Long-acting degradable medical hydrogel and preparation method thereof

Abstract

The invention provides long-acting degradable medical hydrogel. The medical hydrogel is prepared from the following raw materials: a first component and a second component, wherein the first component is a polyethylene glycol derivative with 2-4 arms, and the second component is polyethyleneimine; the medical hydrogel disclosed by the invention has a network structure with high crosslinking density, is long in degradation time, and also has the properties of rapid gelling and low swelling degree.

Description

Technical Field

[0001] The invention relates to a long-acting degradable medical hydrogel and a preparation method thereof, belonging to the field of medical implant materials. Background Art

[0002] Hydrogels are a type of polymer with a three-dimensional network structure of hydrophilic groups, which can swell in water but not dissolve in water. Hydrogels have good physical and chemical properties and biological characteristics, such as high water content, softness, good biocompatibility, and similarity of their microstructure to biological tissues, and are widely studied and applied in biomedical fields such as drug sustained release and transport, tissue engineering, etc.

[0003] Polyethylene glycol (PEG) is a type of non-ionic polymer that has good biocompatibility, non-immunogenicity, and tolerance to protein adsorption. It is a type of synthetic polymer approved by the FDA for clinical use in humans. At present, relevant polyethylene glycol-based medical hydrogel products have been developed both at home and abroad, but these polyethylene glycol-based hydrogel products degrade quickly, and the degradation time is mostly about 3 months or shorter. For example, Stryker's AutoSpray Dural Sealant, Integra Dural SealantSystem, Cyxes Absorbable dura mater sealing medical glue.

[0004] However, there is still a clinical demand for medical hydrogels with long degradation time in the market. Therefore, it is necessary to research and develop a long-term degradable medical hydrogel. Summary of the invention

[0005] Problem that the invention aims to solve

[0006] In view of the technical problems existing in the prior art, the present invention first provides a long-term degradable medical hydrogel. The medical hydrogel has a network structure with high cross-linking density, a long degradation time, and has the properties of rapid gelation and low swelling degree. The medical hydrogel can better prevent adhesion of surgical wounds during the healing process, has good biocompatibility, and is non-irritating to tissues.

[0007] Furthermore, the present invention also provides a method for preparing a long-acting degradable medical hydrogel. The preparation method is simple and easy to implement, the raw materials are easy to obtain, and the method is suitable for mass production.

[0008] Solutions for solving problems

[0009] The present invention provides a long-term degradable medical hydrogel, wherein the raw materials for preparing the medical hydrogel include a first component and a second component; wherein:

[0010] The first component is a 2-4-arm polyethylene glycol derivative, and the second component is polyethyleneimine;

[0011] The polyethylene glycol derivatives include one or a combination of two or more of the structures shown in the following formulas I to IV:

[0012]

[0013] In Formula I-IV,

[0014] R represents each independently

[0015] n each independently represents a natural number, and preferably, n is 5-500.

[0016] Furthermore, the weight average molecular weight of the polyethylene glycol derivative is 2000-20000 Da; and / or the number average molecular weight of the polyethylene imine is 1000-3500 Da, preferably 1500-2000 Da.

[0017] Furthermore, the molar ratio of the electrophilic functional group of the first component to the nucleophilic functional group of the second component is (1:5) to (3:1).

[0018] Furthermore, the first component includes a two-arm polyethylene glycol derivative of the structure shown in formula (I), whose weight average molecular weight is 2000-5000 Da, and the molar ratio of the electrophilic functional group of the first component to the nucleophilic functional group of the second component is (0.8-1.2):(1.2-0.8).

[0019] Furthermore, the medical hydrogel is formed by a cross-linking reaction between the first component and the second component in a solvent, and the solvent includes one or a combination of two or more of water, water for injection, and a buffer solution.

[0020] Furthermore, the in vitro degradation time of the medical hydrogel is more than 5 months.

[0021] Furthermore, the gelation time of the medical hydrogel is less than 3s; and / or the swelling degree of the medical hydrogel is less than 60%; and / or the rupture strength of the medical hydrogel is greater than 7kPa; and / or after the medical hydrogel is immersed in water, the pH value of the immersion liquid obtained is 6-8.

