边滴加边迅速搅拌均匀，即得，避光保存在6℃下备用。(5) According to the volume ratio, first mix the chitosan derivative solution and the sodium alginate solution evenly, then add carbomer 940 sol and mix evenly, then add calcium chloride dropwise into the system at a speed of 0.15mL/min. The solution is added dropwise while stirring rapidly to obtain the solution. Store it away from light at 6°C for later use.
对比例1Comparative example 1
与实施例3的制备方法基本相同，不同之处在于，对比例1中未添加卡波姆940溶胶、壳聚糖衍生物溶液，对比例1中海藻酸钠溶液、氯化钙溶液两者的体积比与实施例1相同。The preparation method is basically the same as that of Example 3. The difference is that in Comparative Example 1, no carbomer 940 sol and chitosan derivative solution were added. In Comparative Example 1, the sodium alginate solution and calcium chloride solution were added. The volume ratio is the same as in Example 1.
对比例2Comparative example 2
与实施例3的制备方法基本相同，不同之处在于，对比例2中未添加卡波姆940溶胶，对比例2中海藻酸钠溶液、壳聚糖衍生物溶液、氯化钙溶液三者的体积比与实施例1相同。The preparation method is basically the same as that of Example 3. The difference is that in Comparative Example 2, no carbomer 940 sol is added. In Comparative Example 2, the sodium alginate solution, chitosan derivative solution, and calcium chloride solution are the same. The volume ratio is the same as in Example 1.
对比例3Comparative example 3
与实施例3的制备方法基本相同，不同之处在于，对比例3中将卡波姆940溶胶替换成了相同质量浓度的透明质酸水溶液，所述透明质酸水溶液是将透明质酸溶解于注射用水中形成的溶液。The preparation method is basically the same as that of Example 3. The difference is that in Comparative Example 3, the carbomer 940 sol is replaced by a hyaluronic acid aqueous solution of the same mass concentration. The hyaluronic acid aqueous solution is made by dissolving hyaluronic acid in Solution formed in water for injection.
对比例4Comparative example 4
与实施例3的制备方法基本相同，不同之处在于，对比例4中将卡波姆940溶胶替换成了相同质量浓度的的明胶水溶液，所述明胶水溶液是将明胶溶解于注射用水中形成的溶液。The preparation method is basically the same as that of Example 3. The difference is that in Comparative Example 4, the carbomer 940 sol is replaced with a gelatin aqueous solution of the same mass concentration. The gelatin aqueous solution is formed by dissolving gelatin in water for injection. solution.
对比例5Comparative example 5
与实施例3的制备方法基本相同，不同之处在于，对比例5中用于内窥镜辅助治疗的注射型水凝胶，按照以下步骤制备；The preparation method is basically the same as that of Example 3, except that the injectable hydrogel used for endoscopic auxiliary treatment in Comparative Example 5 is prepared according to the following steps;
将壳聚糖衍生物溶液与海藻酸钠溶液混合均匀，然后以0.1mL/min的速度向体系中滴加氯化钙溶液，边滴加边迅速搅拌均匀，最后加入卡波姆940溶胶，搅拌均匀后即得，避光保存在4℃下备用。Mix the chitosan derivative solution and sodium alginate solution evenly, then add calcium chloride solution dropwise into the system at a speed of 0.1mL/min, stir quickly while adding, and finally add carbomer 940 sol and stir Once homogeneous, store it at 4°C away from light for later use.
对比例6Comparative example 6
与实施例3的制备方法基本相同，不同之处在于，对比例6中用于内窥镜辅助治疗的注射型水凝胶，按照以下步骤制备；The preparation method is basically the same as that of Example 3, except that the injectable hydrogel used for endoscopic auxiliary treatment in Comparative Example 6 is prepared according to the following steps;
将卡波姆940溶胶与海藻酸钠溶液混合均匀，然后以0.1mL/min的速度向体系中滴加氯化钙溶液，边滴加边迅速搅拌均匀，最后加入壳聚糖衍生物溶液，搅拌均匀后即得，避光保存在4℃下备用。Mix carbomer 940 sol and sodium alginate solution evenly, then add calcium chloride solution dropwise into the system at a speed of 0.1mL/min, stir quickly while adding, and finally add chitosan derivative solution and stir Once homogeneous, store it at 4°C away from light for later use.
