A surgical anti-adhesion biological polysaccharide flushing gel and a preparation method thereof

Abstract

This invention discloses a surgical anti-adhesion biopolysaccharide irrigation solution and its preparation method, which is prepared from the following raw materials in parts by weight: 5-30 parts of sodium carboxymethyl cellulose, 0.1-5 parts of polyethylene oxide with a molecular weight of 1.5 million to 2 million Daltons, 2-16 parts of sodium hyaluronate with a molecular weight of 1.2 million to 2 million Daltons, and 80-100 parts of water for injection. The preparation method includes alkalization of natural plant fibers, carboxymethylation modification of natural plant fibers, dissolution and mixing of the anti-adhesion solution, emulsification treatment, and sterilization and filling. High-purity sodium carboxymethyl cellulose is prepared from natural plant fibers through a modification process, serving as the basic framework of the adhesive solution. In vivo, it can remain incompletely degraded during the adhesion cycle, ensuring the stability of the physical barrier. Sodium hyaluronate with a molecular weight suitable for anti-adhesion effect and polyethylene oxide that increases the strength and adhesion of the irrigation solution are screened to form a synergistic system with sodium carboxymethyl cellulose that degrades synchronously and has complementary strength.

Description

Technical Field

[0001] This invention relates to the field of clinical medical technology, specifically to a surgical anti-adhesion biopolysaccharide irrigation solution and its preparation method. Background Technology

[0002] Postoperative tissue adhesions are a long-standing and critical challenge in clinical medicine. These adhesions are pathological fibrous connections caused by surgical trauma and can occur widely in the abdominal cavity, pericardium, tendons, and pelvis, with an incidence rate as high as 50%–100% in abdominal and pelvic surgeries, often with serious complications. Abdominal surgical adhesions can easily lead to mechanical intestinal obstruction, chronic abdominal pain, secondary infertility, and increase the difficulty of secondary surgeries. Adhesion formation originates from the inflammatory response triggered by surgical trauma: increased local vascular permeability leads to fibrin exudation. If the fibrinolytic system is imbalanced, fibrin cannot be degraded in time, resulting in excessive proliferation of fibroblasts and collagen secretion, forming dense scar tissue that bridges adjacent tissues. This process usually occurs 1–4 weeks post-surgery, and recurrent adhesions are even more difficult to prevent and treat.

[0003] To address the adhesion problem, anti-adhesion materials have undergone three generations of development. The first generation of non-degradable mechanical barrier materials, such as polytetrafluoroethylene, required a second surgery for removal and were prone to causing rejection. The second generation of materials, such as chitin and dextran, had low absorption efficiency and limited functionality, making them unsuitable for the adhesion formation cycle. The third generation of biomaterials, such as hyaluronic acid and polylactic acid, are currently widely used in clinical practice, but these products have some shortcomings, such as difficulty in controlling purity and degradation rate.

[0004] Patent CN103055353B discloses a method for preparing surgical anti-adhesion films: The process involves dissolving raw materials, adjusting the alkali, adding a cross-linking agent, adjusting the acid, casting, drying, soaking, and then drying again. Sodium hyaluronate, hydroxyethyl cellulose, or hydroxypropyl cellulose is dissolved in deionized water, the pH is adjusted to 10-12, 1,4-butanediol diglycidyl ether is added, and the mixture is stirred at 40-50°C to adjust the pH to 2-5. The mixture is then poured into a mold for casting and dried at 40-50°C. It is then soaked in deionized water for 8-10 hours and finally dried to form a film. While the raw materials used in this technology are simple, the steps are relatively cumbersome, especially the long soaking time, which is not conducive to industrial production. Furthermore, 1,4-butanediol diglycidyl ether is an organic compound with slight toxicity and can irritate the skin and respiratory tract.

[0005] The invention patent with announcement number CN115916279A discloses a film-type anti-adhesion composition with excellent mucosal adhesion and swelling properties and its related preparation method: Mucosal adhesion polymers such as sodium alginate and chitosan, and swelling polymers such as sodium glycolate and cross-linked carboxymethyl cellulose are dissolved in distilled water. Plasticizers such as polyethylene glycol 400 and glycerin are added and stirred until uniformly dispersed. After defoaming, the mixture is poured into a certain thickness using a coating device and thoroughly dried in a hot air dryer at 60°C. While the raw materials used in this technology are simple, some embodiments show polymer precipitation leading to uneven film thickness. Precise control of the content of each component is necessary to ensure the quality stability of the film. Although no toxic raw materials are used in the preparation process, the chitosan and other raw materials are deacetylated dextran extracted from shrimp or crab shells. Specific proteins are difficult to completely remove during extraction, posing a risk of sensitization.