[0022] The present invention also provides a method for preparing the medical hydrogel according to the present invention, which comprises the following steps:

[0023] dissolving the first component in a first solvent to obtain a solution A;

[0024] dissolving the second component in a second solvent to obtain a solution B;

[0025] The solution A and the solution B are mixed to obtain a medical hydrogel.

[0026] Furthermore, in the solution A, the mass volume ratio of the first component to the first solvent is 0.05 to 2 g / mL, preferably 0.10 to 0.50 g / mL; and / or,

[0027] In the solution B, the mass volume ratio of the second component to the second solvent is 0.001 to 0.1 g / mL, preferably 0.005 to 0.07 g / mL;

[0028] The solution A and the solution B are mixed in equal volumes to obtain a medical hydrogel.

[0029] The present invention also provides a kit for preparing the medical hydrogel of the present invention, which comprises a first component, a second component and a solvent for dissolving the components;

[0030] Preferably, the first component, the second component and the solvent are stored separately.

[0031] Effects of the Invention

[0032] The medical hydrogel of the invention has a network structure with high cross-linking density, a long degradation time, and simultaneously has the properties of rapid gelation and low swelling degree.

[0033] The medical hydrogel of the present invention has good flexibility and mechanical properties, a rupture strength greater than 7 kPa, can effectively adhere to tissues, seal wounds, reduce pressure on nerves and other tissues, and prevent adhesion of wounds caused by chronic inflammation.

[0034] In addition, the medical hydrogel of the present invention can also directly observe the hemostatic effect through the visual field during surgery.

[0035] The medical hydrogel of the present invention can gel in a short time, and does not need to be dissolved by acidic solution or alkaline solution during the preparation process, thereby reducing the risk of irritation to tissues during use and having good biocompatibility.

[0036] Furthermore, the preparation steps of the medical hydrogel of the present invention are simple and easy to operate, so it is suitable for large-scale industrial mass production and easy to implement and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The medical hydrogel of Example 7 is shown after subcutaneous implantation for one month;

[0038] Figure 2 The figure shows the medical hydrogel of Example 7 after subcutaneous implantation for 2 months;

[0039] Figure 3 The medical hydrogel of Example 7 is shown 5 months after subcutaneous implantation. DETAILED DESCRIPTION

[0040] Various exemplary embodiments, features and aspects of the present invention will be described in detail below. The word "exemplary" used here means "used as an example, embodiment or illustrative". Any embodiment described here as "exemplary" is not necessarily interpreted as being superior or better than other embodiments.

[0041] In addition, in order to better illustrate the present invention, numerous specific details are provided in the following specific embodiments. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In other examples, methods, means, equipment and steps well known to those skilled in the art are not described in detail in order to highlight the subject matter of the present invention.

[0042] Unless otherwise stated, the units used in this specification are all international standard units, and the numerical values ​​and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0043] In this specification, the word "may" means both performing a certain process and not performing a certain process.

[0044] In this specification, the references to "some specific / preferred embodiments", "other specific / preferred embodiments", "embodiments", etc., mean that the specific elements (e.g., features, structures, properties and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not exist in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0045] In this specification, the numerical range expressed using "a numerical value A to a numerical value B" means a range including the endpoints numerical values ​​A and B.

[0046] In this specification, the term “mass-to-volume ratio” is used to refer to the ratio of the mass of a solute to the volume of a solvent, and the unit is “g / mL”.

[0047] <First aspect>

[0048] The first aspect of the present invention provides a long-lasting degradable medical hydrogel, the raw materials for its preparation include a first component and a second component, the first component is a 2-4-arm polyethylene glycol derivative, which contains an electrophilic functional group succinimide ester group, and the second component is polyethyleneimine, which contains a nucleophilic functional group amino group; and

[0049] The polyethylene glycol derivatives include one or a combination of two or more of the structures shown in the following formulas I to IV:

[0050]

[0051] In Formula I-IV,

[0052]

[0053] R represents each independently

[0054] n each independently represents a natural number, and preferably, n is 5-550.

[0055] The long-acting degradable medical hydrogel of the invention has a network structure with high cross-linking density, a long degradation time, and simultaneously has the properties of rapid gelation and low swelling degree.