对比例7Comparative example 7
与实施例3的制备方法基本相同，不同之处在于，对比例7中卡波姆940溶胶按照以下方法制备：The preparation method is basically the same as that of Example 3, except that in Comparative Example 7, the carbomer 940 sol is prepared according to the following method:
在无菌条件下，将卡波姆940在室温下溶解于注射用水中，搅拌均匀后，即得到卡波姆940溶胶。Under sterile conditions, dissolve Carbopol 940 in water for injection at room temperature, and stir evenly to obtain Carbopol 940 sol.
测试例test case
对实施例3～8以及对比例1～7所获注射凝胶进行相关性能测试，测试内容和方法如下：Relevant performance tests were performed on the injection gels obtained in Examples 3 to 8 and Comparative Examples 1 to 7. The test contents and methods are as follows:
(1)注射凝胶稳定性测定(1) Determination of injection gel stability
将实施例3～8和对比例1～7所获注射凝胶置于离心管中，以2000rpm下离心20min后，静置10min，观察其物理状态。Place the injection gels obtained in Examples 3 to 8 and Comparative Examples 1 to 7 into a centrifuge tube, centrifuge at 2000 rpm for 20 minutes, and then let it stand for 10 minutes to observe its physical state.
(2)注射凝胶可注射性试验(2) Injectability test of injection gel
实施例3～8和对比例1～7的注射凝胶配制完成后，置于单针头注射系统中，注射量为2mL，注射前静置30min，静置完成后，将其注射到体外猪结肠组织皮下黏膜下，记录注射时对注射体系施加的注射推力(单位N)，注：当注射推力超过65N之后已不能完成注射。After the injection gels of Examples 3 to 8 and Comparative Examples 1 to 7 are prepared, they are placed in a single-needle injection system with an injection volume of 2 mL. They are allowed to stand for 30 minutes before injection. After the injection is completed, they are injected into the pig colon outside the body. Tissue subcutaneously and submucosally, record the injection thrust (unit N) exerted on the injection system during injection. Note: When the injection thrust exceeds 65N, the injection cannot be completed.
(3)注射凝胶在黏膜下的支撑性能试验(3) Test on the submucosal support performance of injected gel
实施例3～8和对比例1～7的注射凝胶配制完成后，置于单针头注射系统中，注射到体外猪结肠组织皮下黏膜下，注射量为2mL，注射完，静置2h后测量凝胶垫层在黏膜下的支撑高度。After the injection gels of Examples 3 to 8 and Comparative Examples 1 to 7 are prepared, they are placed in a single-needle injection system and injected into the subcutaneous mucosa of the pig colon tissue in vitro. The injection volume is 2 mL. After the injection is completed, let it stand for 2 hours and then measure. The height of submucosal support of the gel pad.
(4)注射凝胶的抗菌性能试验：(4) Antibacterial performance test of injection gel:
采用大肠杆菌对注射凝胶进行表面抗菌活性检测，将lmL实施例3～8以及对比例1～7所获注射凝胶分别与1mL浓度为10
5CFU/mL的菌液共同培养，并设置空白对照组，孵育24h后取各组菌液于96孔板中，并用酶标仪(波长600nm)测其吸光度，并计算抑菌率AR。
Escherichia coli was used to test the surface antibacterial activity of the injection gel. 1 mL of the injection gel obtained in Examples 3 to 8 and Comparative Examples 1 to 7 were co-cultured with 1 mL of bacterial liquid with a concentration of 10 5 CFU/mL, and a blank was set. For the control group, after incubating for 24 hours, take the bacterial liquid of each group into a 96-well plate, measure its absorbance with a microplate reader (wavelength 600 nm), and calculate the antibacterial rate AR.
