Sealing gel and application thereof

Abstract

The invention relates to the technical field of medical sealing gel, in particular to sealing gel and application thereof. The sealing gel provided by the invention comprises an oxidized saccharide compound and acylated polylysine, the oxidation degree of the oxidized saccharide compound is 10-40%, and the grafting rate of the acylated polylysine is 10-40%. When the aldehyde group in the oxidized dextran is in contact with water or liquid, the aldehyde group can be subjected to nucleophilic reaction with the primary amino group in the polylysine to generate a hydrogel adhesive with a cross-linked structure, so that the hydrogel adhesive can be adhered to an ulcer part, and can be used for gelatinizing and physically protecting the wound part and preventing body fluid from running off and being polluted through the wound.

Description

Technical Field

[0001] The present invention relates to the technical field of medical sealing gels, and particularly relates to a sealing gel and its application. Background Art

[0002] Minimally invasive endoscopy is a medical method combining endoscopy technology and minimally invasive surgery, aiming to enter the human body through natural body cavities or small incisions for diagnosis or treatment, reducing the trauma and recovery time caused by traditional open surgery. However, bleeding during endoscopy not only leads to unclear intraoperative vision but also causes serious problems such as postoperative infection or other complications. Currently, the main endoscopy hemostasis techniques are mechanical hemostasis, thermal coagulation hemostasis, or drug hemostasis. However, traditional hemostasis methods are usually complex to operate and the formed tissue is prone to detachment, and even cause secondary ulcers, with the risk of rebleeding. Drug hemostasis is a non-contact hemostasis method, and effective hemostasis can be achieved through methods such as local spraying and injection hemostasis.

[0003] The prior art generally uses a gel material containing a hemostatic drug to stop bleeding at the bleeding site. However, the gel material has poor adhesion, and the gel material is prone to displacement or being washed away by blood flow, resulting in poor hemostasis effect. Summary of the Invention

[0004] Therefore, the technical problem to be solved by the present invention is to overcome the defect of poor adhesion of the sealing gel in the prior art, so as to provide a sealing gel and its application.

[0005] For this purpose, on the one hand, the present invention provides a sealing gel, comprising an oxidized saccharide compound and acylated polylysine, wherein the oxidation degree of the oxidized saccharide compound is 10 - 40%, and the grafting rate of the acylated polylysine is 10 - 40%.

[0006] In some embodiments, the oxidation degree of the oxidized saccharide compound is 20 - 25%; preferably, the oxidation degree of the oxidized saccharide compound is 25%.

[0007] In some embodiments, the grafting rate of the acylated polylysine is 10 - 30%. Preferably, the grafting rate of the acylated polylysine is 25%.

[0008] It should be noted that the present invention does not limit the determination of the oxidation degree of the oxidized saccharide compound in the embodiments, as long as the oxidation degree parameter of the oxidized saccharide compound can be determined. For example, taking oxidized dextran as an example, the present invention measures the oxidation degree by the iodometric method. Add 10 mL of a 1 w / v % aqueous solution of oxidized dextran (dissolved in distilled water at 60°C, cooled to 25°C, and diluted to an appropriate volume with water) to 20 mL of I 2In a solution (0.05 mol / L), 20 mL of sodium hydroxide solution (1 mol / L) was then added. The oxidation reaction was carried out at 25 °C for 15 min. After adding 15 mL of sulfuric acid (6.25 v / v %), using a drop of an aqueous solution containing 20 w / w % dextran as an indicator, 0.1 mol / L sodium thiosulfate was used to titrate the aldehyde group and I 2 The I consumed in the reaction 2 , where 1 mol of aldehyde group reacts with 1 mol of I 2 to form carboxylic acid under alkaline conditions, and mol of I 2 reacts with 2 mol of S 2 O 3 2- ion reaction. Three readings were taken for each titration, and the average value was taken as the final result.

[0009] In some of these embodiments, the mass ratio of the oxidized saccharide compound to the acylated polylysine is 1.5:1 - 50, preferably 1.5:1 - 20.

[0010] In some of these embodiments, the saccharide compound includes at least one of dextran and sucrose. Preferably, the dextran includes dextran, and more preferably, the type of dextran is at least one of Dextran 20, Dextran 40, and Dextran 70.

[0011] In some of these embodiments, the method for preparing the oxidized saccharide compound includes the following steps: mixing an aqueous solution of a saccharide compound and an oxidant for reaction, and purifying to obtain the oxidized saccharide compound, wherein the mass ratio of the saccharide compound to the oxidant is 20:3 - 13, and preferably, the mass ratio of the saccharide compound to the oxidant is 20:3 - 12.4.

