WO2017186168A1 - 医用水凝胶组合物，医用水凝胶及其制备方法与应用 - Google Patents

医用水凝胶组合物，医用水凝胶及其制备方法与应用 Download PDF

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Publication number
WO2017186168A1
WO2017186168A1 PCT/CN2017/082425 CN2017082425W WO2017186168A1 WO 2017186168 A1 WO2017186168 A1 WO 2017186168A1 CN 2017082425 W CN2017082425 W CN 2017082425W WO 2017186168 A1 WO2017186168 A1 WO 2017186168A1
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Prior art keywords
medical hydrogel
component
medical
polylysine
arm
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PCT/CN2017/082425
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English (en)
French (fr)
Inventor
林丽敏
杨亚亚
马骋
邓坤学
袁玉宇
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广州迈普再生医学科技有限公司
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Application filed by 广州迈普再生医学科技有限公司 filed Critical 广州迈普再生医学科技有限公司
Priority to KR1020187034510A priority Critical patent/KR102203199B1/ko
Priority to RU2018141863A priority patent/RU2724057C2/ru
Priority to MX2018013150A priority patent/MX2018013150A/es
Priority to EP17788820.3A priority patent/EP3449956B1/en
Priority to US16/097,473 priority patent/US11065360B2/en
Publication of WO2017186168A1 publication Critical patent/WO2017186168A1/zh
Priority to CONC2018/0012925A priority patent/CO2018012925A2/es

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Definitions

  • the present disclosure relates to a medical hydrogel composition, a medical hydrogel, a preparation method and application thereof, and belongs to the technical field of biomedicine.
  • hydrogels can be used in the field of closure, anti-adhesion or drug loading of wounds in the body.
  • the hydrogel is a gel with water as a dispersion medium and has a three-dimensional network structure. It cannot be dissolved in water, can swell in water, absorb a large amount of water, and increase the volume of the hydrogel.
  • the highly swellable hydrogel will cause compression of the peripheral nerves, which may interfere with the normal function of the body, and may cause oppressive necrosis of the surrounding tissues in severe cases.
  • Patent document CN101843925A provides a low swelling hydrogel having a degree of swelling of from about -50% to about 50%.
  • the raw material used in this patent is trilysine, which is expensive and the resulting low swelling hydrogel is alkaline. Since most tissues have a neutral environment in the human body, if the implant is alkaline, it will have a more severe stimulating effect on surrounding cells.
  • the technical problem to be solved by the present disclosure is to provide a medical hydrogel composition having good biocompatibility, low swelling degree, good biodegradability and low cost, and the medical hydrogel A medical hydrogel prepared from the composition. Further, a medical hydrogel that is non-irritating to tissue is also provided.
  • the present disclosure provides a medical hydrogel composition
  • a medical hydrogel composition comprising a first component and a second component, the first component comprising polylysine and polyethyleneimine;
  • the two components include four-arm-polyethylene glycol-succinimide glutarate, four-arm-polyethylene glycol-succinimide succinate, four-arm-polyethylene glycol-succinimide One or more of the carbonates, wherein the polylysine has a degree of polymerization of 20 or more, preferably 25 to 35.
  • the mass ratio of the polylysine to the polyethyleneimine in the first component is from 0.1 to 10.
  • the polylysine is ⁇ -polylysine and/or poly-L-lysine.
  • the ⁇ -polylysine has a weight average molecular weight of 3,000 to 5,000 Da.
  • the poly-L-lysine has a weight average molecular weight of from 7,500 to 300,000 Da, preferably from 100,000 to 200,000 Da.
  • the polyethyleneimine has a number average molecular weight of from 1,000 to 3,500 Da, preferably from 1,500 to 2,000 Da.
  • the four-arm-polyethylene glycol-succinimide glutarate, four-arm-polyethylene glycol-succinimide The weight average molecular weight of the diester and the four-arm-polyethylene glycol-succinimide carbonate is from 2,000 to 40,000 Da, preferably from 10,000 to 20,000 Da.
  • the medical hydrogel composition is loaded with a drug or an active factor, preferably, the first component and/or the second component Contains drugs or active factors.
  • the present disclosure also provides a medical hydrogel formed by reacting a first component and a second component of the medical hydrogel composition of the present invention; preferably, the medical hydrogel is the first The component and the second component are formed after reacting in a buffer solution.
  • the medical hydrogel is dissolved in the first buffer solution by the first component, and the second component is dissolved in the second buffer solution. Then, it is mixed and formed after the reaction.
  • the medical hydrogel has a degree of swelling of from -10 to 50%, preferably from 5 to 47%.
  • the pH of the infusion solution is 7 to 9.5, preferably 7 to 8.
  • the pH of the first buffer solution is 7.0-7.4 or 9.1-10.0, preferably 7.0-7.4; and the pH of the second buffer solution is 5.0. ⁇ 6.0 or 7.0 to 7.4, preferably 7.0 to 7.4.
