Chitosan or chitin polymer as well as preparation method and application thereof

Abstract

The invention relates to the technical field of biomedical materials, in particular to a chitosan or chitin polymer and a preparation method and application thereof, and the chitosan or chitin polymer is prepared from carboxyalkyl chitin and / or carboxyalkyl chitosan through self intermolecular condensation. The carboxy alkyl substitution degrees of the carboxy alkyl chitin and the carboxy alkyl chitosan are both 0.5-1.3, and the deacetylation degrees of the carboxy alkyl chitin and the carboxy alkyl chitosan are both 0.1-1.0. The preparation method comprises the steps of condensation reaction, dialysis, filling and sterilization. According to the chitosan / chitin polymer disclosed by the invention, no external component is introduced into the structural components, and all the components are derived from the starting materials, so that the biological characteristics of the starting material carboxyl alkyl chitin and / or carboxyl alkyl chitosan can be better reserved, and the safety risk caused by the use of a conventional cross-linking agent is avoided.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, specifically to a chitosan or chitin polymer, its preparation method, and its application. Background Technology

[0002] Hydrogels are three-dimensional polymeric network systems dispersed in water. They are flexible, can maintain a certain shape, and can absorb large amounts of water. Depending on the synthetic materials used, hydrogels are classified into synthetic polymer hydrogels and natural polymer hydrogels. Natural polymers possess advantages such as good biocompatibility, environmental sensitivity, abundant sources, and low cost. However, due to factors such as enzymatic degradation, natural polymers typically have a short retention time in the human body. Therefore, structural modification of natural polymers has become a research hotspot.

[0003] Chitin is a biocompatible, biodegradable, and sustainable natural biomaterial, widely distributed in nature, with annual production second only to cellulose, making it the second largest natural polysaccharide resource. However, chitin is almost insoluble in any solvent (including acidic and alkaline aqueous solutions and various organic solvents), which limits its widespread application. Structurally, chitin is polymerized from N-acetyl-D-glucosamine via β-1,4 glycosidic bonds. Chitosan, on the other hand, is a polysaccharide compound formed by the deacetylation of chitin (generally considered to have a degree of deacetylation greater than 50%), polymerized from glucosamine and N-acetyl-D-glucosamine via β-1,4 glycosidic bonds. Accordingly, the names carboxyalkyl chitin and carboxyalkyl chitosan used in this invention are also distinguished by the degree of deacetylation, with those having a degree of deacetylation greater than 50% referred to as carboxyalkyl chitosan, for ease of understanding of the invention.

[0004] In recent years, improving the water solubility of chitin and chitosan by introducing water-soluble groups onto their backbones has yielded promising results. The introduction of carboxyl groups (especially carboxymethyl groups) is a successful example. Currently, there are commercially available products containing carboxymethyl chitin and carboxymethyl chitosan. For instance, Shijiazhuang Yishengtang Medical Supplies Co., Ltd. produces Shuchongning, a carboxymethyl chitosan irrigation solution, and Shuyining, a carboxymethyl chitosan hydrogel; Shanghai Qisheng Biological Reagents Co., Ltd. produces Qitejie, a carboxymethyl chitin product widely used in intra-articular injections, surgical anti-adhesion, and medical aesthetics.

[0005] Carboxyalkylation improves water solubility but does not fundamentally alter the linear skeleton structure of chitin and chitosan. They still suffer from drawbacks such as short in vivo retention time, poor hydrothermal stability, and unsatisfactory long-term stability, which significantly limits their clinical application. Improving the bio and chemical stability of carboxyalkyl-shell chitin and carboxyalkyl chitosan through cross-linking is the main strategy to address these shortcomings. Currently, cross-linking agents used in biomedical materials mainly include BDDE and DVS, but these are primarily used in sodium hyaluronate cross-linking products and are rarely seen in the field of cross-linked chitosan. Furthermore, due to their potential toxicity, these cross-linking agents are gradually being phased out.

[0006] Therefore, it is urgent to develop a new structural modification strategy to improve the physicochemical properties and biological performance of carboxylchitin and carboxylchitose. Summary of the Invention

[0007] The purpose of this invention is to provide a novel chitosan or chitin polymer, its preparation method, and its applications. This invention achieves self-dehydration condensation modification of carboxyl chitin and carboxyl chitosan without introducing a crosslinking agent, and obtains beneficial effects.