[0012] In some of these embodiments, the oxidant includes at least one of periodate and hydrogen peroxide. Preferably, the periodate includes at least one of potassium periodate and sodium periodate.

[0013] In some of these embodiments, under a stirring state, an aqueous solution of a saccharide compound and an oxidant are mixed for reaction. The rotation speed of the stirring is 400 - 800 rpm, the stirring time is 1 - 36 h, and the reaction temperature is 10 - 70 °C.

[0014] In some of these embodiments, the step of purifying the reaction product of the aqueous solution of the saccharide compound and the oxidant includes dialysis. The cut-off molecular weight of the dialysis bag is 3500 - 5000 Da, and the dialysis time is 16 - 72 h.

[0015] In some of these embodiments, the method for preparing the oxidized saccharide compound further includes the step of drying the oxidized saccharide compound.

[0016] In some embodiments, the method for preparing the acylated polylysine comprises the following steps: reacting an aqueous solution of polylysine with an acid anhydride and purifying to obtain the acylated polylysine, wherein the mass ratio of the acid anhydride to polylysine is 0.1-0.7:1, preferably 0.14-0.66:1.

[0017] In some embodiments, the acid anhydride includes at least one of acetic anhydride, succinic anhydride, and maleic anhydride.

[0018] In some embodiments, the polylysine includes ε-polylysine.

[0019] In some embodiments, the reaction of the aqueous solution of polylysine with the acid anhydride is carried out under stirring, the rotation speed of the stirring is 400-800 rpm, the stirring time is 1-36 h, and the reaction temperature is 10-70 °C.

[0020] In some embodiments, the step of purifying the reaction product of the aqueous solution of polylysine and the acid anhydride includes dialysis. The cut-off molecular weight of the dialysis bag is 3500-5000 Da, and the dialysis time is 16-72 h.

[0021] In some embodiments, the method for preparing the acylated polylysine further includes a step of freeze-drying the acylated polylysine.

[0022] In some embodiments, the sealing gel further includes excipients, and the excipients include at least one of disintegrants, excipients, and lubricants; the disintegrants include at least one of sodium carboxymethyl starch, cross-linked carboxymethyl cellulose sodium, cross-linked povidone, starch, low-substituted hydroxypropyl cellulose, and polyvinylpyrrolidone, pyrrole, wherein the substitution degree of the low-substituted hydroxypropyl cellulose is 13.0-15.9%; the excipients include at least one of lactose pregelatinized starch, mannitol, microcrystalline cellulose, sucrose, lactose, sodium chloride, and calcium sulfate; the lubricants include at least one of magnesium stearate, sodium lauryl sulfate, silica, and talc.

[0023] In some embodiments, the mass fraction of the disintegrant in the sealing gel is 2-6%; the mass fraction of the excipient is 3.8-3.9%; the mass fraction of the color developer is 0.03-0.04%; the mass fraction of the lubricant is 0.2-0.4%.

[0024] The excipients further include preservatives and color developers; the preservatives include at least one of potassium sorbate, chitosan, or sucrose; the color developers include at least one of brilliant blue, bromocresol green, prussian blue, and sodium fluorescein.

[0025] On the other hand, the sealing gel provided by the present invention can be applied to minimally invasive endoscopic surgery. Preferably, the minimally invasive endoscope includes a digestive endoscope.

[0026] The technical solution of the present invention has the following advantages: 1. A sealing gel provided by the present invention includes an oxidized saccharide compound and acylated polylysine. The oxidation degree of the oxidized saccharide compound is 10 - 40%, and the grafting rate of the acylated polylysine is 10 - 40%. When the aldehyde group in the oxidized saccharide compound contacts water or liquid, it can undergo a nucleophilic reaction with the primary amino group in polylysine to produce a cross-linked hydrogel adhesive. While adhering to the ulcer site, it can also gelify, physically protecting the wound site and preventing body fluids from leaking and being contaminated through the wound.

[0027] 2. For a sealing gel provided by the present invention, the oxidation degree of the oxidized saccharide compound is 20 - 25%. The present invention utilizes the oxidized saccharide compound with an oxidation degree of 20 - 25% to form a sealing gel, which can control the degradation time of the sealing gel within 2 - 5 days, enabling the sealing gel to degrade while meeting the hemostatic effect, so as to be applicable to different application scenarios, especially applicable to the application in minimally invasive endoscopy.