[0006] The existing technology has the following problems: First, it lacks polyethylene oxide with a suitable molecular weight as an adhesion enhancer, resulting in poor product adhesion, making it difficult to resist friction in the dynamic environment inside the body and unable to be well fixed to the wound surface that requires anti-adhesion; Second, the molecular weight ratio of sodium hyaluronate in the existing technology is inappropriate. For example, if the molecular weight is too low, the degradation cycle is too fast, and a good anti-adhesion effect cannot be achieved; Third, the alkali concentration and cycle time in the preparation method of the existing technology are not optimized, resulting in unstable sodium carboxymethyl cellulose substitution, poor water solubility, or insufficient film strength. Summary of the Invention

[0007] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0008] Currently, most anti-adhesion materials on the market are absorbable synthetic polymers, such as films made from polyglycolic acid, polylactic acid, and their copolymers. However, commercially available anti-adhesion films, such as polylactic acid films, have insufficient wet tensile strength, making them unable to withstand friction from the dynamic environment within the body; polyvinyl alcohol, when uncrosslinked, has a swelling rate exceeding 300%, making it prone to structural disintegration; hyaluronic acid undergoes rapid enzymatic hydrolysis, requiring excessive crosslinking to maintain performance, but this reduces biocompatibility. Chitosan-based anti-adhesion products, such as chitosan anti-adhesion films and liquids, are deacetylated dextran extracted from shrimp or crab shells, which have a certain anti-adhesion effect. However, their molecular weight is difficult to control in equal amounts, and specific proteins are difficult to completely remove during extraction, leading to significant risks during use and a high likelihood of allergic reactions.

[0009] In view of the problems existing in the prior art, the present invention is proposed.

[0010] The purpose of this invention is to provide a surgical anti-adhesion biopolysaccharide irrigation adhesive and its preparation method. Using natural plant fibers as raw materials, the adhesive is prepared with good biocompatibility, stable performance, and good anti-adhesion effect. This invention solves the problems of existing anti-adhesion materials having too fast a degradation cycle to achieve a good anti-adhesion effect, some raw materials containing irritating components that pose a risk to biosafety, poor product adhesion that makes it difficult to resist friction in the dynamic environment of the body, and inability to be well fixed to the wound surface that requires anti-adhesion.

[0011] To achieve the above objectives, the technical solution of the present invention is: a surgical anti-adhesion biopolysaccharide irrigation solution, prepared from the following raw materials in parts by weight: 5-30 parts of sodium carboxymethyl cellulose, 0.1-5 parts of polyethylene oxide with a molecular weight of 1.5 million to 2 million Daltons, 2-16 parts of sodium hyaluronate with a molecular weight of 1.2 million to 2 million Daltons, and 80-100 parts of water for injection.

[0012] The rinsing solution contains sodium carboxymethyl cellulose, which is prepared by alkalization and carboxymethylation modification of natural plant fibers. The degree of substitution is 0.6-0.8, the purity is ≥98%, and the water content is ≤5%.

[0013] The selection of alkali concentration (10%–50%) and circulation time (2–8 hours) is based on the following: Too low an alkali concentration (below 10%) leads to insufficient cellulose expansion, incomplete carboxymethylation, a substitution degree below 0.6, and poor water solubility; too high a concentration (above 50%) may cause excessive cellulose degradation, a substitution degree above 0.8, and insufficient membrane strength. Too short a circulation time (below 2 hours) results in incomplete reaction and unstable substitution degree; too long a time (above 8 hours) leads to high energy consumption, making further extension unnecessary. These parameters were determined through experimental optimization, using unconventional selection methods to ensure the stability and water solubility of sodium carboxymethyl cellulose.

[0014] Water-soluble gauze refers to gauze with sodium carboxymethyl cellulose as the main component. Its composition is modified natural plant cellulose, with sodium carboxymethyl cellulose (CMC-Na) as the main component. Its function is to serve as a basic framework, provide a physical barrier, and prevent incomplete degradation during the adhesion cycle.

[0015] The molecular weight selection mechanism of sodium hyaluronate: With a molecular weight of 1.2 million to 2 million Daltons, it can reduce inflammation and promote healing, while also enhancing the toughness of the irrigation solution. It can inhibit the release of inflammatory factors, reduce excessive inflammation, promote cell proliferation, and accelerate wound repair. Its hydroxyl groups form strong hydrogen bonds with the carboxyl groups of sodium carboxymethyl cellulose, improving the stretching properties of the biopolysaccharide irrigation solution and enhancing its resistance to friction and breakage. Polyethylene oxide, with a molecular weight of 1.5 million to 2 million Daltons, is used as an adhesion enhancer. Its long-chain molecules entangle with the other two components, increasing the viscoelasticity of the solution and extending its residence time on the wound. It forms a dual three-dimensional network, resulting in increased strength after film formation in vivo. After degradation into ethylene glycol, it is metabolized into harmless substances. Molecular weight synergy is emphasized: The molecular weights of polyethylene oxide and sodium hyaluronate are matched to ensure the formation of the entangled network and prevent precipitation or separation.