[0056] In some specific embodiments, the first component is one or a combination of two or more of disuccinimidyl carbonate-based polyethylene glycol (SC-PEG-SC), three-arm polyethylene glycol succinimidyl carbonate (3-arm PEG-SC), four-arm polyethylene glycol succinimidyl carbonate (4-arm PEG-SC), disuccinimidyl succinate polyethylene glycol (SSA-PEG-SSA), three-arm polyethylene glycol succinimidyl succinate (3-arm PEG-SSA), and four-arm polyethylene glycol succinimidyl succinate (4-arm PEG-SSA). The specific structure of the above polyethylene glycol derivative is as follows:

[0057]

[0058]

[0059] In the present invention, there is no specific limitation on the value of n in each formula, and it can be any natural number independently. For example, the value of n can be 5-550, such as 8-400, and 10-300, etc.; and in the polyethylene glycol derivatives of the above structure, the value of n in each arm can be the same or different. The inventors of the present application found that the medical hydrogel formed by reacting the polyethylene glycol derivatives of the above structure with polyethyleneimine is more stable and has a longer degradation time.

[0060] Furthermore, the present invention can control the molecular weight of the polyethylene glycol derivative by the value of n. In some specific embodiments, the polyethylene glycol derivative of the above structure has a weight average molecular weight of 2000-20000Da, such as 2000Da, 5000Da, 10000Da, 20000Da, etc., preferably 2000-5000Da.

[0061] The second component of the long-acting degradable medical hydrogel in the present invention is polyethyleneimine, which contains a nucleophilic functional group, which can be an amino group, preferably a primary amino group. The inventors found that the use of polyethyleneimine as the second component is more stable than polylysine, and the gel formation is faster than polylysine.

[0062] In some specific embodiments, the number average molecular weight of polyethyleneimine is 1000-3500Da, for example 1200Da, 1800Da, 2200Da, 2500Da, 2800Da, 3000Da, etc., preferably 1500-2000Da, more preferably 1800Da, wherein the molar content of primary amino groups in all amine groups (including primary amine groups, secondary amine groups, and tertiary amine groups) is 20-45%, preferably 35%.

[0063] In the present invention, the succinimide ester group of the first component polyethylene glycol derivative reacts chemically with the primary amine group of the second component polyethylene imine, forming a covalent bond between the two and a network structure with a high cross-linking density. The obtained medical hydrogel has a long degradation time, fast gelation, and low swelling degree, which can reduce the pressure on nerves and other tissues and prevent adhesion of wounds caused by chronic inflammation. In addition, the active functional group of the succinimide ester group of the polyethylene glycol derivative can covalently bond with biological tissues, effectively adhere to tissues, and seal wounds.

[0064] In some specific embodiments, in order to improve the crosslinking degree of the medical hydrogel and enhance the mechanical strength of the medical hydrogel, the molar ratio of the electrophilic functional group of the first component to the nucleophilic functional group of the second component is (1:5) to (3:1). When the molar ratio of the electrophilic functional group of the first component to the nucleophilic functional group of the second component is (1:5) to (3:1), a medical hydrogel with low swelling, high rupture strength and long-term degradability can be obtained.

[0065] Furthermore, the medical hydrogel of the present invention is formed by a cross-linking reaction between the first component and the second component in a solvent, and the solvent includes one or a combination of two or more of water, water for injection, and a buffer solution.

[0066] In some specific embodiments, the medical hydrogel of the present invention has a longer degradation time compared with the existing hydrogel. Specifically, when the first component is any one of disuccinimidyl carbonate-based polyethylene glycol (SC-PEG-SC), three-arm polyethylene glycol succinimidyl carbonate (3-arm PEG-SC), and four-arm polyethylene glycol succinimidyl carbonate (4-armPEG-SC), the medical hydrogel formed by it and the second component polyethylene imine can have an in vitro degradation time of more than 8 months. When the first component is any one of disuccinimidyl succinate polyethylene glycol (SSA-PEG-SSA), three-arm polyethylene glycol succinimidyl succinate (3-arm PEG-SSA), and four-arm polyethylene glycol succinimidyl succinate (4-arm PEG-SSA), the medical hydrogel formed by it and the second component polyethylene imine has an in vitro degradation time of 6-7 months.