[0008] This invention utilizes carboxylchitin and carboxylchitose with specific degrees of carboxyl substitution and deacetylation as raw materials, and adds a condensing agent to induce condensation between the carboxyl and amino groups of two molecules, i.e., intermolecular dehydration condensation. The reaction mechanism is described in [reference needed]. Figure 1 (Taking carboxymethyl chitin and carboxymethyl chitosan as examples). This condensation scheme, by controlling the degree of carboxyl substitution and deacetylation of the raw materials and adjusting the amount of condensing agent, can achieve quantitative control over the degree of carboxyl substitution (the original carboxyl groups in the raw materials minus the carboxyl groups participating in the condensation reaction), the degree of amino substitution (the original amino groups in the raw materials minus the amino groups participating in the condensation reaction), and the degree of condensation (the carboxyl and amino groups participating in the condensation reaction) of the product. The hydrogels of chitin and / or chitosan polymers prepared using this condensation scheme retain the original biological properties of carboxymethyl chitin and carboxymethyl chitosan while also exhibiting viscoelastic properties and shear viscosity with adjustable parameter ranges. Furthermore, it solves the problem of carboxymethyl chitin and carboxymethyl chitosan products being unable to withstand terminal moist heat sterilization, expanding the application fields of this material and improving product safety.

[0009] Specifically, the present invention provides the following technical solution:

[0010] A chitosan or chitin polymer having the structure shown in Formula I, wherein the polymer is prepared by intermolecular condensation of carboxyl chitin or carboxyl chitosan.

[0011]

[0012] Wherein, R1 is H or -R3COOH, R2 is H or -COCO3, and R3 is an alkyl group with no more than 10 carbon atoms.

[0013] Furthermore, the degree of carboxyl substitution of the carboxyl chitin and the carboxyl chitosan is 0.5 to 1.3, and the degree of deacetylation is 0.1 to 1.0.

[0014] Furthermore, the alkyl group of the carboxyalkyl group is an alkyl group with no more than 10 carbon atoms.

[0015] Furthermore, the carboxyl group includes carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, or carboxyhexyl.

[0016] The method for preparing chitosan or chitin polymer according to the present invention includes condensation reaction, dialysis, filling, and sterilization. Specifically, it includes the following steps:

[0017] (1) Dissolution: Dissolve the carboxyl chitin and / or carboxyl chitosan raw materials in purified water or buffer solution to obtain a carboxyl chitin and / or carboxyl chitosan solution;

[0018] (2) Condensation: The condensing agent is added to the carboxyl chitin and / or carboxyl chitose solution, and the condensation reaction is carried out at 5-40°C;

[0019] The condensing agent is selected from one or more of 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine tetrafluoroborate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, and 2-chloro-1-methylpyridine iodide.

[0020] (3) Dialysis, filling and sterilization: The prepared chitin and / or chitosan polymer hydrogel is dialyzed with purified water or buffer solution; the dialyzed gel is filled and sterilized by moist heat to obtain the chitin and / or chitosan polymer hydrogel product.

[0021] In step (1), the buffer solution is one of a phosphate buffer system or a phosphate buffer system / sodium chloride solution, and the pH of the buffer solution is 6.0 to 8.5; the concentration of carboxyl chitin and / or carboxyl chitose in the solution is 0.5% to 5%.

[0022] In step (2), the molar amount of the condensing agent is 1% to 200% of the molar amount of the carboxyl group of the carboxyl chitin or carboxyl chitosan; preferably 5% to 100%.

[0023] In step (3), purified water or buffer solution is used for dialysis. The amount of purified water or buffer solution used is 5 to 50 times the weight of the product (the weight of the entire system at the end of the reaction). The single dialysis time is 4 to 24 hours, and the number of dialysis cycles is 2 to 6.

[0024] The moist heat sterilization is performed at 121℃ for 8–30 minutes.