[0016] Furthermore, a method for preparing a surgical anti-adhesion biopolysaccharide irrigation adhesive is provided, comprising the following steps:

[0017] 1) Alkalization of natural plant fibers: Place natural cellulose into a reaction vessel, add 1.5% urea and pass through 10% to 50% alkaline solution, and circulate the reaction in the reaction vessel at 10 to 30°C for 2 to 8 hours;

[0018] 2) Carboxymethylation modification of natural plant fibers: 50%–85% ethanol and 15%–65% acid solution are introduced into the alkalized reaction vessel and reacted for 1–2 hours; the product after reaction is removed, and the product is pressed to remove the reaction liquid; the reactants are washed with 50%–75% ethanol or 60%–90% isopropanol, and after washing, the degree of substitution of sodium carboxymethyl cellulose is determined by potentiometric titration to ensure that the degree of substitution is 0.6–0.8; and then freeze-dried at -25℃ and vacuum degree ≤10Pa for 8–14 hours to obtain white flocculent sodium carboxymethyl cellulose.

[0019] 3) Preparation of anti-adhesion solution: Weigh sodium carboxymethyl cellulose, polyethylene oxide, sodium hyaluronate, and water for injection according to the specified mass proportions; add sodium carboxymethyl cellulose to water for injection and stir at 40-60℃ for 1-3 hours to form a homogeneous solution; then add polyethylene oxide and sodium hyaluronate sequentially and continue stirring for 30-90 minutes to ensure thorough mixing of all components; emulsify the mixed solution under a pressure of 200-400 bar to ensure uniform dispersion and obtain a preliminary anti-adhesion solution; sterilize the preliminary anti-adhesion solution using a moist heat sterilization method, and then fill it into a special medical device container under aseptic conditions to obtain the finished surgical anti-adhesion biopolysaccharide rinsing adhesive.

[0020] The beneficial effects of this invention are as follows: Cellulose with sodium carboxymethyl cellulose as the main component is generated by carboxymethylation modification of natural cellulose; the adhesive strength of the product is increased by adding 0.1 to 5 parts of polyethylene oxide with a strength of 1.5 million to 2 million Daltons, which is 2.07 to 3.49 MPa. This allows the product to adhere well to the wound surface in vivo, and the increased strength also better withstands the friction of the cavity on the product. This allows the product to adhere better to the wound site while forming a film. The addition of 2 to 16 parts of sodium carboxymethyl cellulose and sodium hyaluronate with a strength of 1.2 million to 2 million Daltons ensures that the product's viscosity is more conducive to film formation on the wound surface, preventing adhesion between tissues.

[0021] The product boasts biocompatibility, stable processing, and outstanding anti-adhesion effects. Its liquid form allows for flexible adaptation to various scenarios, making it suitable for different types of wounds and capable of penetrating deeper and more complex wound environments. The overall technical solution overcomes the problems of excessively rapid metabolism and insufficient adhesion strength of existing anti-adhesion materials, making it highly valuable and suitable for widespread application. Detailed Implementation

[0022] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0023] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0024] Secondly, the term "an embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places throughout this specification does not necessarily refer to the same embodiment, nor is it a single embodiment or an embodiment selectively excluded from other embodiments.

[0025] Example 1

[0026] This embodiment provides a surgical anti-adhesion biopolysaccharide irrigation adhesive and its preparation method.

[0027] Specifically, the alkalization of natural plant fibers involves placing natural cellulose in a reaction vessel, adding urea at a mass of 1.5% of the cellulose, and then passing a 30% alkaline solution through it. The reaction is carried out for 5 hours under the condition that the temperature of the reaction vessel is controlled at 20°C, so that the cellulose is fully alkalized.

[0028] Further, carboxymethylation modification of natural plant fibers: 70% ethanol and 40% acid solution are introduced into the alkalized reaction system and the reaction is continued for 1.5 hours. Then, the reaction product is taken out and the excess reaction liquid is removed by pressing with a press.

[0029] Then, the reactants were rinsed multiple times with 65% ethanol until neutral.

[0030] After rinsing, the degree of substitution of sodium carboxymethyl cellulose was determined by potentiometric titration to ensure that the degree of substitution was between 0.6 and 0.8.

[0031] Finally, the sodium carboxymethyl cellulose was freeze-dried for 12 hours at -25°C and a vacuum of ≤10Pa to obtain white flocculent sodium carboxymethyl cellulose with a purity of ≥98% and a water content of ≤5%.

[0032] Furthermore, prepare the anti-adhesion solution by weighing the following raw materials in the indicated mass proportions: 10 parts water-soluble gauze (i.e., sodium carboxymethyl cellulose), 0.5 parts polyethylene oxide with a molecular weight of 1.8 million Daltons, 5 parts sodium hyaluronate with a molecular weight of 1.8 million Daltons, and 90 parts water for injection.

[0033] Add the weighed water-soluble gauze (i.e., sodium carboxymethyl cellulose) to water for injection and stir at 50°C for 2 hours until a transparent and homogeneous solution is formed.

[0034] Subsequently, polyethylene oxide and sodium hyaluronate were added in sequence, and the mixture was stirred at the same temperature for 45 minutes to ensure that all components were fully mixed and homogeneous, with no visible precipitation or stratification.