[0067] In the present invention, the gelation time of the medical hydrogel is less than 3s, the swelling degree is less than 60%, and the rupture strength is greater than 7Kpa. When used, the medical hydrogel can quickly fill the gaps in the wound surface, gel to form a non-flowable hydrogel with a certain mechanical strength, effectively adhere to tissues, seal wounds, reduce pressure on nerves and other tissues, and prevent adhesion of wounds caused by chronic inflammation. It can be used in narrow areas of the brain, spine and peripheral nerves where they are densely distributed, as well as areas with large amounts of bleeding.

[0068] In the present invention, the medical hydrogel also has good biocompatibility. When the medical hydrogel is soaked in water, the pH value of the obtained soaking liquid is 6 to 8, preferably 7 to 8, and has no stimulation to tissues.

[0069] In some specific embodiments, when the first component is disuccinimidyl carbonate polyethylene glycol (SC-PEG-SC) or disuccinimidyl succinate polyethylene glycol (SSA-PEG-SSA), the weight-average molecular weight of the first component is 2000-5000 Da, and the molar ratio of the electrophilic functional group of the first component to the nucleophilic functional group of the second component is (0.8-1.2):(1.2-0.8), the inventors found that the medical hydrogel obtained in this case has the best comprehensive performance, and can have low swelling and high rupture strength while achieving rapid gelation and long-term degradation. Specifically, the swelling degree is less than 30% and the rupture strength is higher than 25 kPa.

[0070] <Second Aspect>

[0071] The second aspect of the present invention also provides a method for preparing the medical hydrogel according to the first aspect of the present invention, comprising the following steps:

[0072] dissolving the first component in a first solvent to obtain a solution A;

[0073] dissolving the second component in a second solvent to obtain a solution B;

[0074] The solution A and the solution B are mixed to obtain a medical hydrogel.

[0075] The first component is a 2-4-arm polyethylene glycol derivative containing an electrophilic functional group, and the second component is a polyethylene imine containing a nucleophilic functional group.

[0076] After the solution A and the solution B of the present invention are mixed, for example, a double mixer can be used for mixing, and the polyethylene glycol derivative and the polyethyleneimine undergo Michael addition reaction to form a gel quickly, that is, to generate the medical hydrogel of the present invention.

[0077] In the present invention, the first solvent and the second solvent are the same or different, preferably, the first solvent and the second solvent are the same. The present invention does not specifically limit the first solvent for dissolving the first component and the second solvent for dissolving the second component, and can be one or a combination of two or more of any feasible water in the art such as water, water for injection, buffer solution, etc., more preferably water and / or water for injection.

[0078] Specifically, the water can be any water commonly used in the art, such as ultrapure water, deionized water, purified water, etc. The buffer can be a phosphate buffer, a carbonate buffer, a borate buffer, etc. The buffer can be selected according to the stability of the nucleophilic or electrophilic components in the buffer and the physicochemical properties of the formed hydrogel.

[0079] In some specific embodiments, in the solution A, the mass volume ratio of the first component to the first solvent is 0.05-2 g / mL, preferably 0.10-0.50 g / mL; in the solution B, the mass volume ratio of the second component to the second solvent is 0.001-0.1 g / mL, preferably 0.005-0.07 g / mL; the solution A and solution B are mixed in equal volumes to obtain a medical hydrogel.

[0080] <Third Aspect>

[0081] The third aspect of the present invention provides a medical hydrogel kit, which includes the first component and the second component described in the first aspect of the present invention, and a solvent for dissolving each component; preferably, the first component, the second component, and the solvent are stored separately. Specifically, the medical hydrogel kit of the present invention includes the first component, the second component, the first solvent, and the second solvent.

[0082] In the present invention, the first component and the second component can be separated, and the first component and the second component are mixed when used. In the actual application process, the first component and the second component can be stored separately, or can be stored in the form of being pre-dissolved in a solvent. The present invention does not limit the storage method of each component, and those skilled in the art can select a specific storage method as needed, which is within the scope of the present invention.

[0083] <Fourth Aspect>

[0084] The fourth aspect of the present invention provides an application of the medical hydrogel according to the first aspect of the present invention in preparing a hemostatic product or an anti-adhesion product. The medical hydrogel of the present invention is mainly for patients whose wounds or wound surfaces need not cause scarring during healing, and the medical hydrogel needs to be completely degraded only after the wound or wound surface has completed scarring repair, so as to play an anti-adhesion role.