抑菌率计算公式如式1所示：The formula for calculating the antibacterial rate is as shown in Equation 1:
其中：AR表示抑菌率，空白对照组吸光度值为空白对照组(未加入注射凝胶的细菌培养液)在600nm处的吸光度值；实验组吸光度值为加入细菌培养液的实验组在600nm处吸光度值。测试结果见表10。Among them: AR represents the antibacterial rate. The absorbance value of the blank control group is the absorbance value at 600nm of the blank control group (bacterial culture medium without injection gel); the absorbance value of the experimental group is the absorbance value of the experimental group with bacterial culture liquid added at 600nm. Absorbance values. The test results are shown in Table 10.
表10 实施例3～8以及对比例1～7所获注射凝胶性能测试结果Table 10 Injection gel performance test results obtained in Examples 3 to 8 and Comparative Examples 1 to 7
以上述依据本发明的理想实施例为启示，通过上述的说明内容，相关工作人员完全可以在不偏离本项发明技术思想的范围内，进行多样的变更以及修改。本项发明的技术性范围并不局限于说明书上的内容，必须要根据权利要求范围来确定其技术性范围。Taking the above-mentioned ideal embodiments of the present invention as inspiration and through the above description, relevant workers can make various changes and modifications without departing from the scope of the technical idea of the present invention. The technical scope of the present invention is not limited to the content in the description, and must be determined based on the scope of the claims.
Claims (24)
- 一种注射型水凝胶，其特征在于，包括以下质量份数的组分：An injectable hydrogel is characterized in that it includes the following components in parts by mass:海藻酸钠0.1～120份，壳聚糖衍生物0.01～20份，氯化钙0.01～15份，卡波姆0.01～9份；0.1 to 120 parts of sodium alginate, 0.01 to 20 parts of chitosan derivatives, 0.01 to 15 parts of calcium chloride, 0.01 to 9 parts of carbomer;所述注射型水凝胶还包括良溶剂，所述良溶剂为海藻酸钠注射用良溶剂、壳聚糖衍生物注射用良溶剂、氯化钙注射用良溶剂和卡波姆注射用良溶剂。The injectable hydrogel also includes a good solvent, and the good solvent is a good solvent for sodium alginate injection, a good solvent for chitosan derivative injection, a good solvent for calcium chloride injection, and a good solvent for carbomer injection. .
- 根据权利要求1所述的注射型水凝胶，其特征在于，所述注射型水凝胶还包括0.01～3份着色剂，所述良溶剂还包括着色剂注射用良溶剂。The injectable hydrogel according to claim 1, wherein the injectable hydrogel further includes 0.01 to 3 parts of colorant, and the good solvent further includes a good solvent for colorant injection.
- 根据权利要求2所述的注射型水凝胶，其特征在于，所述着色剂包括靛蓝二磺酸钠、亚甲基蓝、埃文斯蓝、亮蓝、台盼蓝、甲苯胺蓝中的一种或多种。The injectable hydrogel according to claim 2, wherein the coloring agent includes one of sodium indigo disulfonate, methylene blue, Evans blue, brilliant blue, trypan blue, toluidine blue or Various.
- 根据权利要求1所述的注射型水凝胶，其特征在于，所述壳聚糖衍生物包括壳聚糖季铵盐、烷基化壳聚糖、羧甲基壳聚糖、对羟基苯甲酸壳聚糖酯中的一种或多种。The injectable hydrogel according to claim 1, wherein the chitosan derivatives include chitosan quaternary ammonium salt, alkylated chitosan, carboxymethyl chitosan, p-hydroxybenzoic acid One or more chitosan esters.