[0035] The resulting mixed solution was placed in a high-pressure emulsification device and emulsified at a pressure of 300 bar to ensure fine dispersion of the solution and obtain a preliminary anti-blocking liquid.

[0036] Finally, the preliminary anti-adhesion solution was sterilized by moist heat sterilization (121℃, 15min) and then filled into a special medical device container under aseptic conditions to obtain the finished anti-adhesion biological polysaccharide rinsing adhesive for surgical use.

[0037] Example 2

[0038] This embodiment provides a surgical anti-adhesion biopolysaccharide irrigation adhesive and its preparation method.

[0039] Specifically, the alkalization of natural plant fibers involves placing natural cellulose in a reaction vessel, adding urea at a mass of 1.5% of the cellulose, and passing in a 40% alkaline solution. Under the condition that the temperature of the reaction vessel is controlled at 25°C, the reaction is carried out in a cyclical manner for 6 hours to fully alkalize the cellulose.

[0040] Further, carboxymethylation modification of natural plant fibers: 75% ethanol and 50% acid solution were introduced into the alkalized reaction system, and the reaction was continued for 1.8 hours.

[0041] The reaction product was then removed, and excess reaction liquid was removed by pressing. The reactants were then rinsed multiple times with 70% isopropanol until neutral.

[0042] After rinsing, the degree of substitution of sodium carboxymethyl cellulose was determined by potentiometric titration to ensure that the degree of substitution was between 0.6 and 0.8.

[0043] Finally, the sodium carboxymethyl cellulose was freeze-dried for 10 hours at -25℃ and a vacuum degree ≤10Pa to obtain white flocculent sodium carboxymethyl cellulose with a purity ≥98% and a water content ≤5%.

[0044] Furthermore, prepare the anti-adhesion solution: weigh the raw materials according to the following mass proportions: 20 parts water-soluble gauze (i.e., sodium carboxymethyl cellulose), 3 parts polyethylene oxide with a molecular weight of 1.7 million Daltons, 12 parts sodium hyaluronate with a molecular weight of 1.7 million Daltons, and 90 parts water for injection.

[0045] Add the weighed water-soluble gauze (i.e., sodium carboxymethyl cellulose) to water for injection and stir at 55°C for 2.5 hours until a transparent and homogeneous solution is formed.

[0046] Subsequently, polyethylene oxide and sodium hyaluronate were added in sequence, and the mixture was stirred at the same temperature for 75 minutes to ensure that all components were fully mixed and homogeneous, with no visible precipitation or stratification.

[0047] The resulting mixed solution was placed in a high-pressure emulsification device and emulsified at a pressure of 350 bar to ensure fine dispersion of the solution and obtain a preliminary anti-blocking solution.

[0048] Finally, the preliminary anti-adhesion solution was sterilized by moist heat sterilization (121℃, 15min) and then filled into a special medical device container under aseptic conditions to obtain the finished anti-adhesion biological polysaccharide rinsing adhesive for surgical use.

[0049] Example 3

[0050] This embodiment provides a surgical anti-adhesion biopolysaccharide irrigation adhesive and its preparation method.

[0051] Alkalization of natural plant fibers: Place natural cellulose in a reaction vessel, add urea at a mass of 1.5% of the cellulose, and pass in a 50% alkaline solution. Under the condition that the temperature of the reaction vessel is controlled at 30℃, carry out a circulating reaction for 4 hours to fully alkalize the cellulose.

[0052] Carboxymethylation modification of natural plant fibers: 75% ethanol and 50% acid solution were introduced into the alkalized reaction system and the reaction was continued for 2 hours.

[0053] The reaction product was then removed, and excess reaction liquid was removed by pressing. The reactants were then rinsed multiple times with 75% ethanol until neutral.

[0054] After rinsing, the degree of substitution of sodium carboxymethyl cellulose was determined by potentiometric titration to ensure that the degree of substitution was between 0.6 and 0.8.

[0055] Finally, the sodium carboxymethyl cellulose was freeze-dried for 11 hours at -25℃ and a vacuum of ≤10Pa to obtain white flocculent sodium carboxymethyl cellulose with a purity of ≥98% and a water content of ≤5%.

[0056] Preparation of anti-adhesion solution: Weigh the raw materials according to the following mass proportions: 8 parts water-soluble gauze (i.e., sodium carboxymethyl cellulose), 0.8 parts polyethylene oxide with a molecular weight of 1.9 million Daltons, 9 parts sodium hyaluronate with a molecular weight of 1.9 million Daltons, and 95 parts water for injection.

[0057] Add the weighed water-soluble gauze (i.e., sodium carboxymethyl cellulose) to water for injection and stir at 45°C for 1.5 hours until a transparent and homogeneous solution is formed.

[0058] Subsequently, polyethylene oxide and sodium hyaluronate were added in sequence, and the mixture was stirred at the same temperature for 70 minutes to ensure that all components were fully mixed and homogeneous, with no visible precipitation or stratification.