  • the present disclosure also provides a method for preparing the above medical hydrogel, comprising the following steps:
  • the first mixed solution and the second mixed solution are mixed to obtain a medical hydrogel.
  • the concentration of the polylysine in the first mixed solution is 1 to 50 mg/mL, and the concentration of the polyethyleneimine. Is 1 to 50 mg/mL; in the second mixture, the four-arm-polyethylene glycol-succinimide glutarate, four-arm-polyethylene glycol-succinimide succinate
  • concentration of the four-arm-polyethylene glycol-succinimide carbonate or a mixture thereof is 100 to 200 mg/mL, and the first mixed liquid and the second mixed liquid are mixed in an equal volume to obtain a medical hydrogel.
  • the second mixed liquid further includes a color developing agent, and preferably, the color developing agent includes FD&C Blue#1, FD&C Blue#2 One or more of methylene blue.
  • the present invention also provides a medical hydrogel kit comprising the medical hydrogel composition of the present invention and a buffer solution for dissolving the components of the medical hydrogel composition.
  • the first component and the second component of the medical hydrogel composition are separately stored; preferably, the medical hydrogel
  • the polylysine and polyethyleneimine in the first component of the composition are stored separately.
  • the invention also provides an application to the above medical hydrogel in a hemostatic aid, a lung leakage prevention or a cerebrospinal fluid leakage product, and an anti-adhesion article.
  • the prepared medical hydrogel has a low degree of swelling of only -10% to 50%, and can be applied to a narrow portion where the brain, the spine, and peripheral nerves are densely distributed.
  • the medical hydrogel prepared by the present disclosure has good biocompatibility and good antibacterial and biodegradability. Further, the medical hydrogel of the present disclosure can also have an effect of not stimulating the tissue.
  • Figure 1 shows the growth state of cells cultured in the extract of medical hydrogel I of Example 1 for 24 hours
  • Figure 3 shows the degradation of the medical hydrogel IV of Example 4 subcutaneously implanted in rats at the time of five-week dissection
  • Figure 4 shows the degradation of the medical hydrogel XI of the subcutaneously implanted in Comparative Example 4 at 5 weeks anatomy
  • Figure 5 shows a histological section of a portion of a medical hydrogel IV implanted subcutaneously in Example 5 at five weeks of anatomy;
  • Figure 6 shows a histological section of a portion of a medical hydrogel XI implanted subcutaneously with a ratio of 4 in a five-week anatomy
  • Figure 7 shows a picture of the dura of the test animal dog
  • Figure 8 shows a picture of the test animal dog after dural suture
  • Figure 9 is a photograph showing the injection of a medical hydrogel after dural suture of a test animal dog
  • Figure 10 is a photograph showing the release of the skull of the test animal dog after the dural injection
  • Fig. 11 is a graph showing the healing effect of the healing position of the incision site of the dura mater of the test animal dog after 4 weeks of feeding.
  • the present disclosure provides a medical hydrogel composition and a medical hydrogel obtained by reacting different components of the medical hydrogel composition.
  • the medical hydrogel composition of the present disclosure primarily comprises a first component comprising a nucleophile and a second component comprising an electrophile, the nucleophile comprising polylysine and polyethyleneimine (PEI),
  • the electrophile includes four-arm-polyethylene glycol-succinimide glutarate (4-arms-PEG-SG), four-arm-polyethylene glycol-succinimide succinate (4 -arms-PEG-SS), one or more of four-arm-polyethylene glycol-succinimide carbonate (4-arms-PEG-SC).
  • first component and the second component may be separated, and the first component and the second component are mixed at the time of use.
  • the polylysine and polyethyleneimine (PEI) in the first component are also separated, and polylysine and polyethyleneimine (PEI) are mixed several hours before use or at the time of use. .
  • polylysine and polyethyleneimine can be stored separately, and dissolved in the same solvent before use or at the time of use.
  • polylysine may also be stored in a pre-dissolved form in a solvent, for example, may be dissolved in a small amount of a buffer solution, diluted with a buffer solution before use, or dissolved in a buffer solution according to the concentration at the time of use. Store.
  • polylysine dissolved in a buffer solution Polyethyleneimine (PEI) is mixed.
  • the second component is redissolved in the solvent before use or at the time of use.
  • the present disclosure is not limited to the manner in which the components of the medical hydrogel composition are stored, and those skilled in the art can select specific storage methods as needed, and are all within the scope of the present disclosure.
  • the polylysine of the present disclosure may be ⁇ -polylysine and/or poly-L-lysine, and the degree of polymerization of the polylysine is 20 or more, preferably 25 to 35.
  • polylysine having a degree of polymerization of 20 or more is added, and the crosslinking density can be increased to lower the equilibrium swelling degree.