- 根据权利要求1所述的注射型水凝胶，其特征在于，所述卡波姆包括卡波姆940、卡波姆941、卡波姆980、卡波姆981、卡波姆971P、卡波姆71G、卡波姆934P、卡波姆1342、卡波姆974P、卡波姆956P、卡波姆5984、卡波姆ETD2020和卡波姆Ultrez10中的一种或多种。The injectable hydrogel according to claim 1, wherein the carbomer includes carbomer 940, carbomer 941, carbomer 980, carbomer 981, carbomer 971P, carbomer One or more of carbomer 71G, carbomer 934P, carbomer 1342, carbomer 974P, carbomer 956P, carbomer 5984, carbomer ETD2020 and carbomer Ultrez10.
- 根据权利要求1所述的注射型水凝胶，其特征在于，所述海藻酸钠注射用良溶剂包括水、氯化钠溶液和磷酸缓冲液中的一种或多种；所述氯化钠溶液的质量百分含量为0.9wt％，所述磷酸缓冲液的pH值为5.5～7.5。The injectable hydrogel according to claim 1, wherein the good solvent for sodium alginate injection includes one or more of water, sodium chloride solution and phosphate buffer; the sodium chloride The mass percentage of the solution is 0.9wt%, and the pH value of the phosphate buffer is 5.5-7.5.
- 根据权利要求1所述的注射型水凝胶，其特征在于，所述壳聚糖衍生物注射用良溶剂和所述氯化钙注射用良溶剂独立地包括水和/或乙醇。The injectable hydrogel according to claim 1, wherein the good solvent for injection of chitosan derivatives and the good solvent for injection of calcium chloride independently include water and/or ethanol.
- 根据权利要求1所述的注射型水凝胶，其特征在于，所述卡波姆注射用良溶剂包括水、乙醇、丙二醇和甘油中的一种或多种。The injectable hydrogel according to claim 1, wherein the good solvent for carbomer injection includes one or more of water, ethanol, propylene glycol and glycerol.
- 根据权利要求2或3所述的注射型水凝胶，其特征在于，所述着色剂注射用良溶剂包括水和/或乙醇。The injectable hydrogel according to claim 2 or 3, wherein the good solvent for colorant injection includes water and/or ethanol.
- 权利要求1～9任一项所述的注射型水凝胶的制备方法，其特征在于，包括以下步骤：The preparation method of the injectable hydrogel according to any one of claims 1 to 9, characterized in that it includes the following steps:将所述注射水凝胶的各组分混合，得到所述注射型水凝胶。Each component of the injectable hydrogel is mixed to obtain the injectable hydrogel.
- 根据权利要求10所述的制备方法，其特征在于，所述注射水凝胶的组分不包括着色剂时，所述混合包括以下步骤：The preparation method according to claim 10, characterized in that when the components of the injection hydrogel do not include colorants, the mixing includes the following steps:在无菌条件下，将海藻酸钠溶解于海藻酸钠注射用良溶剂中，得到海藻酸钠溶液；Under sterile conditions, dissolve sodium alginate in a good solvent for sodium alginate injection to obtain a sodium alginate solution;在无菌条件下，将壳聚糖衍生物溶解于壳聚糖衍生物注射用良溶剂中，得到壳聚糖衍生物溶液；Under sterile conditions, dissolve the chitosan derivative in a good solvent for chitosan derivative injection to obtain a chitosan derivative solution;在无菌条件下，将氯化钙溶解于氯化钙注射用良溶剂中，得到氯化钙溶液，Under sterile conditions, dissolve calcium chloride in a good solvent for calcium chloride injection to obtain a calcium chloride solution.在无菌条件下，将卡波姆溶解于卡波姆注射用良溶剂中后进行溶胀，得到卡波姆溶胶，Under sterile conditions, dissolve carbomer in a good solvent for carbomer injection and then swell to obtain carbomer sol.将所述海藻酸钠溶液、所述壳聚糖衍生物溶液和所述卡波姆溶胶混合得到混合溶液；Mix the sodium alginate solution, the chitosan derivative solution and the carbomer sol to obtain a mixed solution;向所述混合溶液中滴加所述氯化钙溶液。The calcium chloride solution was added dropwise to the mixed solution.