[0059] The resulting mixed solution was placed in a high-pressure emulsification device and emulsified at a pressure of 250 bar to ensure fine dispersion of the solution and obtain a preliminary anti-blocking liquid.

[0060] Finally, the preliminary anti-adhesion solution was sterilized by moist heat sterilization (121℃, 15min) and then filled into a special medical device container under aseptic conditions to obtain the finished anti-adhesion biological polysaccharide rinsing adhesive for surgical use.

[0061] Comparative Example 1

[0062] The steps of alkalization and carboxymethylation modification of natural plant fibers are the same as in Example 1.

[0063] The difference is that the anti-adhesion solution is prepared by weighing the following raw materials in the indicated mass proportions: 8 parts water-soluble gauze (i.e., sodium carboxymethyl cellulose), 0.5 parts polyethylene oxide with a molecular weight of 1.8 million Daltons, 9 parts sodium hyaluronate with a molecular weight of 1.2 million Daltons, and 90 parts water for injection.

[0064] Add the weighed sodium carboxymethyl cellulose to water for injection and stir at 50°C for 2 hours until a transparent and homogeneous solution is formed.

[0065] Subsequently, polyethylene oxide and sodium hyaluronate were added sequentially, and the mixture was stirred at the same temperature for 60 minutes to ensure thorough and uniform mixing of all components. The resulting mixture was then placed in a high-pressure emulsification device and emulsified at 300 bar to ensure fine dispersion and obtain a preliminary anti-blocking solution.

[0066] Finally, the preliminary anti-adhesion solution was sterilized by moist heat sterilization (121℃, 15min) and then filled into a special medical device container under aseptic conditions to obtain the finished anti-adhesion biological polysaccharide rinsing adhesive for surgical use.

[0067] Comparative Example 2

[0068] The steps of alkalization and carboxymethylation modification of natural plant fibers are the same as in Example 2.

[0069] The difference is that the anti-adhesion solution is prepared by weighing the following raw materials in the indicated mass proportions: 8 parts water-soluble gauze (i.e., sodium carboxymethyl cellulose), 0.08 parts polyethylene oxide with a molecular weight of 1.8 million Daltons, 9 parts sodium hyaluronate with a molecular weight of 1.8 million Daltons, and 90 parts water for injection.

[0070] The weighed sodium carboxymethyl cellulose was added to water for injection and stirred at 50°C for 2 hours until a clear, homogeneous solution was formed. Subsequently, polyethylene oxide and sodium hyaluronate were added sequentially, and stirring was continued at the same temperature for 60 minutes to ensure that all components were thoroughly mixed.

[0071] The resulting mixed solution was placed in a high-pressure emulsification device and emulsified at a pressure of 300 bar to ensure fine dispersion of the solution and obtain a preliminary anti-blocking liquid.

[0072] Finally, the preliminary anti-adhesion solution was sterilized by moist heat sterilization (121℃, 15min) and then filled into a special medical device container under aseptic conditions to obtain the finished anti-adhesion biological polysaccharide rinsing adhesive for surgical use.

[0073] Comparative Example 3

[0074] The steps of alkalization and carboxymethylation modification of natural plant fibers are the same as in Example 2.

[0075] The difference is that the anti-adhesion solution is prepared by weighing the following raw materials in the following proportions by weight: 8 parts of water-soluble gauze (i.e., sodium carboxymethyl cellulose), 0.5 parts of polyethylene oxide with a molecular weight of 1.7 million Daltons, 9 parts of sodium hyaluronate with a molecular weight of 1.5 million Daltons, and 90 parts of water for injection.

[0076] Add the weighed sodium carboxymethyl cellulose to water for injection and stir at 55°C for 2.5 hours until a clear and homogeneous solution is formed.

[0077] Subsequently, polyethylene oxide and sodium hyaluronate were added sequentially, and the mixture was stirred at the same temperature for 75 minutes to ensure thorough and uniform mixing of all components. The resulting mixture was then placed in a high-pressure emulsification device and emulsified at 350 bar to ensure fine dispersion and obtain a preliminary anti-blocking solution.

[0078] Finally, the preliminary anti-adhesion solution was sterilized by moist heat sterilization (121℃, 15min) and then filled into a special medical device container under aseptic conditions to obtain the finished anti-adhesion biological polysaccharide rinsing adhesive for surgical use.

[0079] Comparative Example 4

[0080] The steps of alkalization and carboxymethylation modification of natural plant fibers are the same as in Example 3.

[0081] The difference is that the anti-adhesion solution is prepared by weighing the following raw materials in the indicated mass proportions: 8 parts water-soluble gauze (i.e., sodium carboxymethyl cellulose), 0.08 parts polyethylene oxide with a molecular weight of 1.9 million Daltons, 9 parts sodium hyaluronate with a molecular weight of 1.5 million Daltons, and 95 parts water for injection.

[0082] Add the weighed sodium carboxymethyl cellulose to water for injection and stir at 45°C for 1.5 hours until a clear and homogeneous solution is formed.

[0083] Subsequently, polyethylene oxide and sodium hyaluronate were added in sequence, and the mixture was stirred at the same temperature for 70 minutes to ensure that all components were thoroughly mixed.