[0085] Example

[0086] The embodiments of the present invention will be described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. The polyethyleneimine used in the examples has a number average molecular weight of 1800 Da and a molar content of primary amine groups in all amine groups of 35%, and was purchased from Aladdin Reagent Company.

[0087] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. If the manufacturers of reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0088] Example 1

[0089] 0.4167 g of disuccinimidyl carbonate-based polyethylene glycol (SC-PEG-SC, weight average molecular weight 2000 Da) was dissolved in 1.5 mL of water for injection to obtain a solution A with a mass volume ratio of 0.278 g / mL; 0.05 g of polyethyleneimine was dissolved in 1.5 mL of water for injection to obtain a solution B with a mass volume ratio of 0.033 g / mL; wherein the molar ratio of the electrophilic functional group (succinimidyl ester group) to the nucleophilic functional group (primary amine group) was about 1:1. Solution A and solution B were extruded at a volume ratio of 1:1 through a double mixing syringe to form a medical hydrogel.

[0090] Example 2

[0091] 1.0418g of four-arm polyethylene glycol succinimidyl carbonate (4-arm-PEG-SC, weight average molecular weight 10000Da) was dissolved in 3mL of water for injection to obtain solution A with a mass volume ratio of 0.347g / mL; 0.05g of polyethyleneimine was dissolved in 3mL of water for injection to obtain solution B with a mass volume ratio of 0.017g / mL; the molar ratio of electrophilic functional group (succinimidyl ester group) to nucleophilic functional group (primary amine group) was about 1: 1. Solution A and solution B were extruded at a volume ratio of 1: 1 through a double mixing syringe to form a medical hydrogel.

[0092] Example 3

[0093] 1.25g of disuccinimidyl carbonate-based polyethylene glycol (SC-PEG-SC, weight average molecular weight 2000Da) was dissolved in 5mL of water for injection to obtain solution A with a mass volume ratio of 0.250g / mL; 0.15g of polyethyleneimine was dissolved in 5mL of water for injection to obtain solution B with a mass volume ratio of 0.030g / mL; the molar ratio of electrophilic functional groups (succinimidyl ester groups) to nucleophilic functional groups (primary amine groups) was about 1:1. Solution A and solution B were extruded at a volume ratio of 1:1 through a double mixing syringe to form a medical hydrogel.

[0094] Example 4

[0095] 1.7396g of disuccinimidyl carbonate-based polyethylene glycol (SC-PEG-SC, weight average molecular weight 5000Da) was dissolved in 5mL of water for injection to obtain solution A with a mass volume ratio of 0.348g / mL; 0.0835g of polyethyleneimine was dissolved in 5mL of water for injection to obtain solution B with a mass volume ratio of 0.017g / mL; the molar ratio of electrophilic functional groups (succinimidyl ester groups) to nucleophilic functional groups (primary amine groups) was about 1:1. Solution A and solution B were extruded at a volume ratio of 1:1 through a double mixing syringe to form a medical hydrogel.

[0096] Example 5

[0097] 1.5g of three-arm polyethylene glycol succinimidyl carbonate (3-arm PEG-SC, weight average molecular weight 20000Da) was dissolved in 5mL of water for injection to obtain solution A with a mass volume ratio of 0.300g / mL; 0.135g of polyethyleneimine was dissolved in 5mL of water for injection to obtain solution B with a mass volume ratio of 0.027g / mL; the molar ratio of electrophilic functional group (succinimidyl ester group) to nucleophilic functional group (primary amine group) was about 1:5. Solution A and solution B were extruded at a volume ratio of 1:1 through a double mixing syringe to form a medical hydrogel.

[0098] Example 6

[0099] 1.0418g of disuccinimidyl succinate polyethylene glycol (SSA-PEG-SSA, weight average molecular weight 5000Da) was dissolved in 3mL of water for injection to obtain solution A with a mass volume ratio of 0.347g / mL; 0.05g of polyethyleneimine was dissolved in 3mL of water for injection to obtain solution B with a mass volume ratio of 0.017g / mL; the molar ratio of electrophilic functional group (succinimidyl ester group) to nucleophilic functional group (primary amine group) was about 1: 1. Solution A and solution B were extruded at a volume ratio of 1: 1 through a double mixing syringe to form a medical hydrogel.