- 根据权利要求11所述的制备方法，其特征在于，所述滴加的速度为0.1～0.15mL/min。The preparation method according to claim 11, characterized in that the dropping speed is 0.1 to 0.15 mL/min.
- 根据权利要求11所述的制备方法，其特征在于，所述海藻酸钠溶液的质量浓度为0.1～60g/L。The preparation method according to claim 11, characterized in that the mass concentration of the sodium alginate solution is 0.1-60g/L.
- 根据权利要求11所述的制备方法，其特征在于，所述壳聚糖衍生物溶液的质量浓度为0.1～40g/L。The preparation method according to claim 11, characterized in that the mass concentration of the chitosan derivative solution is 0.1-40g/L.
- 根据权利要求11所述的制备方法，其特征在于，所述氯化钙溶液的质量浓度为0.1～50g/L。The preparation method according to claim 11, characterized in that the mass concentration of the calcium chloride solution is 0.1-50g/L.
- 根据权利要求11所述的制备方法，其特征在于，所述卡波姆溶胶的质量浓度为0.1～30g/L。The preparation method according to claim 11, characterized in that the mass concentration of the carbomer sol is 0.1-30g/L.
- 根据权利要求11所述的制备方法，其特征在于，制备所述海藻酸钠溶液和制备所述壳聚糖衍生物溶液的溶解温度独立地为20～90℃。The preparation method according to claim 11, characterized in that the dissolution temperatures of preparing the sodium alginate solution and preparing the chitosan derivative solution are independently 20 to 90°C.
- 根据权利要求11或16所述的制备方法，其特征在于，制备所述卡波姆溶胶的溶解温度为20～75℃，制备所述卡波姆溶胶的溶胀温度为室温，制备所述卡波姆溶胶的溶胀时间为24h。The preparation method according to claim 11 or 16, characterized in that the dissolution temperature of the carbomer sol is 20-75°C, the swelling temperature of the carbomer sol is room temperature, and the carbomer sol is prepared at room temperature. The swelling time of Musol is 24h.
- 权利要求10所述的制备方法，其特征在于，所述注射水凝胶的组分包括着色剂时，所述混合包括以下步骤：The preparation method of claim 10, wherein when the components of the injectable hydrogel include a colorant, the mixing includes the following steps:在无菌条件下，将海藻酸钠溶解于海藻酸钠注射用良溶剂中，得到海藻酸钠溶液；Under sterile conditions, dissolve sodium alginate in a good solvent for sodium alginate injection to obtain a sodium alginate solution;在无菌条件下，将壳聚糖衍生物溶解于壳聚糖衍生物注射用良溶剂中，得到壳聚糖衍生物溶液；Under sterile conditions, dissolve the chitosan derivative in a good solvent for chitosan derivative injection to obtain a chitosan derivative solution;在无菌条件下，将氯化钙、着色剂溶解于氯化钙注射用良溶剂和着色剂注射用良溶剂中，得到氯化钙-着色剂溶液，Under sterile conditions, dissolve calcium chloride and colorant in a good solvent for calcium chloride injection and a good solvent for colorant injection to obtain a calcium chloride-colorant solution,在无菌条件下，将卡波姆溶解于卡波姆注射用良溶剂中后进行溶胀，得到卡波姆溶胶，Under sterile conditions, dissolve carbomer in a good solvent for carbomer injection and then swell to obtain carbomer sol.将所述海藻酸钠溶液、所述壳聚糖衍生物溶液和所述卡波姆溶胶混合得到混合溶液；Mix the sodium alginate solution, the chitosan derivative solution and the carbomer sol to obtain a mixed solution;向所述混合溶液中滴加所述氯化钙-着色剂溶液。The calcium chloride-colorant solution was added dropwise to the mixed solution.
- 根据权利要求19所述的制备方法，其特征在于，所述氯化钙-着色剂溶液中，所述着色剂的质量浓度为0.1～10gL。The preparation method according to claim 19, wherein the mass concentration of the colorant in the calcium chloride-colorant solution is 0.1 to 10gL.