[0025] The chitosan or chitin polymer obtained by the above preparation method has an elastic modulus of up to 1647 Pa and a viscous modulus of up to 283 Pa before moist heat sterilization, exhibiting a large degree of adjustability. After moist heat sterilization, its viscoelasticity and shear viscosity are comparable to those of commercially available hyaluronic acid fillers for cosmetic purposes, intra-articular injections, and postoperative anti-adhesion applications. The chitosan / chitin polymer content is 5–30 mg / mL, preferably 10–20 mg / mL.

[0026] The chitosan or chitin polymer prepared by this invention can be used to prepare intra-injectable formulations, intra-filler formulations, or topical drug carrier formulations. The chitosan (or chitin) polymer provided by this invention has a wide range of viscoelastic moduli and shear viscosity, high thermal and metabolic stability, and certain antibacterial activity, showing good application prospects in the fields of medical aesthetics, intra-articular injection, postoperative anti-adhesion, and topical gel formulations.

[0027] This invention achieves condensation modification of carboxyl alkyl chitin and carboxyl alkyl chitosan without introducing a crosslinking agent, and obtains beneficial effects:

[0028] (1) The chitosan or chitin polymer provided by the present invention does not introduce any foreign components in its structural composition. Its composition is entirely derived from the starting materials, which can better preserve the biological characteristics of the starting materials carboxyl chitin and / or carboxyl chitosan.

[0029] (2) The chitosan or chitin polymer provided by the present invention does not use a cross-linking agent in its preparation process, and there is zero residue of "cross-linking agent" after in vivo degradation, thus avoiding the safety risks caused by the use of conventional cross-linking agents.

[0030] (3) The chitosan or chitin polymer provided by the present invention can achieve quantitative control of the degree of carboxyl substitution, degree of amino substitution and degree of condensation of the product by using carboxyl chitin and / or carboxyl chitosan with specific degree of carboxyl substitution and degree of deacetylation, and by adjusting the amount of condensing agent. Combined with the material structure-performance relationship, the physicochemical properties of the material can be precisely controlled.

[0031] (4) The chitosan or chitin polymer provided by the present invention is prepared in water in all steps including material dissolution, condensation reaction and product dialysis. The whole preparation process is green and environmentally friendly. The reaction conditions are mild and the reaction process does not require acid, alkali or other materials. The production equipment is simple and conducive to commercial production.

[0032] (5) The chitosan or chitin polymer provided by the present invention, while maintaining the original biological characteristics of carboxyl chitin and / or carboxyl chitosan, also has range-adjustable viscoelastic properties and kinetic viscosity, which can match different clinical application requirements, including filling applications that require high elastic modulus and anti-adhesion applications that require high shear viscosity; at the same time, it solves the problem of instability of carboxyl chitin and carboxyl chitosan in terminal moist heat sterilization, and can withstand terminal moist heat sterilization, providing biosafety guarantee for the clinical application of the product.

[0033] (6) The chitosan or chitin polymer provided by this invention exhibits metabolic stability that is far more durable than that of non-crosslinked products. In clinical applications, it can effectively prolong its retention time in the body, thereby prolonging the duration of drug effect, reducing the frequency of administration, and improving patient compliance.

[0034] (7) The chitosan or chitin polymer provided by the present invention is non-irritating in animal skin test safety test, maintains the biocompatibility characteristics of carboxyl chitin and / or carboxyl chitosan, and is safe for clinical application without compatibility risk.

[0035] (8) The chitosan or chitin polymer provided by the present invention exhibits superior antibacterial activity in antibacterial tests, further enhancing its clinical application prospects. Attached Figure Description

[0036] Figure 1 The mechanism is the self-molecular dehydration condensation reaction of carboxymethyl chitin and carboxymethyl chitosan.

[0037] Figure 2 This is an intradermal irritation test.

[0038] Figure 3 For the skin degradation test. Detailed Implementation

[0039] To enable those skilled in the art to better understand the technical solutions of the present invention, the present invention will be described in detail below with reference to specific embodiments. The description in this part is only exemplary and explanatory, and should not be used to limit the scope of protection of the present invention in any way.

[0040] The technical solution of the present invention will be clearly and completely described below with reference to embodiments thereof. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The description of the embodiments is merely illustrative and is in no way intended to limit the present invention or its application or use. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0041] Unless otherwise specifically stated, the numerical values ​​set forth in these embodiments do not limit the scope of the invention. Techniques and methods known to those skilled in the art may not be discussed in detail, but where appropriate, such techniques and methods should be considered part of the specification. In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limiting.