[0084] The resulting mixed solution was placed in a high-pressure emulsification device and emulsified at a pressure of 250 bar to ensure fine dispersion of the solution and obtain a preliminary anti-blocking liquid.

[0085] Finally, the preliminary anti-adhesion solution was sterilized by moist heat sterilization (121℃, 15min) and then filled into a special medical device container under aseptic conditions to obtain the finished anti-adhesion biological polysaccharide rinsing adhesive for surgical use.

[0086] Comparative Test Example 1

[0087] The viscosity and pH test results of the above formulation are shown in the table below:

[0088] Group pH Viscosity (cp) Example 1 7.48~7.67 10.31~12.16 Example 2 6.25~6.98 23.32~25.86 Example 3 6.41~7.26 13.28~15.48 Comparative Example 1 6.75~7.03 8.28~9.69 Comparative Example 2 6.62~7.44 11.05~12.62 Comparative Example 3 6.70~7.10 9.50~10.80 Comparative Example 4 6.55~7.35 10.20~11.90

[0089] The above results were obtained by following the test methods specified in General Chapter 0631 pH value determination and General Chapter 0633 viscosity determination (method 3, rotational viscometer determination) of the 2020 edition of the Chinese Pharmacopoeia, Part IV.

[0090] Comparative Test Example 2

[0091] The anti-adhesion biopolysaccharide rinsing solution prepared in the above embodiments was compared with a commercially available anti-adhesion rinsing solution for surgical use in terms of in vitro enzymatic hydrolysis characteristics. The degradation rate comparison results are shown in the table below:

[0092] Group 48-hour degradation rate 120-hour degradation rate Example 1 65% 100% Example 2 46% 92% Example 3 53% 97% Comparative Example 1 79% 100% Comparative Example 2 58% 99% Comparative Example 3 75% 100% Comparative Example 4 62% 98% Commercially available products 60% 100%

[0093] The specific methods for the above in vitro enzymatic hydrolysis test are as follows:

[0094] 1. Objective: To observe the degradation of anti-adhesion materials in vitro using biological enzymes and to study the biodegradability of this type of product.

[0095] 2. Materials: 1 electronic balance, 2g lysozyme, pH 7.4 phosphate buffer, 1 100mL volumetric flask, 2 10mL pipettes, 4 100mL beakers, 80 300mL Erlenmeyer flasks, 1 constant temperature shaker, 2 vacuum desiccators, and 1 centrifuge.

[0096] method:

[0097] (1) Preparation of lysozyme solution: Weigh 500 mg of lysozyme using an electronic balance, put it into a 100 mL volumetric flask, and make up to 100 mL with pH 7.4 phosphate buffer to prepare lysozyme solution. The concentration of this lysozyme is 5 mg / mL.

[0098] (2) Take 10 mL of each sample with a pipette and add them to different Erlenmeyer flasks (50 mL). Repeat each sample in 10 flasks and write the labels.

[0099] (3) Add 10 mL of lysozyme solution to each shake flask using a pipette and mix well.

[0100] (4) Place all the shake flasks on a constant temperature shaker at 37°C and 60 rpm.

[0101] 4. Analysis and testing:

[0102] (1) After culturing on a shaker for 48 hours, take two shake flasks of the sample for processing. First, transfer 50 mL of the shake flask liquid into 300 mL Erlenmeyer flasks, add 80 mL of 95% ethanol to each flask, shake thoroughly, and let stand for 20 minutes.

[0103] (2) Centrifuge the liquid in each bottle at 6000 rpm, discard the supernatant, and collect the solids.

[0104] (3) Place the solid in a beaker and vacuum dry it to constant weight. Weigh it using an electronic balance and record the weight.

[0105] (4) Every 48 hours thereafter, take two shake flasks of the sample and perform the same operation as above.

[0106] 5. Result Processing:

[0107] (1) The degradation of the sample is expressed as the degradation rate: Degradation rate = (total weight before reaction - total weight after drying) / sample weight before reaction × 100%. It should be noted that: total weight before reaction = dry weight of sample before reaction + dry weight of lysozyme.

[0108] (2) Each time, two shake flasks were treated separately, and the average of the two was taken as the true degradation rate.

[0109] (3) The dry matter weight of the sample before reaction refers to the weight of the substance obtained after precipitating the product sample with 4 times its volume of 95% ethanol, collecting the precipitate and drying it under vacuum.

[0110] Comparative Test Example 3

[0111] The anti-adhesion biopolysaccharide irrigation solution prepared in the above embodiments was compared with commercially available surgical anti-adhesion irrigation solution in terms of tissue adhesion. The results are shown in the table below:

[0112] Group Adhesion strength (MPa) Example 1 2.07 Example 2 2.36 Example 3 3.49 Comparative Example 1 2.14 Comparative Example 2 2.23 Comparative Example 3 2.10 Comparative Example 4 2.18 Commercially available products 0.20

[0113] The above test results were obtained in accordance with YY / T0729.2-2009 "Test methods for adhesive properties of tissues - Part 1: Overlap - Shear tensile strength".