[0100] Example 7

[0101] 1.25 g of disuccinimidyl succinate polyethylene glycol (SSA-PEG-SSA, weight average molecular weight 2000 Da) was dissolved in 5 mL of water for injection to obtain a solution A with a mass volume ratio of 0.250 g / mL; 0.15 g of polyethylene imine was dissolved in 5 mL of water for injection to obtain a solution B with a mass volume ratio of 0.030 g / mL; the molar ratio of the electrophilic functional group (succinimidyl ester group) to the nucleophilic functional group (primary amine group) was about 1: 1. Solution A and solution B were extruded at a volume ratio of 1: 1 through a double mixing syringe to form a medical hydrogel.

[0102] Example 8

[0103] 1.25g of four-arm polyethylene glycol succinimidyl succinate (4-arm PEG-SSA, weight average molecular weight 20000Da) was dissolved in 5mL of water for injection to obtain solution A with a mass volume ratio of 0.250g / mL; 0.15g of polyethyleneimine was dissolved in 5mL of water for injection to obtain solution B with a mass volume ratio of 0.030mg / mL; the molar ratio of electrophilic functional group (succinimidyl ester group) to nucleophilic functional group (primary amine group) was about 1:5. Solution A and solution B were extruded at a volume ratio of 1:1 through a double mixing syringe to form a medical hydrogel.

[0104] Example 9

[0105] 2.5g of three-arm polyethylene glycol succinimidyl succinate (3-arm PEG-SSA, weight average molecular weight 10000Da) was dissolved in 5mL of water for injection to obtain solution A with a mass volume ratio of 0.500mg / mL; 0.03g of polyethyleneimine was dissolved in 5mL of water for injection to obtain solution B with a mass volume ratio of 0.006mg / mL; the molar ratio of electrophilic functional group (succinimidyl ester group) to nucleophilic functional group (primary amine group) was about 3: 1. Solution A and solution B were extruded at a volume ratio of 1: 1 through a double mixing syringe to form a medical hydrogel.

[0106] Comparative Example 1

[0107] 0.4167g of disuccinimidyl glutarate polyethylene glycol (SG-PEG-SG, weight average molecular weight 2000Da) was dissolved in 1.5mL of water for injection to obtain solution A with a mass volume ratio of 0.278g / mL; 0.05g of polyethyleneimine was dissolved in 1.5mL of water for injection to obtain solution B with a mass volume ratio of 0.033g / mL; the molar ratio of electrophilic functional group (succinimidyl ester group) to nucleophilic functional group (primary amine group) was about 1: 1. Solution A and solution B were extruded at a volume ratio of 1: 1 through a double mixing syringe to form a medical hydrogel.

[0108] Comparative Example 2

[0109] 1.0418g of four-arm polyethylene glycol succinimidyl glutarate (4-arm PEG-SG, weight average molecular weight 10000Da) was dissolved in 3mL of water for injection to obtain solution A with a mass volume ratio of 0.347g / mL; 0.05g of polyethyleneimine was dissolved in 3mL of water for injection to obtain solution B with a mass volume ratio of 0.017g / mL; the molar ratio of electrophilic functional group (succinimidyl ester group) to nucleophilic functional group (primary amine group) was about 1: 1. Solution A and solution B were extruded at a volume ratio of 1: 1 through a double mixing syringe to form a medical hydrogel.

[0110] Performance Testing

[0111] 1. In vitro degradation experiment

[0112] The solutions A and B prepared in Examples 1 to 9 and Comparative Examples 1 and 2 were extruded in equal volumes using a double mixing syringe to form a hydrogel with a thickness of 2 mm, and then the hydrogel was completely immersed in a PBS buffer with a pH value of 7.2±0.2, and sealed and placed in a 37±1°C constant temperature box, and the degradation of the hydrogel was observed and recorded. The change of the hydrogel in the buffer was until it was invisible to the naked eye, which was the in vitro degradation time of the hydrogel. The observation time lasted for 12 months, and the degradation of the hydrogel was observed once a month. The results are shown in Table 1.