[0028] 3. Application of the sealing gel provided by the present invention in minimally invasive endoscopic surgery. The sealing gel provided by the present invention has small particles, which facilitates the sealing gel to be placed into the catheter through the endoscope. At the same time, the sealing gel gels quickly, has a high hemostasis efficiency, and can degrade within 2 - 5 days, that is, it meets the hemostatic effect and can achieve effective degradation.

[0029] 4. The sealing gel provided by the present invention can be sprayed through the endoscope, and the sealing gel is transported by the catheter to be sprayed on the bleeding site, so as to achieve hemostasis of the lesion during the operation, avoiding secondary damage to the lesion. At the same time, the sealing gel provided by the present invention has a short gelling time and strong adhesion, not only significantly improving the hemostatic effect, but also avoiding the movement of the sealing gel caused by liquid flow. Description of the Drawings

[0030] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the following drawings are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0031] Figure 1 is a physical diagram of the sealing gel formed in Example 1 of the present invention; Figure 2 is a physical diagram of the gel-like sealing gel in Example 1 of the present invention; Figure 3 It is a schematic structural diagram of the fixture in Experimental Example 2 of the present invention; Figure 4 It is a physical diagram of the hemostasis of the ulcer by spraying the sealing gel on the artificial gastric ulcer in Experimental Example 5 of the present invention; Reference numerals: 1 - clamping rod; 2 - bonding plane; 3 - substrate. Detailed implementation manners

[0032] The following embodiments are provided to better further understand the present invention. It is not limited to the described optimal implementation manner, and does not constitute a limitation to the content and protection scope of the present invention. Any product that is the same as or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with those of other existing technologies falls within the protection scope of the present invention.

[0033] For those embodiments where specific experimental steps or conditions are not indicated, the operations or conditions of the conventional experimental steps described in the literature in this field can be followed. For the reagents or instruments whose manufacturers are not indicated, they are all conventional reagent products that can be obtained through commercial purchase.

[0034] In the embodiments of the present invention, the model of dextran is taken as Dextran 70, and polylysine is taken as ε - polylysine.

[0035] Preparation Example 1 This preparation example provides a preparation method of an oxidized saccharide compound. The specific steps and methods are as follows: (1) Dissolve 20 g of dextran in 100 mL of distilled water to form a mixed solution A; (2) Dissolve 7.0 g of sodium periodate in 40 mL of distilled water to form a mixed solution B. At 70 °C, mix and stir the mixed solution A and the mixed solution B at a rotation speed of 400 rpm (the rotation speed is set to 400 rpm) for 1 h to form a mixed solution C; (3) Use a cellulose dialysis bag with a cut-off molecular weight of 3500 Da to dialyze the mixed solution C for 16 h, then place the dialyzed solution at 40 °C and air-dry it for 48 h, and then vacuum-dry it at 25 °C for 24 h. Mechanically crush the obtained product into fine powder with a particle size of 50 - 500 microns, and thoroughly dry it under vacuum at 50 °C for 24 h to obtain oxidized dextran with an oxidation degree of 25%. Among them, the measurement method of the oxidation degree of dextran is measured by the iodometric method.

[0036] Preparation Example 2 This preparation example provides a preparation method of an oxidized saccharide compound. The specific steps and methods are the same as those in Preparation Example 1, except that the amount of sodium periodate in step (2) is 3.0 g.

[0037] Obtain oxidized dextran with an oxidation degree of 10%.

[0038] Preparation Example 3 This preparation example provides a method for preparing an oxidized saccharide compound. The specific steps and methods are the same as those in Preparation Example 1, except that the amount of sodium periodate in step (2) is 5.6 g.

[0039] Obtain oxidized dextran with an oxidation degree of 20%.

[0040] Preparation Example 4 This preparation example provides a method for preparing an oxidized saccharide compound. The specific steps and methods are the same as those in Preparation Example 1, except that the amount of sodium periodate in step (2) is 9.0 g.

[0041] Obtain oxidized dextran with an oxidation degree of 30%.

[0042] Preparation Example 5 This preparation example provides a method for preparing an oxidized saccharide compound. The specific steps and methods are the same as those in Preparation Example 1, except that the amount of sodium periodate in step (2) is 12.4 g.

[0043] Obtain oxidized dextran with an oxidation degree of 40%.

[0044] Preparation Example 6 This preparation example provides a method for preparing acylated polylysine. The specific steps and methods are as follows: (1) Add polylysine to water to make the concentration of polylysine in water 0.1 g / mL, and stir at 400 rpm for 0.5 h at 25 °C; (2) Add succinic anhydride to the solution obtained in step (1), and stir and react at 400 rpm at 70 °C for 1 h, where the mass ratio of succinic anhydride to polylysine is 0.34:1; (3) After the reaction is completed, dialyze the reaction solution through a cellulose dialysis bag with a molecular weight cut-off of 3500 Da for 16 h, and then freeze-dry for 24 h. Confirm the chemical structure of the compound by HNMR (400 MHz, Bruker) to obtain acylated polylysine with a grafting rate of 25%.