  • the weight average molecular weight of ⁇ -polylysine is preferably 3,000 to 5,000 Da
  • the weight average molecular weight of poly-L-lysine is preferably from 7,500 to 300,000 Da, preferably from 100,000 to 200,000 Da.
  • the polyethyleneimine (PEI) has a number average molecular weight of from 1,000 to 3,500 Da, preferably from 1,500 to 2,000 Da.
  • the mass ratio of the polylysine to the polyethyleneimine is from 0.1 to 10.
  • the second component of the medical hydrogel composition of the present disclosure comprises four-arm-polyethylene glycol-succinimide glutarate, four-arm-polyethylene glycol-succinimide succinate, and
  • the four-arm-polyethylene glycol-succinimide carbonate has a weight average molecular weight of from 2,000 to 40,000 Da, preferably from 10,000 to 20,000 Da.
  • polylysine including ⁇ -polylysine and poly-L-lysine
  • polylysine may exist in the form of its hydrochloride, hydrobromide or other salt, both Within the scope of the disclosure.
  • the medical hydrogel composition is loaded with a drug or an active factor.
  • the first component and/or the second component contain a drug or an active factor.
  • the drug may be an antibacterial agent, an anti-inflammatory drug, an anticancer drug, or the like for preventing/reducing the risk of post-operative infection or inhibiting the growth of cancer cells.
  • the active factor may be a growth factor or the like for promoting tissue growth.
  • the drug and/or active factor is added by adding a drug and/or an active factor to the first component and/or the second component. In general, it is preferred to add the drug to the second component. In addition, the drug can be grafted into the first component by a chemical modification method.
  • the present disclosure also provides a medical hydrogel in which a first component of a medical hydrogel composition of the present disclosure is dissolved in a first buffer solution, and a second component of a medical hydrogel composition The components are dissolved in the second buffer solution, and then mixed and formed after the reaction.
  • the medical hydrogel according to the present disclosure wherein the medical hydrogel has a degree of swelling of from 10 to 50%, preferably from 5 to 47%.
  • the degree of swelling of the medical hydrogel of the present disclosure means the time at which the medical hydrogel is formed when the crosslinking is effectively completed and the medical hydrogel is placed in the physiological saline or PBS solution in a free state.
  • the change in volume or weight between the hours after the hour at which the hydrogel can reasonably be assumed to have reached its equilibrium swollen state. Can be expressed by the following formula:
  • Swelling degree % [(weight at 24 h - initial formation weight) / initial formation weight] ⁇ 100%.
  • the pH of the obtained soaking solution is 7 ⁇ 9.5, preferably 7-8.
  • the acidity and alkalinity (pH value) of the medical hydrogel of the present disclosure or the pH value of the soaking liquid is measured by placing a certain amount of medical hydrogel in pure water, and the weight of pure water. The pH of the soaking solution was tested by placing it at 80 times the medical hydrogel and at a constant temperature of 37 ° C for 24 hours.
  • the pH of the first buffer solution for dissolving the nucleophilic reagent is 7.0-7.4 or 9.1-10.0
  • the pH of the second buffer solution for dissolving the electrophile is 5.0-6.0 or 7.0. ⁇ 7.4.
  • the pH of the solvent used to dissolve the nucleophile and the electrophile has a large effect on the pH of the hydrogel produced.
  • the pH of the buffer solution for dissolving the nucleophilic reagent is 7.0 to 7.4
  • the prepared medical hydrogel is nearly neutral, has little irritation to tissues, and is favorable for growth of cells and tissues.
  • the pH of the buffer solution for dissolving the nucleophile and the electrophile is 7.0-7.4
  • the prepared medical hydrogel is neutral, and is not irritating to tissues and cells, and is more suitable for cell and tissue growth.
  • the present disclosure also provides a method for preparing a medical hydrogel.
  • the first component comprises polylysine and polyethyleneimine
  • the second component comprises four-arm-polyethylene glycol-succinimide glutarate, four-arm-polyethylene glycol One or more of succinimide succinate, tetra-arm-polyethylene glycol-succinimide carbonate.
  • a double mixer can be used for mixing, a nucleophilic reagent (polylysine and polyethylene) in the first mixed liquid.
  • Electrophile in the second mixture and the second mixture four-arm-polyethylene glycol-succinimide glutarate, four-arm-polyethylene glycol-succinimide succinate, four arms
  • a Michael addition reaction occurs in one or more of polyethylene glycol-succinimide carbonates, which can be rapidly gelatinized to form the medical hydrogel of the present disclosure.
  • the medical hydrogel has excellent properties of low swelling and has good biocompatibility, degradability and antibacterial effect.
  • the pH of the first buffer solution for dissolving the nucleophilic reagent is 7.0-7.4 or 9.1-10.0
  • the pH of the second buffer solution for dissolving the electrophile is 5.0-6.0 or 7.0. ⁇ 7.4.