[0042] Example 1: Preparation of carboxyl chitin and carboxyl chitosan

[0043] Chitin was added to a 50% sodium hydroxide aqueous solution and alkalized at 10°C for 18 hours. Then, chloroacetic acid (14 times the molar amount of chitin monomer) was added dropwise at 10–20°C. After the addition was complete, the reaction was continued at 20°C for 40 hours. The reaction was stopped, and the reactants were precipitated with 80%–95% ethanol to obtain crude carboxymethyl chitin. This crude product was dissolved in purified water, precipitated with ethanol, and dried to obtain carboxymethyl chitin. The degree of carboxymethyl substitution was determined to be 1.30 and the degree of deacetylation was 0.11 by elemental analysis. This batch of product was named carboxymethyl chitin raw material 1. Referring to the preparation method of carboxymethyl chitin raw material 1, the amount of chloroacetic acid was reduced to 10, 7, and 5 times, and the alkalization temperature was adjusted to 10–20°C and the etherification temperature to 10–25°C to obtain carboxymethyl chitin raw material 2, carboxymethyl chitin raw material 3, and carboxymethyl chitin raw material 4. The degree of carboxymethyl substitution and degree of deacetylation were determined by elemental analysis, and the results are shown in Table 1.

[0044] Carboxymethyl chitin raw material 1 was added to a 33% sodium hydroxide aqueous solution and reacted with stirring at 20°C for 72 h. Carboxymethyl chitosan was obtained by precipitation with 80%–95% ethanol. Elemental analysis revealed a carboxymethyl substitution degree of 1.24 and a deacetylation degree of 0.51. This batch of product was designated as carboxymethyl chitosan raw material 1. Following the preparation method of carboxymethyl chitosan raw material 1, carboxymethyl chitosan raw material 2 and carboxymethyl chitosan raw material 3 were prepared using carboxymethyl chitin raw material 2 and carboxymethyl chitosan raw material 3 as raw materials. Using carboxymethyl chitin raw material 4 as raw material, the reaction time was extended to 168 h, following the preparation method of carboxymethyl chitosan raw material 1, to obtain carboxymethyl chitosan raw material 4. Elemental analysis was used to determine the carboxymethyl substitution degree and deacetylation degree of the prepared carboxymethyl chitin and carboxymethyl chitosan. The results are shown in Table 1.

[0045] Table 1. Data on the degree of carboxymethyl substitution and degree of deacetylation of carboxymethyl chitin and carboxymethyl chitosan.

[0046] Raw material name Degree of carboxymethyl substitution Deacetylation Carboxymethyl chitin raw material 1 1.30 0.11 Carboxymethyl chitin raw material 2 0.94 0.16 Carboxymethyl chitin raw material 3 0.72 0.21 Carboxymethyl chitin raw material 4 0.60 0.14 Carboxymethyl chitosan raw material 1 1.24 0.51 Carboxymethyl chitosan raw material 2 0.92 0.63 Carboxymethyl chitosan raw material 3 0.74 0.54 Carboxymethyl chitosan raw material 4 0.59 0.90

[0047] Besides the aforementioned method of alkaline deacetylation, carboxymethyl chitosans and / or chitins with different degrees of deacetylation (including complete deacetylation, i.e., a degree of deacetylation of 1.0) can also be obtained through substitution reactions between substituted acetic acid (such as chloroacetic acid) and chitosans and / or chitins with different degrees of deacetylation (including complete deacetylation, i.e., a degree of deacetylation of 1.0). Similarly, substituted acetic acid (such as chloroacetic acid) can be replaced with other substituted alkyl carboxylic acids (such as chloropropionic acid, chlorobutyric acid, etc.) to obtain carboxylalkyl chitins and / or carboxylalkyl chitosans. This embodiment is merely an example of a method for preparing carboxylalkyl chitins and / or carboxylalkyl chitosans.