[0045] Preparation Example 7 This preparation example provides a method for preparing acylated polylysine. The specific steps and methods are the same as those in Preparation Example 6, except that the mass ratio of succinic anhydride to polylysine in step (2) is 0.14:1.

[0046] Obtain acylated polylysine with a grafting rate of 10%.

[0047] Preparation Example 8 This Preparation Example provides a method for preparing acylated polylysine. The specific steps and methods are the same as those in Preparation Example 6, except that in step (2), the mass ratio of succinic anhydride to polylysine is 0.28:1.

[0048] Acylated polylysine with a grafting rate of 20% was obtained.

[0049] Preparation Example 9 This Preparation Example provides a method for preparing acylated polylysine. The specific steps and methods are the same as those in Preparation Example 6, except that in step (2), the mass ratio of succinic anhydride to polylysine is 0.46:1.

[0050] Acylated polylysine with a grafting rate of 30% was obtained.

[0051] Preparation Example 10 This Preparation Example provides a method for preparing acylated polylysine. The specific steps and methods are the same as those in Preparation Example 6, except that in step (2), the mass ratio of succinic anhydride to polylysine is 0.66:1.

[0052] Acylated polylysine with a grafting rate of 40% was obtained.

[0053] Preparation Example 11 This Preparation Example provides a method for preparing oxidized saccharide compounds. The specific steps and methods are as follows: (1) Dissolve 20 g of dextran in 100 mL of distilled water to form a mixed solution A; (2) Dissolve 7.0 g of potassium periodate in 40 mL of distilled water to form a mixed solution B. At 10 °C, mix and stir the mixed solution A and the mixed solution B at a rotation speed of 500 rpm for 36 h to form a mixed solution C; (3) Use a cellulose dialysis bag with a cut-off molecular weight of 5000 Da to dialyze the mixed solution C for 72 h. Then, place the dialyzed solution at 40 °C and air-dry it for 48 h, and then vacuum-dry it at 25 °C for 24 h. Mechanically crush the obtained product into fine powder with a particle size of 50 - 500 microns, and thoroughly dry it under vacuum at 50 °C for 24 h to obtain oxidized dextran with an oxidation degree of 25%. Among them, the measurement method of the oxidation degree of dextran is measured by the iodometric method.

[0054] Preparation Example 12 This Preparation Example provides a method for preparing oxidized saccharide compounds. The specific steps and methods are as follows: (1) Dissolve 20 g of dextran in 100 mL of distilled water to form a mixed solution A; (2) Dissolve 7.0 g of hydrogen peroxide in 40 mL of distilled water to form mixture B. At 30 °C and a rotation speed of 700 rpm, mix and stir mixture A and mixture B for 5 h to form mixture C; (3) Use a cellulose dialysis bag with a molecular weight cut-off of 4000 Da to dialyze mixture C for 16 h. Then place the dialyzed solution at 40 °C and air-dry it for 48 h, and then vacuum-dry it at 25 °C for 24 h. Mechanically crush the obtained product into fine powder with a particle size of 50 - 500 microns, and thoroughly dry it under vacuum at 50 °C for 24 h to obtain oxidized dextran with an oxidation degree of 25%. Among them, the measurement method of the oxidation degree of dextran is measured by the iodometric method.

[0055] Preparation Example 13 This preparation example provides a method for preparing acylated polylysine, and the specific steps and methods are as follows: (1) Add polylysine to water to make the concentration of polylysine in water 0.1 g / mL, and stir at 25 °C and a rotation speed of 500 rpm for 0.5 h; (2) Add acetic anhydride to the solution prepared in step (1), and stir and react at 10 °C and a rotation speed of 500 rpm for 36 h. Among them, the mass ratio of succinic anhydride to polylysine is 0.34:1; (3) After the reaction is completed, dialyze the reaction solution through a cellulose dialysis bag with a molecular weight cut-off of 5000 Da for 48 h, then freeze-dry it for 24 hours, and confirm the chemical structure of the compound by HNMR (400 MHz, Bruker) to obtain acylated polylysine with a grafting rate of 25%.