  • the pH of the first buffer solution for dissolving the nucleophilic reagent is 7.0 to 7.4, the obtained medical hydrogel is neutral.
  • the poly-lysine concentration is 1 to 50 mg/mL, and the polyethyleneimine is a concentration of 1 to 50 mg/mL; in the second mixture, the four-arm-polyethylene glycol-succinimide glutarate, four-arm-polyethylene glycol-succinimide succinate
  • concentration of the four-arm-polyethylene glycol-succinimide carbonate or a mixture thereof is 100 to 200 mg/mL, and the first mixed liquid and the second mixed liquid are mixed in an equal volume to obtain a medical hydrogel.
  • a blue developer may be added to the second mixture containing the electrophile, and the optional blue developer includes: FD&C Blue#1, FD&C Blue#2, methylene blue, etc.
  • the present disclosure also provides a medical hydrogel kit comprising a medical hydrogel composition according to the present disclosure and a first buffer solution and a second buffer solution of the present disclosure.
  • a medical hydrogel kit comprising: a first component, a second component, a first buffer solution, and a second buffer solution, the first component comprising polylysine and polyethylene
  • the second component comprises four-arm-polyethylene glycol-succinimide glutarate, four-arm-polyethylene glycol-succinimide succinate, four-arm-polyethylene One or more of the alcohol-succinimide carbonates, wherein the polylysine has a degree of polymerization of 20 or more, preferably 25 to 35.
  • a medical hydrogel kit wherein the first component and the second component may be separately stored, and the first component and the second component are mixed at the time of use.
  • the nucleophilic reagent polylysine and polyethyleneimine (PEI) in the first component can also be stored separately, and polylysine and polyethyleneimine are used several hours before use or at the time of use. (PEI) mixing.
  • polylysine and polyethyleneimine can be stored separately, and dissolved in the same solvent before use or at the time of use.
  • the polylysine may be pre-dissolved in the first buffer solution for storage, for example, may be dissolved in a small amount of the first buffer solution, diluted before use, or dissolved in the first concentration according to the use. Store in buffer solution.
  • polylysine dissolved in the first buffer solution is mixed with undissolved polyethyleneimine (PEI).
  • the second component of the present disclosure may be stored separately and dissolved in a solvent prior to use.
  • the present disclosure has no limitation on the storage mode and usage mode of each component in the medical hydrogel kit, and can select a suitable storage method and usage mode according to needs.
  • the medical hydrogel of the present disclosure can be used for hemostasis aids, prevention of lung leakage or cerebrospinal fluid leakage products, anti-adhesion articles, etc., such as: arteriovenous reconstruction suture needle eye closure, Dural suture needle sealing, dural reconstruction and sealing, prevention of lung leakage after pneumonectomy, anti-adhesion of spinal dural area and other applications.
  • 4-arms-PEG-SG (Beijing Key Kai Technology Co., Ltd.), 4-arms-PEG-SS (Beijing Key Kai Technology Co., Ltd.), 4-arms-PEG-SC (Beijing Key Kai Technology Co., Ltd.), ⁇ - Polylysine (Shanghai Yantuo Biotechnology Co., Ltd.), poly-L-lysine (Shanghai Ji Ning Industrial Co., Ltd.), polyethyleneimine (Dow Chemical (China) Co., Ltd.), trilysine ( Simaga), 4-arm-PEG-SH (Beijing Key Kai Technology Co., Ltd.).
  • 0.5 g of 4-arms-PEG-SG (weight average molecular weight 15 kDa, the same below) was dissolved in 5 mL of an acidic sodium hydrogen phosphate buffer solution having a pH of 5.60 to obtain a solution A having a concentration of 100 mg/mL; ⁇ -polylysine (weight average molecular weight 3500 Da, degree of polymerization 25-35, the same below) and 80 mg of polyethyleneimine (number average molecular weight 1800 Da, the same below) are dissolved in 5 mL of an alkaline buffer solution having a pH of 9.90. A solution B having a concentration of 20 mg/mL was obtained; and the solution A and the solution B were sprayed by the same dose through a double mixer to form a medical hydrogel I.
  • 0.5 g of 4-arms-PEG-SG was dissolved in 5 mL of an acidic sodium hydrogen phosphate buffer solution having a pH of 5.60 to obtain a solution A at a concentration of 100 mg/mL; 50 mg of ⁇ -polylysine and 50 mg were taken.
  • the polyethyleneimine was dissolved in 5 mL of physiological saline having a pH of 7.4 to obtain a solution B having a concentration of 20 mg/mL; and the solution A and the solution B were sprayed at the same dose by a double mixer to form a medical hydrogel II.
  • 0.5 g of 4-arms-PEG-SC was dissolved in 5.0 mL of physiological saline having a pH of 7.4 to obtain a solution A at a concentration of 100 mg/mL, and FD&C Blue #1 developer was added to the solution A; 60 mg was obtained.