[0114] Comparative Test Example 4

[0115] The anti-adhesion solution prepared in the above embodiments was compared with commercially available products in the experiment to prevent pelvic adhesions in New Zealand rabbits. The results of the comparison of adhesion degree are shown in the table below:

[0116] Group Non-stick Mild moderate Severe Example 1 0 / 3 3 / 3 0 / 3 0 / 3 Example 2 0 / 3 3 / 3 0 / 3 0 / 3 Example 3 3 / 3 0 / 3 0 / 3 0 / 3 Comparative Example 1 0 / 3 2 / 3 1 / 3 0 / 3 Comparative Example 2 0 / 3 2 / 3 1 / 3 0 / 3 Comparative Example 3 0 / 3 1 / 3 2 / 3 0 / 3 Comparative Example 4 0 / 3 1 / 3 2 / 3 0 / 3 Blank control 0 / 3 0 / 3 3 / 3 0 / 3 Commercially available comparison 1 / 3 2 / 3 0 / 3 0 / 3

[0117] 1. Study Objective: Current surgical adhesion solutions have unsatisfactory clinical efficacy, and the prevention of postoperative adhesions using isolation materials is a hot research topic. This study uses a New Zealand rabbit uterine injury model to compare the in vivo safety and efficacy of a bio-polysaccharide irrigation adhesive with commercially available surgical anti-adhesion irrigation solutions.

[0118] 2. Test materials

[0119] Test instruments: biopolysaccharide rinsing solutions from Examples 1, 2, 3, Comparative Examples 1, 2, 3, and 4.

[0120] Controlled instrument: Surgical anti-adhesion irrigation solution.

[0121] Experimental animals: 27 female common New Zealand rabbits, 4-6 months old, weighing 3.0-3.5 kg, identified by ear tags and cage cards.

[0122] Adjunctive medications: anesthetics propofol and isoflurane; antibiotics ceftiofur sodium.

[0123] 3. Test conditions and design

[0124] Husbandry conditions: Animals are housed in a standard environment with alternating 12-hour light and dark cycles, a temperature of 16–26°C, and a relative humidity of 40%–70%. After passing quarantine, animals are allowed to adapt for at least 7 days, fasted for 12 hours before surgery, and given free access to food and water during the trial period. Veterinarians monitor the animals' health throughout the trial. Animals are euthanized after the trial or in special circumstances, in accordance with animal welfare and ethical principles.

[0125] Experimental grouping: The animals were randomly divided into the test device group, the control device group, and the blank control group, with a total of 27 animals, 3 animals in each group. The observation point was 14 days after the operation.

[0126] Experimental model: Referring to relevant studies, a rabbit model of uterine serosal layer injury and pelvic adhesions with a length of 1cm and a width of 0.5-1cm was established to simulate the application scenario of clinical surgery.

[0127] Experimental procedure: After quarantine, the animals were weighed and recorded. After grouping, the animals were fasted for 12 hours before surgery. Anesthesia was induced with propofol (5.5 mg / kg, intravenous injection in the ear) and maintained with isoflurane inhalation anesthesia. The animals were fixed in a prone position, and after skin preparation and disinfection, open surgery was performed. Mechanical damage was made to the left uterine serosa (rubbed with a file). The blank control group received no intervention. The pelvic cavity of the test and control groups was flushed with 50 mL of the drug (covering the scraped surface and aspirating excess fluid). After closing the abdomen, a self-adhesive bandage was applied. Ceftiofur sodium was injected intramuscularly after surgery to prevent infection.

[0128] 4. Evaluation Indicators and Methods

[0129] Safety assessment: First, a general observation, paying attention to the animal's diet, excretion, activity, and surgical wound healing; second, an anatomical observation of organs, visually inspecting the liver, lungs, spleen, kidneys, reproductive organs, etc. for any abnormalities such as swelling or bleeding after the animal is euthanized.

[0130] Evaluation of effectiveness: Dissection was performed 14 days post-surgery, based on the modified American Society for Reproductive Medicine (ASRM) adhesion grading criteria.

[0131] 5. Test Results

[0132] Safety results: Gross observation showed that the wounds of the animals in the test device group of Example 3 healed well without adverse reactions; the test device groups and control device groups of Examples 1, 2, Comparative Examples 1, 2, 3, and 4 showed mild inflammatory reactions at the healing site, and the control device group showed redness, swelling and induration, but no suppuration; the blank control group showed mild redness and swelling and suppuration of the wound. No abnormalities were found in the major tissues and organs during organ dissection.

[0133] Validity results (adhesion score results):

[0134] Animal Group Product Group No. 1 No. 2 No. 3 Average score Example 1 2 2 2 2 Example 2 2 2 2 2 Example 3 0 0 0 0 Comparative Example 1 2 2 4 2.67 Comparative Example 2 2 2 3 2.33 Comparative Example 3 4 3 2 3 Comparative Example 4 2 3 3 2.67 Blank control 3 3 4 3.33 Commercially available comparison 2 2 0 1.33

[0135] The blank control group had moderate adhesions, with an average score of 3.33.