[0056] Preparation Example 14 This preparation example provides a method for preparing acylated polylysine, and the specific steps and methods are as follows: (1) Add polylysine to water to make the concentration of polylysine in water 0.1 g / mL, and stir at 25 °C and a rotation speed of 400 rpm for 0.5 h; (2) Add maleic anhydride to the solution prepared in step (1), and stir and react at 30 °C and a rotation speed of 800 rpm for 15 h. The mass ratio of maleic anhydride to polylysine is 0.34:1; (3) After the reaction is completed, dialyze the reaction solution through a cellulose dialysis bag with a molecular weight cut-off of 4500 Da for 72 h, then freeze-dry it for 24 hours, and confirm the chemical structure of the compound by HNMR (400 MHz, Bruker) to obtain acylated polylysine with a grafting rate of 25%.

[0057] Example 1 This example provides a method for preparing a sealing gel, and the specific steps and parameters are as follows: Take 1.5 g of oxidized dextran, 1.5 g of acylated polylysine, 0.06 g of starch, 0.12 g of lactose, 0.9 mg of brilliant blue, 0.09 g of polyvinylpyrrolidone, and 0.01 g of sodium stearate, and mix them evenly by stirring to obtain a sealed gel. Among them, the oxidized dextran is the oxidized dextran with an oxidation degree of 25% prepared in Preparation Example 1, and the acylated polylysine is the acylated polylysine with a grafting rate of 25% prepared in Preparation Example 6.

[0058] See the physical picture of the sealed gel in Figure 1 ; Spray 3 g of the sealed gel into 10 mL of water, and the sealed gel quickly becomes gel-like. See Figure 2 .

[0059] Example 2 This example provides a method for preparing a sealed gel. The specific steps and parameters are the same as those in Example 1, except that the amount of acylated polylysine is 5 g.

[0060] Example 3 This example provides a method for preparing a sealed gel. The specific steps and parameters are the same as those in Example 1, except that the amount of acylated polylysine is 10 g.

[0061] Example 4 This example provides a method for preparing a sealed gel. The specific steps and parameters are the same as those in Example 1, except that the amount of acylated polylysine is 20 g.

[0062] Example 5 This example provides a method for preparing a sealed gel. The specific steps and parameters are the same as those in Example 1, except that the amount of acylated polylysine is 50 g.

[0063] Example 6 This example provides a method for preparing a sealed gel. The specific steps and parameters are the same as those in Example 3, except that the oxidized dextran is the oxidized dextran with an oxidation degree of 10% prepared in Preparation Example 2.

[0064] Example 7 This example provides a method for preparing a sealed gel. The specific steps and parameters are the same as those in Example 3, except that the oxidized dextran is the oxidized dextran with an oxidation degree of 20% prepared in Preparation Example 3.

[0065] Example 8 This example provides a method for preparing a sealed gel. The specific steps and parameters are the same as those in Example 3, except that the oxidized dextran is the oxidized dextran with an oxidation degree of 30% prepared in Preparation Example 4.

[0066] Example 9 This example provides a method for preparing a sealing gel. The specific steps and parameters are the same as those in Example 3, except that the oxidized dextran is the oxidized dextran with a 40% oxidation degree prepared in Preparation Example 5.

[0067] Example 10 This example provides a method for preparing a sealing gel. The specific steps and parameters are the same as those in Example 3, except that the acylated polylysine is the acylated polylysine with a grafting rate of 10% prepared in Preparation Example 7.

[0068] Example 11 This example provides a method for preparing a sealing gel. The specific steps and parameters are the same as those in Example 3, except that the acylated polylysine is the acylated polylysine with a grafting rate of 20% prepared in Preparation Example 8.

[0069] Example 12 This example provides a method for preparing a sealing gel. The specific steps and parameters are the same as those in Example 3, except that the acylated polylysine is the acylated polylysine with a grafting rate of 30% prepared in Preparation Example 9.

[0070] Example 13 This example provides a method for preparing a sealing gel. The specific steps and parameters are the same as those in Example 3, except that the acylated polylysine is the acylated polylysine with a grafting rate of 40% prepared in Preparation Example 10.

[0071] Example 14 This example provides a method for preparing a sealing gel. The specific steps and parameters are as follows: Take 1.5 g of oxidized dextran, 1.5 g of acylated polylysine, 0.06 g of low-substituted hydroxypropyl cellulose (substitution degree of 15.9%), and 0.12 g of lactose, and mix them evenly by stirring to obtain a sealing gel. Among them, the oxidized dextran is the oxidized dextran with a 25% oxidation degree prepared in Preparation Example 1, and the acylated polylysine is the acylated polylysine with a grafting rate of 25% prepared in Preparation Example 6.