  • ⁇ -polylysine and 90 mg of polyethyleneimine were dissolved in 5.0 mL of physiological saline having a pH of 7.4 to obtain a solution B having a concentration of 30 mg/mL; and solution A and solution B were sprayed by the same dose of a double mixer. Out, form a medical hydrogel VII.
  • 0.5 g of 4-arm-PEG-SH (weight average molecular weight 15 kDa) was dissolved in 2.5 mL of a pH 6.0 6.0 solution of sodium dihydrogen phosphate to obtain a solution A having a concentration of 200 mg/mL;
  • the arms-PEG-SG was dissolved in 2.5 mL of a sodium hydrogen phosphate-sodium carbonate buffer solution having a pH of 9.6 to obtain a solution B having a concentration of 200 mg/mL.
  • Solution A and Solution B were sprayed through a duplex mixer to form a medical hydrogel VIII.
  • the syringe is a double syringe containing a nucleophile and a buffer solution 1 for dissolving the nucleophile, an electrophile and a buffer solution for dissolving the electrophile 2
  • the nucleophile is trilysine
  • the buffer solution 1 is a borate buffer solution having a pH of about 10
  • the electrophile is 4-arm-PEG-SG
  • the buffer solution 2 is at a pH of about
  • the phosphate buffer solution of 4.5 was sprayed with the nucleophile dissolved in the buffer solution 1 and the electrophile dissolved in the buffer solution 2 by a double mixer to form a medical hydrogel IX.
  • 0.5 g of 4-arm-PEG-SG was dissolved in 2.5 mL of physiological saline having a pH of 7.4 to obtain a solution A having a concentration of 200 mg/mL; 0.1 g of polyethyleneimine was dissolved in a pH of 7.4 of 2.5 mL. In a normal saline solution, a concentration of 40 mg/mL was obtained.
  • Solution B; Solution A and Solution B were sprayed through the same dose of a double mixer to form a medical hydrogel X.
  • 0.5 g of 4-arm-PEG-SG was dissolved in 2.5 mL of a buffer solution of sodium dihydrogen phosphate at pH 6.0 to obtain a solution A at a concentration of 200 mg/mL; 0.1 g of ⁇ -polylysine was dissolved.
  • a solution B having a concentration of 40 mg/mL was obtained in 2.5 mL of a sodium hydrogen phosphate-sodium carbonate buffer solution having a pH of 9.6.
  • Solution A and Solution B were sprayed through the same mixer at the same dose to form a medical hydrogel XI.
  • Example 1 21.61% 9.10
  • Example 2 18.04% 7.31
  • Example 3 7.37% 7.44
  • Example 4 43.34% 7.02
  • Example 5 37.92% 7.15
  • Example 6 12.56% 7.30
  • Example 7 40.68% 7.21 Comparative example 1 129.05% 8.64 Comparative example 2 198.30% 8.55
  • the solvents for dissolving the electrophile and the nucleophile in Example 1 and Comparative Example 1-2 were respectively an acidic solution and an alkaline solution, and the corresponding soaking liquid of the medical hydrogel was alkaline.
  • the buffer solution for dissolving the nucleophile was neutral
  • the soaking solution of the prepared medical hydrogel was neutral.
  • the cultured cells were contacted by the extract, and the cytotoxicity of the medical hydrogel prepared in Example 1 and Example 4 on the cells in vitro was evaluated for cell morphology and proliferation observation.
  • the specific process of the experiment was as follows: experimental group: the medical hydrogel was extracted with a serum medium at a ratio of 0.1 g/mL, The obtained extract is defined as a 100% concentration extract; the 100% concentration of the extract is serially diluted with serum medium, and the concentration gradient after dilution is 100%, 50% and 25%, The concentration gradient of the extract was used to culture the cells; the control group: only the serum medium was used, and the remaining cell culture conditions were the same as those of the experimental group.
  • the medical hydrogel I of Example 1 and the medical hydrogel IV of Example 4 were used to prepare the extract, the extraction temperature was (37 ⁇ 1) ° C, and the extraction time was (24 ⁇ 2) h.
  • Cell culture conditions culture in a sterile carbon dioxide incubator at 37 °C.
  • FIG. 1 shows the growth state of cells cultured in the extract of medical hydrogel I of Example 1 for 24 hours
  • FIG. 2 shows the growth of cells cultured in the extract of medical hydrogel IV of Example 4 for 24 hours. status.
  • the extract of the medical hydrogel I of Example 1 has a greater influence on the growth of L929 cells than the control group, and the extract of the medical hydrogel I has a greater influence on the growth of the L929 cells.
  • the concentration of the liquid decreased, the cytotoxicity decreased, and the growth state of the cells was close to that of the control group.