[0048] Examples 2-6

[0049] Carboxymethyl chitosan raw material 1 was dispersed in a phosphate buffer / sodium chloride solution (pH = 6.80) with a carboxymethyl chitosan concentration of 2.5% and stirred until dissolved. Then, condensing agent 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM) was added to the system (the molar ratio of carboxymethyl chitosan carboxyl groups to DMTMM was 1:1 to 15:1), and the mixture was stirred until homogeneous and reacted at 25°C for 18 h. After the reaction, the resulting gel was dialyzed against a phosphate buffer / sodium chloride solution (pH = 6.80) for 72 h to remove small molecule impurities. The viscoelastic modulus (2.5 Hz) and shear viscosity (10 1 / s) of the sample were measured, and the results are shown in Table 2.

[0050] Table 2 Modulus and Shear Viscosity of Condensation Reaction Samples

[0051]

[0052]

[0053] The results showed that after the addition of the condensing agent, carboxymethyl chitosan underwent its own molecular dehydration condensation reaction, which significantly improved both the viscoelastic modulus and shear viscosity. Furthermore, as the amount of condensing agent increased, the degree of condensation increased, and the viscoelastic modulus of the sample also increased accordingly.

[0054] Examples 7-9

[0055] Carboxymethyl chitosan raw material 1 was dispersed in a phosphate buffer system / sodium chloride solution (pH = 6.80) with a carboxymethyl chitosan concentration of 1.0% to 3.5% and stirred until dissolved. Then, the condensing agent DMTMM was added to the system (the molar ratio of carboxymethyl chitosan carboxyl groups to DMTMM was 1:1 and 15:1). After stirring evenly, the mixture was reacted at 25°C for 18 h. After the reaction was completed, the resulting gel was dialyzed with PBS for 72 h to remove small molecule impurities. The viscoelastic modulus (2.5 Hz) and shear viscosity (10 1 / s) of the sample were measured and compared with those of Example 6. The results are shown in Table 3.

[0056] Table 3 Changes in viscoelastic modulus and shear viscosity of samples during the condensation reaction.

[0057] reaction sequence Example 6 Example 7 Example 8 Example 9 Raw material concentration 2.5％ 1.0％ 1.5％ 3.5％ Molar ratio of carboxymethyl chitosan carboxyl group to DMTMM 15 / 1 1 / 1 1 / 1 15 / 1 Post-dialysis feedstock concentration (mg / mL) 20.8 9.5 13.0 26.0 Elastic modulus (Pa) 131.2 119.8 320.3 794.2 Viscous modulus (Pa) 31.88 18.51 34.86 40.54 Shear viscosity (Pa·s) 25.09 4.163 6.500 49.60

[0058] The results showed that increasing the concentration of raw materials significantly improved the viscoelastic modulus and shear viscosity of the samples. By adjusting the concentration of raw materials in the condensation reaction, gel materials with a wide range of viscoelastic modulus and shear viscosity can be prepared, which have potential applications in medical, cosmetic, filling and shaping, anti-adhesion after surgery, drug delivery, and sustained and controlled release of drugs.

[0059] Example 10

[0060] Carboxymethyl chitin raw material 1 was dispersed in a phosphate buffer system / sodium chloride solution (pH = 6.80) and stirred until it was uniformly dissolved to a carboxymethyl chitin concentration of 2.5%. Then, a condensing agent (DMTMM) was added to the system (the molar ratio of carboxymethyl chitin carboxyl groups to DMTMM was 1:1). After stirring evenly, the mixture was allowed to stand at 25°C for 18 hours. After the reaction was completed, the resulting gel was dialyzed with PBS for 72 hours to remove the condensing agent residue. The viscoelastic modulus (2.5 Hz) and shear viscosity (10 1 / s) of the sample were measured and compared with those of Example 2 (carboxymethyl substitution degree of raw material 1.24, deacetylation degree 0.51). The results are shown in Table 4.

[0061] Table 4. Changes in gel modulus and shear viscosity of condensation reactions with different raw materials.

[0062] reaction sequence Example 2 Example 10 Raw material concentration 2.5％ 2.5％ Molar ratio of carboxyl groups to DMTMM in raw materials 1 / 1 1 / 1 Post-dialysis feedstock concentration (mg / mL) 21.6 17.4 Elastic modulus (Pa) 1647 49.36 Viscous modulus (Pa) 282.7 11.17 Shear viscosity (Pa·s) 18.01 23.72

[0063] The results showed that, under the condition that the degree of carboxymethyl substitution of the raw materials was basically the same, and the reaction concentration and the amount of condensing agent added were the same, the higher the degree of deacetylation, the less water the sample absorbed during dialysis, and the modulus also increased. The underlying reason was the increase in the degree of condensation.