[0072] Example 15 This example provides a method for preparing a sealing gel. The specific steps and parameters are as follows: Take 1.5 g of oxidized dextran, 1.5 g of acylated polylysine, 0.19 g of low-substituted hydroxypropyl cellulose (substitution degree of 13%), and 0.12 g of lactose, and mix them evenly by stirring to obtain a sealing gel. Among them, the oxidized dextran is the oxidized dextran with an oxidation degree of 25% prepared in Preparation Example 1, and the acylated polylysine is the acylated polylysine with a grafting rate of 25% prepared in Preparation Example 6.

[0073] Comparative Example 1 This comparative example provides a method for preparing a sealing gel. The specific steps and parameters are the same as those in Example 3, except that the oxidation degree of the oxidized dextran is 5%.

[0074] The method for preparing the oxidized dextran is the same as that in Preparation Example 1, except that the mass of sodium periodate is 1.5 g.

[0075] Comparative Example 2 This comparative example provides a method for preparing a sealing gel. The specific steps and parameters are the same as those in Example 3, except that the oxidation degree of the oxidized dextran is 45%.

[0076] The method for preparing the oxidized dextran is the same as that in Preparation Example 1, except that the mass of sodium periodate is 15.2 g.

[0077] Comparative Example 3 This comparative example provides a method for preparing a sealing gel. The specific steps and parameters are the same as those in Example 3, except that the grafting rate of the acylated polylysine is 5%.

[0078] The method for preparing the oxidized dextran is the same as that in Preparation Example 6, except that the mass ratio of succinic anhydride to polylysine is 0.070:1.

[0079] Comparative Example 4 This comparative example provides a method for preparing a sealing gel. The specific steps and parameters are the same as those in Example 3, except that the grafting rate of the acylated polylysine is 45%.

[0080] The method for preparing the acylated polylysine is the same as that in Preparation Example 6, except that the mass ratio of succinic anhydride to polylysine is 0.72:1.

[0081] Comparative Example 5 This comparative example provides a method for preparing a sealing gel. The specific steps and parameters are the same as those in Example 3, except that the oxidation degree of the oxidized dextran is 5% and the grafting rate of the acylated polylysine is 5%.

[0082] The method for preparing the acylated polylysine is the same as that in Preparation Example 6, except that the mass ratio of succinic anhydride to polylysine is 0.070:1.

[0083] The method for preparing the oxidized dextran is the same as that in Preparation Example 1, except that the mass of sodium periodate is 1.50 g.

[0084] Comparative Example 6 This comparative example provides a method for preparing a sealing gel. The specific steps and parameters are the same as those in Example 3, except that the oxidation degree of oxidized dextran is 45%, and the grafting rate of acylated polylysine is 45%.

[0085] The preparation method of the acylated polylysine is the same as that in Preparation Example 6, except that the mass ratio of succinic anhydride to polylysine is 0.72:1.

[0086] The preparation method of the oxidized dextran is the same as that in Preparation Example 1, except that the mass of sodium periodate is 15.2 g.

[0087] Experimental Example 1 The particle sizes of the sealing gels prepared in Examples 1-15 and Comparative Examples 1-6 and two commercial products on the market were measured using a laser particle size analyzer (Bettersize2600). The results are shown in Table 1.

[0088] Experimental Example 2 The adhesion of the sealing gels prepared in Examples 1-15 and Comparative Examples 1-6 and two commercial products on the market was detected. The main raw materials of the two commercial products on the market are fibrin adhesives. The detection results are shown in Table 1.

[0089] The detection method is as follows: 1. Take 8.298 g of sodium chloride and 0.368 g of calcium chloride dihydrate into 1 L of ultrapure water, and stir well to dissolve the above materials to obtain a wound simulation solution. This solution contains 142 mmol of sodium ions and 2.5 mmol of calcium ions, which is equivalent to human serum or wound exudate.

[0090] 2. Place the outer epidermis of the pigskin downward on a gauze soaked in phosphate buffer solution (PBS, pH 7.4 ± 0.2), and use a knife to remove the inner epidermal fat layer completely. The thickness after removing the fat layer should be ≤ 5 mm, and then spray PBS on the inner epidermis of the pigskin to keep it moist.

[0091] 3. Cut the pigskin into squares of 2.5 cm (±0.005 cm) × 2.5 cm (±0.005 cm), and 2 pieces are required for each group of detections and used in parallel.

[0092] 4. Take one piece of pigskin, remove the PBS on the outer surface with filter paper, stick the outer surface on the edge of the test fixture with 502 glue, and press moderately to cure for about 10 min. Operate on the other piece of pigskin in the same way.