  • the medical hydrogel I prepared in Example 1 was alkaline, demonstrating that the alkaline extract affected the growth of the cells to some extent.
  • Fig. 2 It can be seen from Fig. 2 that the growth state of the cells in the 100% concentration of the medical hydrogel IV is close to that of the control group. As the concentration of the extract decreases, the cytotoxicity decreases, and the cell growth shows a better trend. The growth state is superior to the control group cell growth state.
  • the medical hydrogel IV prepared in Example 4 was neutral, indicating that the extract of the neutral pH environment did not have any hindrance to the growth of L929 cells, and the neutral medical hydrogel was safer in human use.
  • the antibacterial evaluation experiment was carried out using the agar diffusion method: after the sterilized broth agar medium was dissolved, about 20 mL of a plate having a diameter of 10 cm was poured, and it was solidified to obtain an agar plate.
  • the test bacterial solution was uniformly applied to the agar plate by a sterile cotton swab, and an experimental strain was coated on each agar plate, and then uniformly punched with a sterile steel ring having a diameter of 10 mm, and each hole was punched with 3 holes.
  • the medical hydrogel or ⁇ -polylysine was injected into the well, and the medical hydrogel or ⁇ -polylysine formed by the same volume of solution was injected into each well, and cultured at 37 ° C for 24 hours at a constant temperature, and then taken out.
  • the experiment was repeated twice and the effective diameter of the inhibition zone was calculated.
  • the effective diameter of the inhibition zone (mm) the actual diameter of the inhibition zone (mm) - the pore diameter (10 mm).
  • the effective diameter of the inhibition zone was less than 10 mm, which was low sensitivity or drug resistance.
  • the effective diameter of the inhibition zone was moderately sensitive between 10-15 mm, and the effective diameter of the inhibition zone was more than 15 mm.
  • ⁇ -polylysine is a powder and dissolves in water, in order to make a better comparison with the medical hydrogel of the present disclosure, ⁇ -polylysine adopts a paper method, that is, a certain concentration of ⁇ -poly La is prepared.
  • a solution of the acid 40 mg/mL
  • the solution was dropped on a paper liquid having a diameter of 8 mm, and after drying, the dried paper was placed on a nutrient agar plate.
  • the medical hydrogel IV of Example 4, the medical hydrogel V of Example 5, the medical hydrogel X-XI of Comparative Example 3-4, and the ⁇ -polylysine solution were selected for antibacterial experiments, and the selected strains were selected.
  • the concentration is about 10 6 cfu/mL.
  • the effective diameter of the inhibition zone is shown in Table 2 below:
  • Example 4 11.5 10.2
  • Example 5 11.3 10.0 Comparative example 3 9.2 9.0 Comparative example 4 5.7 5.5 ⁇ -polylysine 4.3 4.1
  • the in vitro and in vivo degradation experiments were carried out using the medical hydrogel IV of Example 4, and the degradation of the medical hydrogel IV was observed at different time points.
  • the method of the in vitro degradation experiment is as follows: the solution A and the solution B prepared in the embodiment 4 are injected into an equal volume of a tube having a diameter of 6 mm and a height of 7 mm to prepare a hydrogel. Remove the hydrogel, place the hydrogel in a clear glass bottle and add a PBS buffer solution with a pH of 7.2 ⁇ 0.2, completely submerge the hydrogel, seal the glass bottle, and place the glass bottle in a 37 ⁇ 1 ° C incubator The hydrogel was observed one week, three weeks, and five weeks after the experiment, and the degradation of the hydrogel was recorded. The results are shown in Table 3.
  • the method of in vivo degradation experiments was as follows: 8 healthy experimental rats were randomly divided into 4 groups of 2 rats each. Then, the rats were anesthetized, and the medical hydrogel IV of Example 4 was implanted subcutaneously into the abdomen of the rats, and the wounds were closed and fed normally. Anatomy was performed one week, three weeks, five weeks, and three months after surgery (a group was randomly selected at each time point for dissection) to observe the degradation of medical hydrogel IV in rats. The results are shown in Table 3:
  • the medical hydrogel of the present disclosure can maintain the morphology of the hydrogel at three weeks, the hydrogel is not visible to the naked eye at five weeks, and the hydrogel has completely degraded at three months. It usually takes a certain time for wound healing. Tissue adhesion and cerebrospinal fluid leakage usually occur about two weeks after surgery.
  • the hydrogel of the present disclosure can still maintain the shape of the hydrogel at three weeks, which is beneficial to promote wound healing. Reduces the risk of tissue adhesion and leakage of cerebrospinal fluid.
  • FIG. 3 shows the degradation of the medical hydrogel IV of the subcutaneous implantation of Example 4 at the time of five-week dissection
  • FIG. 4 shows the subcutaneous implantation of the medical hydrogel of Comparative Example 4 at the time of five-week dissection.