[0113] Table 1 In vitro degradation time of medical hydrogel

[0114] sample In vitro degradation time / month Example 1 12 Example 2 8 Example 3 12 Example 4 8 Example 5 10 Example 6 6 Example 7 6 Example 8 7 Example 9 7 Comparative Example 1 3 Comparative Example 2 3

[0115] As can be seen from Table 1, the in vitro degradation time of the medical hydrogels of Examples 1 to 9 of the present invention is long, and is greater than the in vitro degradation time of the medical hydrogels of Comparative Examples 1 and 2. In addition, the in vitro degradation time of the hydrogels formed by the reaction of polyethylene glycol succinimidyl carbonate and polyethylene imine, i.e., the medical hydrogels of Examples 1 to 5, can reach more than 8 months; the in vitro degradation time of the hydrogels formed by the reaction of polyethylene glycol succinimidyl carbonate and polyethylene imine, i.e., the medical hydrogels of Examples 6 to 9, is 6 to 7 months.

[0116] 2. Subcutaneous implant degradation experiment.

[0117] Rats were selected as experimental animals, and three sample points were implanted subcutaneously on both sides of the rat spine (the medical hydrogel of Example 7 of the present invention was used for the experiment), 0.5 mL / point, and the sample implantation method was carried out according to the surgical operation process specified in "GB / T16886.6-2022 / ISO 10993-6:2016 Biological Evaluation of Medical Devices Part 6: Local Reaction Test after Implantation". The animals were observed every day after the operation, and no abnormalities were found, including local, systemic and behavioral abnormalities. The results are as follows: Figure 1-2 shown.

[0118] like Figure 1 As shown, hydrogel can be seen by naked eye observation 1 month after surgery; Figure 2 As shown, macroscopic observation at 2 months after surgery showed no significant difference in the size of the hydrogel compared to that at 1 month after surgery; Figure 3 As shown, macroscopic observation 5 months after surgery showed no significant difference in the size of the hydrogel compared to that of the hydrogel 1 month after surgery, and the hydrogel did not degrade.

[0119] The above animal experiment results show that the medical hydrogel of the present invention has not been degraded at the subcutaneous implantation site for 5 months, and no abnormal subcutaneous lesions are observed at the implantation site, and has high biosafety.

[0120] 3. Gelation time

[0121] Equal volumes of solution A and solution B prepared in Examples 1 to 9 and Comparative Examples 1 and 2 were respectively filled into a double mixing syringe, and the two-component mixer was evenly pushed. After solution A and solution B were mixed by the two-component mixer, they were sprayed onto a watch glass, and timing was started at the same time until a gel was completely formed (no flowing liquid). This time was recorded as the gelation time. The results are shown in Table 2.

[0122] 4. Swelling test

[0123] The swelling degree refers to the change in volume or weight between the moment when the gel cross-linking is effectively completed and the moment when it is placed in a free state in physiological saline or PBS solution for 24 hours (at this time point it can be reasonably assumed that the hydrogel has reached its equilibrium swelling state). The detection method is as follows: The solution A and solution B prepared in Examples 1 to 9 and Comparative Examples 1 and 2 are respectively filled into a double mixing syringe, injected into the template in equal volumes, and weighed after the gel is formed. The gel is transferred to a centrifuge tube, PBS buffer is added, and the sample is taken out after 24 hours, the surface moisture is absorbed with filter paper, and weighed. The swelling rate is calculated according to the following formula, and the results are shown in Table 2.

[0124] Swelling rate % = (final weight at 24h - initial formation mass) / initial formation mass × 100%

[0125] 5. Bursting strength test

[0126] The rupture strength of the hydrogel reflects its mechanical properties during use. The detection method is as follows: a hole with a diameter of about 0.2 cm is made on a pig casing, and the solution A and solution B prepared in Examples 1 to 9 and Comparative Examples 1 and 2 are respectively filled into a double-mixed syringe, and equal volumes are extruded and sprayed onto the hole to form a gel, with the amount of gel being about 2 mL, and pressurized with physiological saline until the gel breaks, and the maximum pressure number on the digital readout connected to the sensor is recorded, and the results are shown in Table 2.

[0127] 6. pH test

[0128] The acidity and alkalinity (pH value) of the medical hydrogel of the present invention or the pH value of the soaking solution is measured by the following method: a certain amount of the medical hydrogel is placed in physiological saline, kept at a constant temperature of 37° C. for 24 hours, and the pH value of the soaking solution is tested. The results are shown in Table 2.