[0136] The control group showed mild adhesions, with an average score of 1.33.

[0137] Example 1: The tested device group showed mild adhesion, with an average score of 2.

[0138] Example 2: The tested device group showed mild adhesion, with an average score of 2.

[0139] Example 3: The tested device group showed no adhesion, with an average score of 0.

[0140] Comparative Example 1 showed moderate adhesion, with an average score of 2.67.

[0141] Comparative Example 2 showed moderate adhesion, with an average score of 2.33.

[0142] Comparative Example 3 showed moderate adhesion, with an average score of 3.

[0143] The four comparative examples showed moderate adhesion, with an average score of 2.67.

[0144] 6. Experimental Conclusions

[0145] Safety: Under the conditions of this test, no safety abnormalities were observed in the tested device.

[0146] Efficacy: The test device in Example 3 reduced the occurrence of purulent inflammation, prevented pelvic adhesions, and reduced the degree of adhesions, and was not inferior to the control device.

[0147] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A surgical anti-adhesion biopolysaccharide irrigation adhesive, characterized in that: It is prepared from the following raw materials in parts by weight: 5-30 parts sodium carboxymethyl cellulose, 0.1-5 parts polyethylene oxide with a molecular weight of 1.5 million to 2 million Daltons, 2-16 parts sodium hyaluronate with a molecular weight of 1.7 million to 2 million Daltons, and 80-100 parts water for injection.

2. The surgical anti-adhesion biopolysaccharide irrigation adhesive as described in claim 1, characterized in that: The sodium carboxymethyl cellulose is prepared by alkalization and carboxymethylation modification of natural plant fibers, with a degree of substitution of 0.6 to 0.8, a purity of ≥98%, and a water content of ≤5%.

3. The surgical anti-adhesion biopolysaccharide irrigation adhesive as described in claim 1, characterized in that: The polyethylene oxide and sodium hyaluronate have matching molecular weights, forming an entangled network.

4. The surgical anti-adhesion biopolysaccharide irrigation adhesive as described in claim 1, characterized in that: The composition includes 5-15 parts sodium carboxymethyl cellulose, 0.1-1 part polyethylene oxide, 2-8 parts sodium hyaluronate, and 80-100 parts water for injection.

5. The surgical anti-adhesion biopolysaccharide irrigation adhesive as described in claim 1, characterized in that: The composition includes 15-30 parts sodium carboxymethyl cellulose, 1-5 parts polyethylene oxide, 8-16 parts sodium hyaluronate, and 80-100 parts water for injection.

6. The surgical anti-adhesion biopolysaccharide irrigation adhesive as described in claim 1, characterized in that: The composition includes 5-10 parts sodium carboxymethyl cellulose, 0.1-1 part polyethylene oxide, 6-12 parts sodium hyaluronate, and 80-100 parts water for injection.

7. A method for preparing a surgical anti-adhesion biopolysaccharide irrigation adhesive as described in any one of claims 1-6, characterized in that: Includes the following steps: 1) Alkalization of natural plant fibers: Place natural cellulose into a reaction vessel, add 1.5% urea and pass through 10% to 50% alkaline solution, and circulate the reaction in the reaction vessel at 10 to 30°C for 2 to 8 hours; 2) Carboxymethylation modification of natural plant fibers: 50%–85% ethanol and 15%–65% acid solution are introduced into the alkalized reaction vessel and reacted for 1–2 hours; the product after reaction is removed, and the product is pressed to remove the reaction liquid; the reactants are washed with 50%–75% ethanol or 60%–90% isopropanol, and after washing, the degree of substitution of sodium carboxymethyl cellulose is determined by potentiometric titration to ensure that the degree of substitution is 0.6–0.8; and then freeze-dried at -25℃ and vacuum degree ≤10Pa for 8–14 hours to obtain white flocculent sodium carboxymethyl cellulose. 3) Preparation of anti-adhesion solution: Weigh out sodium carboxymethyl cellulose, polyethylene oxide, sodium hyaluronate, and water for injection according to the specified mass proportions; add sodium carboxymethyl cellulose to water for injection and stir at 40-60℃ for 1-3 hours to form a homogeneous solution; then add polyethylene oxide and sodium hyaluronate sequentially, and continue stirring for 30-90 minutes to ensure thorough mixing of all components; emulsify the mixed solution under a pressure of 200-400 bar to ensure uniform dispersion and obtain a preliminary anti-adhesion solution; The initial anti-adhesion solution is sterilized by moist heat sterilization and then filled into a special medical device container under aseptic conditions to obtain the finished anti-adhesion biological polysaccharide rinsing adhesive for surgical use.

8. The method for preparing a surgical anti-adhesion biopolysaccharide irrigation adhesive as described in claim 7, characterized in that: The continued stirring time is 30-60 minutes or 60-90 minutes, depending on the amount of raw materials.