  • Degradation As shown in Fig. 3, there were a large number of hyperplastic capillaries in the subcutaneous implantation site of the five-week anatomy, no fluid accumulation under the skin, no necrosis; the medical hydrogel IV of Example 4 could not be found, and the degradation was obvious (in the figure) Black granules are stitches). As shown in Fig.
  • Figure 5 shows a partial histological section (20x) of the medical hydrogel IV implanted subcutaneously in Example 5 at five weeks of anatomy.
  • the implant material (medical hydrogel IV of Example 4) was in the form of fine particles.
  • a small amount of fibrous tissue hyperplasia was observed around the implant material, and a small amount of lymphocyte infiltration (1-5/PHF) was observed, more macrophage infiltration (5-10/HPF), and more capillary proliferation (4-7 /HPF).
  • a fibrous cystic cavity of the thin band-like cyst wall is formed around the implant material.
  • the results of the inflammation and necrosis scores are shown in Table 4.
  • the results of fibrosis and repair scoring are shown in Table 5, and the overall score is 9.
  • Fig. 6 shows a histological section (20x) of a medical hydrogel XI implanted in a subcutaneous manner of rats in a five-week anatomy.
  • the implant material (medical hydrogel XI of Comparative Example 4) was fragmented and the inside was loose. It was found that many fibroblasts grew into the material, and the percentage of residual material was about 1-5%. There were no obvious gaps between the surrounding tissues. More fibrous tissue hyperplasia was observed around the implant material, with a small amount of lymphocyte infiltration (1-5/PHF), more macrophage infiltration (5-10/HPF), and a small amount of multinucleated giant cell infiltration (1-2). /HPF), more capillary proliferation (4-7 / HPF).
  • a medium-thick banded fibrous sac is formed around the implant material, and a large range of fat cells are infiltrated (21-40%).
  • the results of the inflammation and necrosis scores are shown in Table 6.
  • the results of fibrosis and repair scoring are shown in Table 7, and the comprehensive score of inflammation and fibrosis is 14.
  • the medical hydrogel IV of Example 4 has better biocompatibility with the tissue, and the medical hydrogel IV of Example 4 has completely degraded under the skin of the rat at eight weeks, and Proportion 4 of the medical hydrogel XI is still partially undegraded.
  • the implant in the body acts as a foreign body and should be removed or degraded after it has completed its specific purpose.
  • the post-traumatic repair time of most medical procedures in the human body is roughly 1-8 weeks, so the medical hydrogel IV of Example 4 is more suitable for clinical use in the degradation time.
  • the test animal dog was anesthetized, the left parietal part of the test animal dog was cut open, and the skull of 3 cm ⁇ 2.5 cm size was taken out. Bone; the left dura mater of the test animal dog was cut open, the length was 2.0 cm, and the dural incision was sutured with a suture (4-0 nylon thread) with an interval of 2-3 mm between the needles.
  • the medical hydrogel IV of Example 4 was injected into the suture site; after the medical hydrogel IV was solidified, the removed skull was placed back and the wound skin was sutured; the test animal dog was kept for 4 weeks.
  • Observation indicators (1) Postoperative qualitative evaluation of the behavior of the test dog is normal, total health information (such as wound healing, appetite, weight), and abnormal behavior caused by leakage of cerebrospinal fluid. (2) Before the test animal dog is sacrificed, the intracranial pressure of the test animal dog is measured using a lumbar puncture package, and the value is recorded, and then the intracranial pressure is increased by injecting physiological saline to increase the intracranial pressure to 200 mm water column, and Keep it for at least 5 s, and there is no leakage of cerebrospinal fluid in the eye area. (3) Visually observe the location of the dural incision, the degradation and adhesion of the medical hydrogel IV (and brain tissue).
  • Figure 7 is a photograph showing the dural incision of the test animal dog
  • Figure 8 is a picture showing the dural suture of the test animal dog
  • Figure 9 is a picture showing the injection of the medical hydrogel after the dural suture of the test animal dog.
  • Fig. 10 is a view showing a picture of the healing of the incision position of the dura mater of the test animal dog after 4 weeks of feeding
  • Fig. 11 is a view showing the repairing effect of the healing position of the incision position of the dura mater of the test animal dog after 4 weeks of feeding.
  • the medical hydrogel IV formed in the present disclosure has low swelling, neutrality, good biocompatibility, in vivo degradation, antibacterial effect, and no leakage of cerebrospinal fluid.
  • the medical hydrogel composition, the medical hydrogel and the preparation method and application thereof according to the embodiments of the present disclosure can be applied to the field of biomedical technology, and particularly can be used for hemostasis aid, preventing lung leakage or cerebrospinal fluid leakage.
  • Products, anti-adhesive products, etc. such as: arteriovenous reconstruction suture needle eye closure, dural suture needle sealing, dural reconstruction and sealing, prevention of lung leakage after pneumonectomy, anti-adhesion of spinal dural area, etc. in.