[0093] 5. Weigh 0.3 g of hemostatic powder and mix it with 0.45 mL of the wound simulation solution formed in step (1) of this experimental example to form a gel, and stirring can be used to accelerate the formation.

[0094] 6. Apply the sealing gel evenly on the inner surface of a piece of fixed pigskin (to ensure even adhesion without overflowing to the edge of the pigskin), then bond the two pieces of pigskin together and gently press for 5 minutes.

[0095] 7. Turn on the testing equipment of the material testing machine, open the adhesion testing method, confirm the tensile speed (2 mm / min) parameter in the method, and start the test after confirmation.

[0096] 8. Place the specimen in the fixture of the material testing machine. For the fixture schematic diagram, refer to Figure 3 . Specifically, use the two bonded pieces of pigskin as the substrate 3 and attach them to the bonding plane 2, fix them in the testing machine with the clamping rod 1, make the force direction perpendicular to the bonding surface, and load the specimen with the upper fixture at a speed of 2 mm / min until failure. Observe the maximum force value at the time of failure, which is the adhesion force, and record it. Conduct 3 parallel tests and record the average value.

[0097] Experimental Example 3 Pour 3 g of the sealing gel into a petri dish containing 15 ml of deionized water and start timing. Stop timing after obtaining the gel. The measured time is the gel formation time. The test results are shown in Table 1, where the sealing gel is the sealing gel prepared in Examples 1-15 and Comparative Examples 1-6.

[0098] Experimental Example 4 Respectively add the sealing gels prepared in Examples 1-15 and Comparative Examples 1-6 into glass tubes (with a diameter of 16 mm) containing 3 ml of PBS buffer solution, seal the test tubes, and let them stand at 37°C. Record the time when the sealing gel is fully degraded.

[0099] During the degradation process, after a certain period of time, remove the supernatant, rinse the remaining gel with distilled water. If there is still gel remaining, continue to soak the sealing gel with PBS buffer solution until there is no gel remaining. Record the degradation time. Repeat each sample 3 times and take the average value.

[0100] Table 1 Test Results of Sealing Gel Performance

[0101] According to the data in Table 1, it can be seen that compared with the sealing gels provided in Comparative Examples 1-6 and commercially available products 1 and 2, the sealing gel formed by the saccharide compound with an oxidation degree of 10-40% and the acylated polylysine with a grafting rate of 10-40% selected in the examples of the present invention has a stronger adhesion force, a short gel formation time, and at the same time, the sealing gel provided in the examples of the present invention has good degradation performance.

[0102] In terms of the effect of adhesion, as the oxidation degree of the oxidized saccharide compound gradually increases, the adhesion of the sealing gel first increases and then decreases. As the grafting rate of acylated polylysine gradually increases, the adhesion of the sealing gel first decreases, then increases, and then decreases. Therefore, when the oxidation degree of the oxidized saccharide compound is 20-25% and the grafting rate of acylated polylysine is 10-30%, the formed sealing gel has strong adhesion. In terms of the effect of gelation time, as the oxidation degree of the oxidized saccharide compound gradually increases, the gelation time of the sealing gel gradually prolongs. As the grafting rate of acylated polylysine gradually increases, the gelation time of the sealing gel changes little. Therefore, generally speaking, when the oxidation degree of the oxidized saccharide compound is 20-25% and the grafting rate of acylated polylysine is 10-30%, the formed sealing gel has strong adhesion and short gelation time. In terms of degradation time, as the oxidation degree of the oxidized saccharide compound gradually increases, the degradation time of the sealing gel gradually shortens. When the oxidation degree of the oxidized dextran is 20-25%, the formed sealing gel can control the degradation time of the sealing gel within 2-5 days, so that the sealing gel can be degraded on the premise of meeting the hemostatic effect, so as to be more suitable for digestive endoscopy.

[0103] Experimental Example 5 Method for constructing artificial gastric ulcer model: Before endoscopic examination, heparin (200 IU / kg) was injected intravenously. The endoscope was inserted into the stomach when the animal was in the lateral position. The target area was marked with an argon plasma coagulator, and then isotonic saline was injected into the submucosa. An artificial gastric ulcer of about 2 cm in size was created by endoscopic submucosal dissection (ESD). Two gastric ulcers were created in each animal. To maximize bleeding, no hemostasis was performed during ESD.

[0104] Experimental steps: Take 3 g of the sealing gel prepared in Example 3 and spray it on the bleeding site, and record the hemostasis time. The physical diagram of this experimental example is shown in Figure 4 .