[0064] Example 11

[0065] The chitosan polymer gels prepared in Examples 5 and 9 were sterilized at 121°C for 8 min. The viscoelastic modulus (2.5 Hz) and shear viscosity (10 1 / s) of the products were measured, and the results are shown in Table 5.

[0066] Table 5. Rheological test results of sterilized chitosan polymer gel and commercially available products.

[0067]

[0068]

[0069] (Note: Commercially available products 1-3 are carboxymethyl chitin derivatives, and commercially available products 4-9 are condensed sodium hyaluronate products. Commercially available product 1 is Shuyining, manufactured by Shijiazhuang Yishengtang Medical Supplies Co., Ltd., batch number 20240505; commercially available product 2 is Qitejie, manufactured by Shanghai Qisheng Biological Reagents Co., Ltd., batch number M2311CH71; commercially available product 3 is KioMedineVSOne, manufactured by KiOmed Pharma SA, batch number 14KA231025; commercially available product 4 is Synvisc, manufactured by Genzyme Corporation, batch number CRSP006B; commercially available product 5 is Butyl-Glycoside Condensed Sodium Hyruan ONE, manufactured by LG...) Chem, Ltd., batch number SIH22068; Product 6 is Haimei, manufactured by Shanghai Qisheng Biological Reagents Co., Ltd., batch number Q2305QS11; Product 7 is Gong Ankang, manufactured by Changzhou Bairuiji Biopharmaceutical Co., Ltd., batch number 2311010; Product 8 is Hairuiji, manufactured by Changzhou Bairuiji Biopharmaceutical Co., Ltd., batch number 2302008; Product 9 is Gong Weijia, manufactured by Zhejiang Jingjia Medical Technology Co., Ltd., batch number JG240408.

[0070] The results showed that the viscoelastic modulus and shear strength of the prepared condensed carboxymethyl chitosan hydrogel after moist heat sterilization were comparable to those of commercially available products. Specifically, the sterilized product of Example 5 was comparable to commercially available sodium hyaluronate products 7 / 8 / 9 for anti-adhesion applications, and superior to commercially available carboxymethyl chitin and carboxymethyl chitosan products 1 / 2 / 3 for anti-adhesion applications; the sterilized product of Example 9 was comparable to commercially available sodium hyaluronate products 4 / 5 / 6 for cosmetic filling and intra-articular injection applications.

[0071] Example 12

[0072] This case study used New Zealand rabbits for an intradermal reaction test, with commercially available product a (Liposil, manufactured by Shanghai Qisheng Biological Reagent Co., Ltd., batch number M2303CG41) as a control. The study investigated the non-specific acute irritation of the sterilized product b from Example 5 on the local skin and evaluated the biocompatibility of the material. Results are as follows: Figure 2 As shown.

[0073] Depend on Figure 2 Experiments showed that no erythema or other irritation was observed in intradermal injection product b (injection site: left back) at 0h (immediately after injection), 24h, 48h, and 72h post-injection, with no significant difference compared to commercially available product a (injection site: right back). This indicates that the polymer hydrogel prepared by this invention has high safety and can be used as a medical injection material. Furthermore, the wheal protrusion at the injection site of the commercially available product disappeared at 24h post-injection, while the wheal protrusion of the polymer hydrogel prepared by this invention showed no significant change at 72h post-injection, suggesting that the polymer hydrogel prepared by this invention has better in vivo degradation stability than commercially available product a.

[0074] Example 13

[0075] This case study used mice for a skin degradation test, using commercially available product a (Liposil, manufactured by Shanghai Qisheng Biological Reagent Co., Ltd., batch number M2303CG41) as a control, to examine the skin degradation stability of sterilized product b from Example 5 in mice. The results are as follows: Figure 3 As shown.