[0129] Table 2 Performance test results of medical hydrogel

[0130] sample Gelation time / s Swelling rate / % Bursting strength / kPa pH Example 1 1.01 1.36 36.64 7.26 Example 2 1.13 35.36 41.26 7.36 Example 3 1.64 5.31 26.65 7.47 Example 4 1.24 25.36 55.41 7.21 Example 5 0.95 12.59 17.65 7.94 Example 6 0.85 20.35 30.94 7.35 Example 7 0.98 15.68 34.10 7.20 Example 8 0.87 14.65 9.25 7.62 Example 9 1.03 45.36 26.14 7.11 Comparative Example 1 0.82 21.36 31.03 7.32 Comparative Example 2 0.95 39.63 29.46 7.06

[0131] As can be seen from Table 2, the gelling time, swelling rate and pH value of the medical hydrogels of Examples 1 to 9 of the present invention can reach comparable levels compared to Comparative Examples 1 and 2; and the rupture strength of the medical hydrogel of the present invention is greater than 7 kPa, which can meet clinical needs. In addition, compared with Examples 2, 5, 8, and 9, Examples 1, 3, 4, 6, and 7 of the present invention can have a higher rupture strength while meeting the low swelling degree, that is, when the swelling degree is less than 30%, the rupture strength is greater than 25 kPa.

[0132] It should be noted that, although the technical solution of the present invention is introduced with specific examples, those skilled in the art will appreciate that the present invention should not be limited thereto.

[0133] The embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles of the embodiments, practical applications, or technical improvements in the market, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

Claims

1. A long-lasting degradable medical hydrogel, characterized in that: The raw materials for preparing the medical hydrogel include a first component and a second component; wherein, The first component is a 2-4-arm polyethylene glycol derivative, and the second component is polyethyleneimine; The polyethylene glycol derivatives include one or a combination of two or more of the structures shown in the following formulas I to IV: In Formula I-IV, R represents each independently n each independently represents a natural number, and preferably, n is 5-500.

2. The medical hydrogel according to claim 1, characterized in that The weight average molecular weight of the polyethylene glycol derivative is 2000 to 20000 Da; and / or, The number average molecular weight of the polyethyleneimine is 1000-3500 Da, preferably 1500-2000 Da.

3. The medical hydrogel according to claim 1 or 2, characterized in that: The molar ratio of the electrophilic functional group of the first component to the nucleophilic functional group of the second component is (1:5) to (3:1).

4. The medical hydrogel according to any one of claims 1 to 3, characterized in that: The first component includes a two-arm polyethylene glycol derivative of the structure shown in formula (I), whose weight average molecular weight is 2000-5000 Da, and the molar ratio of the electrophilic functional group of the first component to the nucleophilic functional group of the second component is (0.8-1.2):(1.2-0.8).

5. The medical hydrogel according to any one of claims 1 to 4, characterized in that: The medical hydrogel is formed by a cross-linking reaction between the first component and the second component in a solvent, and the solvent includes one or a combination of two or more of water, water for injection, and a buffer solution.

6. The medical hydrogel according to any one of claims 1 to 5, characterized in that: The in vitro degradation time of the medical hydrogel is more than 5 months.

7. The medical hydrogel according to any one of claims 1 to 5, characterized in that: The gelation time of the medical hydrogel is less than 3 seconds; and / or, The swelling degree of the medical hydrogel is less than 60%; and / or The medical hydrogel has a rupture strength greater than 7 kPa; and / or After the medical hydrogel is soaked in water, the pH value of the obtained soaking liquid is 6-8.

8. A method for preparing the medical hydrogel according to any one of claims 1 to 7, characterized in that: The following steps are involved: dissolving the first component in a first solvent to obtain a solution A; dissolving the second component in a second solvent to obtain a solution B; The solution A and the solution B are mixed to obtain a medical hydrogel.

9. The preparation method according to claim 8, characterized in that: In the solution A, the mass volume ratio of the first component to the first solvent is 0.05 to 2 g / mL, preferably 0.10 to 0.50 g / mL; and / or, In the solution B, the mass volume ratio of the second component to the second solvent is 0.001 to 0.1 g / mL, preferably 0.005 to 0.07 g / mL; The solution A and the solution B are mixed in equal volumes to obtain a medical hydrogel.

10. A kit for preparing the medical hydrogel according to any one of claims 1 to 7, characterized in that: It comprises a first component, a second component and a solvent for dissolving the components; preferably, the first component, the second component and the solvent are stored separately.

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