[0105] The hemostasis time recorded in this experimental example was 2 minutes, which proved that the sealing gel provided by the present invention can effectively stop bleeding and has a short hemostasis time.

[0106] Obviously, the above embodiments are only examples clearly described and not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to enumerate all the implementation manners here. And the obvious changes or modifications derived therefrom are still within the protection scope of the present invention.

Claims

1. A sealing gel, characterized in that: including oxidized carbohydrates and acylated polylysine, The oxidation degree of the oxidized sugar compound is 10-40%, and the grafting rate of the acylated polylysine is 10-40%.

2. The sealing gel according to claim 1, characterized in that The oxidation degree of the oxidized sugar compound is 20-25%; and / or, The grafting rate of the acylated polylysine is 10-30%.

3. The sealing gel according to claim 2, characterized in that: The oxidation degree of the oxidized sugar compound is 25%; and / or, The grafting rate of the acylated polylysine is 25%; and / or, The sugar compound includes at least one of dextran and sucrose.

4. The sealing gel according to claim 3, characterized in that The mass ratio of the oxidized carbohydrate compound to the acylated polylysine is 1.5:1-50; and / or, The glucan includes dextran.

5. The sealing gel according to any one of claims 1 to 4, characterized in that: The method for preparing the oxidized sugar compound comprises the following steps: mixing a sugar compound aqueous solution and an oxidant for reaction, and purifying to obtain the oxidized sugar compound, wherein the mass ratio of the sugar compound to the oxidant is 20:3-13.

6. The sealing gel according to claim 5, characterized in that The oxidant comprises at least one of periodate and hydrogen peroxide; and / or, Under stirring, the sugar compound aqueous solution and the oxidant are mixed and reacted, the stirring speed is 400-800 rpm, the stirring time is 1-36 hours, and the reaction temperature is 10-70° C.; and / or, The step of purifying the mixed reaction product of the saccharide compound aqueous solution and the oxidant comprises dialysis, wherein the molecular weight cutoff of the dialysis bag used for dialysis is 3500-5000Da, and the dialysis time is 16-72h; and / or, The method for preparing the oxidized carbohydrate compound further comprises the step of drying the oxidized dextran.

7. The sealing gel according to any one of claims 1 to 4, characterized in that: The method for preparing the acylated polylysine comprises the following steps: reacting a polylysine aqueous solution with an acid anhydride, and purifying the polylysine to obtain the acylated polylysine, wherein the mass ratio of the acid anhydride to the polylysine is 0.1-0.7:

1.

8. The sealing gel according to claim 7, characterized in that The acid anhydride comprises at least one of acetic anhydride, succinic anhydride and maleic anhydride; and / or, The polylysine comprises ε-polylysine; and / or, Under stirring, reacting the polylysine aqueous solution and the acid anhydride, the stirring speed is 400-800 rpm, the stirring time is 1-36 hours, and the reaction temperature is 10-70° C.; and / or, The step of purifying the reaction product of the polylysine aqueous solution and the acid anhydride comprises dialysis, wherein the molecular weight cutoff of the dialysis bag used for dialysis is 3500-5000Da, and the dialysis time is 16-72h; and / or, The method for preparing the acylated polylysine further comprises the step of freeze-drying the acylated polylysine.

9. The sealing gel according to claim 1, characterized in that: The sealing gel further comprises auxiliary materials, and the auxiliary materials comprise at least one of a disintegrant, an excipient and a lubricant.

10. The sealing gel according to claim 9, characterized in that The auxiliary materials also include preservatives, color developers; and / or, The disintegrant comprises at least one of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, starch, low-substituted hydroxypropyl cellulose, and polyvinyl pyrrolidone, wherein the degree of substitution of the low-substituted hydroxypropyl cellulose is 13.0-15.9%; and / or, The excipients include at least one of lactose pregelatinized starch, mannitol, microcrystalline cellulose, sucrose, lactose, sodium chloride, and calcium sulfate; and / or, The lubricant comprises at least one of magnesium stearate, sodium lauryl sulfate, silicon dioxide and talc; and / or, The color developing agent comprises at least one of brilliant blue, bromocresol green, Prussian blue and sodium fluorescein; and / or, The mass fraction of the disintegrant in the sealed gel is 2-6%; and / or, The mass fraction of the excipient is 3.8-3.9%; and / or, The mass fraction of the developer is 0.03-0.04%; and / or, The mass fraction of lubricant is 0.2-0.4%.

11. Use of the sealing gel according to any one of claims 1 to 10 in minimally invasive endoscopic surgery.

12. The use according to claim 11, characterized in that: The minimally invasive endoscope includes a digestive endoscope.

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