[0076] Depend on Figure 3 Experiments showed that subcutaneous injection product b (injection site: left back) still had obvious wheals at the injection site 360 ​​hours after injection, while the wheals disappeared 24 hours after injection of commercially available product a (injection site: right back). This indicates that the polymer hydrogel prepared by the present invention has better in vivo degradation stability than commercially available product a.

[0077] Example 14

[0078] This case study is an antibacterial experiment. Using commercially available product a (Liposil, manufactured by Shanghai Qisheng Biological Reagent Co., Ltd., batch number M2303CG41) as a control, the antibacterial activity of sterilized product b from Example 5 was investigated.

[0079] Dilute samples a and b twice with sterile physiological saline to prepare test solutions. Take 1 ml of each dilution and add 0.1 ml of Staphylococcus aureus solution (10-100 CFU) to each solution and mix thoroughly. Add the mixture to agar medium at approximately 42°C and mix well. After cooling and solidification, incubate upside down at 32°C. Count the colonies after 24 hours and calculate the inhibition rate.

[0080] Table 6 Antibacterial Data

[0081] Sample Name Product A Product B Comparison colonies 38 22 54 Antibacterial rate 29.6％ 59.3％ -

[0082] Note: Antibacterial rate = (1 - Sample colony count / Control colony count) x 100%

[0083] Table 6 shows that the sterilization product in Example 5 has a much better antibacterial effect than commercially available product a.

[0084] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A chitosan or chitin polymer, characterized in that: Having the structure shown in Formula I, the polymer is prepared from carboxyl chitin or carboxyl chitosan through intermolecular condensation. Wherein, R1 is H or -R3COOH, R2 is H or -COCO3, and R3 is an alkyl group with no more than 10 carbon atoms.

2. The chitosan or chitin polymer according to claim 1, characterized in that: The degree of carboxyl substitution of the carboxyl chitin and the degree of deacetylation of the carboxyl chitose are both 0.5 to 1.3 and 0.1 to 1.

0.

3. The chitosan or chitin polymer according to claim 1, characterized in that: The alkyl group of the carboxyalkyl group is an alkyl group with no more than 10 carbon atoms.

4. The chitosan or chitin polymer according to claim 1, characterized in that: The carboxyl group includes carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, or carboxyhexyl.

5. The method for preparing chitosan or chitin polymer according to any one of claims 1-4, characterized in that: This includes condensation reaction, dialysis, filling, and sterilization.

6. The method for preparing chitosan or chitin polymer according to claim 5, characterized in that, Includes the following steps: (1) Dissolution: Dissolve the carboxyl chitin and / or carboxyl chitosan raw materials in purified water or buffer solution to obtain a carboxyl chitin and / or carboxyl chitosan solution; (2) Condensation: The condensing agent is added to the carboxyl chitin and / or carboxyl chitose solution, and the condensation reaction is carried out at 5-40°C; The condensing agent is selected from one or more of 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine tetrafluoroborate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, and 2-chloro-1-methylpyridine iodide. (3) Dialysis, filling and sterilization: The prepared chitin and / or chitosan polymer hydrogel is dialyzed with purified water or buffer solution; the gel obtained after dialysis is filled and sterilized by moist heat to obtain the chitin and / or chitosan polymer hydrogel product.

7. The method for preparing chitosan or chitin polymer according to claim 6, characterized in that: In step (1), the buffer solution is one of a phosphate buffer system or a phosphate buffer system / sodium chloride solution, and the pH of the buffer solution is 6.0 to 8.5; the concentration of carboxyl chitin and / or carboxyl chitose in the solution is 0.5% to 5%.

8. The method for preparing chitosan or chitin polymer according to claim 6, characterized in that: In step (2), the molar amount of the condensing agent is 1% to 200% of the molar amount of the carboxyl group of the carboxyl chitin or carboxyl chitosan.

9. The method for preparing chitosan or chitin polymer according to claim 6, characterized in that: In step (3), purified water or buffer solution is used for dialysis. The amount of purified water or buffer solution used is 5 to 50 times the weight of the product. The single dialysis time is 4 to 24 hours, and the number of dialysis cycles is 2 to 6.

10. The use of the chitosan or chitin polymer according to any one of claims 1-4 in the preparation of intra-injection formulations, intra-filler formulations, or drug carrier formulations.

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