- 权利要求1～9任一项所述的注射型水凝胶或权利要求10～20任一项所述的制备方法制备得到的注射型水凝胶作为粘膜下注射液的应用。The injectable hydrogel according to any one of claims 1 to 9 or the injectable hydrogel prepared by the preparation method according to any one of claims 10 to 20 is used as a submucosal injection.
- 根据权利要求21所述的应用，其特征在于，所述粘膜下注射液为内窥镜辅助治疗的粘膜下注射液。The application according to claim 21, characterized in that the submucosal injection is a submucosal injection for endoscopic-assisted treatment.
- 权利要求1～9任一项所述的注射型水凝胶或权利要求10～20任一项所述的制备方法制备得到的注射型水凝胶在内窥镜辅助治疗中的应用。Application of the injectable hydrogel according to any one of claims 1 to 9 or the injectable hydrogel prepared by the preparation method according to any one of claims 10 to 20 in endoscope-assisted treatment.
- 根据权利要求23所述的应用，其特征在于，所述应用为：进行所述内窥镜辅助治疗之前，采用单针头注射体系将注射水凝胶注入病变表面黏膜和黏膜下肌层之间；The application according to claim 23, characterized in that the application is: before performing the endoscopic auxiliary treatment, a single needle injection system is used to inject the injection hydrogel between the diseased surface mucosa and the submucosal muscle layer;所述注射水凝胶为权利要求1～9任一项所述的注射型水凝胶或权利要求10～20任一项所述的制备方法制备得到的注射型水凝胶。The injectable hydrogel is an injectable hydrogel according to any one of claims 1 to 9 or an injectable hydrogel prepared by the preparation method according to any one of claims 10 to 20.
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| PCT/CN2022/087941 WO2023201575A1 (en) | 2022-04-20 | 2022-04-20 | Injection type hydrogel, preparation method therefor, and use of injection type hydrogel as submucosal injection for endoscope adjuvant treatment |
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| US20070078108A1 (en) * | 2003-10-21 | 2007-04-05 | Yaizu Suisankagaku Industry Co., Ltd. | Liquid composition for bulging mucous membrane for use in endoscopic surgery comprising a chitosan derivative containing carbohydrate chains |
| US20120058193A1 (en) * | 2010-09-07 | 2012-03-08 | Dean-Mo Liu | Injectable smart gel and method for fabricating the same |
| US20200114047A1 (en) * | 2017-06-12 | 2020-04-16 | Korea Mcnulty's Co., Ltd. | Liquid-phase composition containing alginic acid or pharmaceutically acceptable salt thereof and colloidal polysaccharide |
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| CN114377214A (en) * | 2022-03-01 | 2022-04-22 | 南京工业大学 | Injectable sodium alginate hydrogel for assisting EMR or ESD operation |
-
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| US20070078108A1 (en) * | 2003-10-21 | 2007-04-05 | Yaizu Suisankagaku Industry Co., Ltd. | Liquid composition for bulging mucous membrane for use in endoscopic surgery comprising a chitosan derivative containing carbohydrate chains |
| US20120058193A1 (en) * | 2010-09-07 | 2012-03-08 | Dean-Mo Liu | Injectable smart gel and method for fabricating the same |
| US20200114047A1 (en) * | 2017-06-12 | 2020-04-16 | Korea Mcnulty's Co., Ltd. | Liquid-phase composition containing alginic acid or pharmaceutically acceptable salt thereof and colloidal polysaccharide |
| CN111759858A (en) * | 2020-06-02 | 2020-10-13 | 杭州英健生物科技有限公司 | PH-sensitive digestive tract mucosa protective gel and application thereof |
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| CN114377214A (en) * | 2022-03-01 | 2022-04-22 | 南京工业大学 | Injectable sodium alginate hydrogel for assisting EMR or ESD operation |
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