  • the medical hydrogel prepared by the present disclosure has good biocompatibility and good antibacterial and biodegradability. Further, the medical hydrogel of the present disclosure can also have an effect of not stimulating the tissue.

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Abstract

一种医用水凝胶组合物，一种医用水凝胶及其制备方法与应用，以及一种医用水凝胶试剂盒。医用水凝胶组合物包括：第一组分和第二组分，第一组分包括聚赖氨酸和聚乙烯亚胺；第二组分包括四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯中的一种或几种，其中，聚赖氨酸的聚合度为20以上。医用水凝胶由医用水凝胶组合物的第一组分和第二组分反应后形成。医用水凝胶试剂盒包括医用水凝胶组合物和用于溶解医用水凝胶组合物各组分的缓冲溶液。该医用水凝胶的溶胀度为-10～50％，可应用在脑、脊椎以及周围神经分布密集的狭小部位。

Description

医用水凝胶组合物，医用水凝胶及其制备方法与应用 技术领域
本公开涉及一种医用水凝胶组合物，医用水凝胶及其制备方法与应用，属于生物医药技术领域。
背景技术
在临床上，医用水凝胶可被用于体内创面的封闭、防粘连或载药等领域。水凝胶，是以水为分散介质的凝胶，具有三维空间网络结构，其不能在水中溶解，能够在水中溶胀，吸收大量的水分，使水凝胶体积增大。但是，在脑、脊椎以及周围神经分布密集的狭小部位，高溶胀性的水凝胶则会对周围神经造成压迫，而可能干扰机体的正常功能，严重时周围组织可能出现压迫性坏死。
目前在临床上的医用水凝胶大部分具有高溶胀度，比如Coseal混合胶、Duraseal混合胶。根据记载(Evaluation of Absorbable Surgical Sealants:In vitro Testing)这两种胶具有极高的溶胀度，分别在PBS溶液中浸泡三天，重量相应增加了558％，98％。
专利文件CN101843925A提供了一种低溶胀水凝胶，水凝胶的溶胀度大约-50％至大约50％。但是该专利中使用的原料是三赖氨酸，价格昂贵，并且所制得的低溶胀水凝胶呈碱性。由于在人体中，大部分组织的环境为中性，若植入物为碱性，则对周围细胞会产生较为严重的刺激作用。
发明内容
技术问题
有鉴于此，本公开要解决的技术问题是，提供一种生物相容性好、溶胀度低，具有良好的生物降解性并且成本较低的医用水凝胶组合物及由该医用水凝胶组合物制备得到的医用水凝胶。进一步地，还提供一种对组织无刺激的医用水凝胶。
解决方案
为了解决上述技术问题，本公开提供了一种医用水凝胶组合物，包括第一组分和第二组分，所述第一组分包括聚赖氨酸和聚乙烯亚胺；所述第二组分包括四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯中的一种或几种，其中，所述聚赖氨酸的聚合度为20以上，优选为25～35。
对于上述医用水凝胶组合物，在一种具体的实现方式中，在所述第一组分中，所述聚赖氨酸与所述聚乙烯亚胺的质量比为0.1～10。
对于上述医用水凝胶组合物，在一种具体的实现方式中，所述聚赖氨酸为ε-聚赖氨酸和/或聚-L-赖氨酸。
对于上述医用水凝胶组合物，在一种具体的实现方式中，所述ε-聚赖氨酸的重均分子量为3000～5000Da。
对于上述医用水凝胶组合物，在一种具体的实现方式中，所述聚-L-赖氨酸的重均分子量为7500～300000Da，优选100000～200000Da。
对于上述医用水凝胶组合物，在一种具体的实现方式中，所述聚乙烯亚胺的数均分子量为1000～3500Da，优选为1500～2000Da。
对于上述医用水凝胶组合物，在一种具体的实现方式中，所述四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯和四臂-聚乙二醇-琥珀酰亚胺碳酸酯的重均分子量均为2000～40000Da，优选为10000～20000Da。
对于上述医用水凝胶组合物，在一种具体的实现方式中，所述医用水凝胶组合物负载有药物或活性因子，优选地，所述第一组分和/或第二组分中含有药物或活性因子。
本公开还提供了一种医用水凝胶，其由本发明的医用水凝胶组合物的第一组分和第二组分反应后形成；优选地，所述医用水凝胶由所述第一组分和所述第二组分在缓冲溶液中反应后形成。
对于上述医用水凝胶，在一种具体的实现方式中，所述医用水凝胶由所述第一组分溶于第一缓冲溶液中，所述第二组分溶于第二缓冲溶液中，然后混合、反应后形成。
对于上述医用水凝胶，在一种具体的实现方式中，所述医用水凝胶的溶胀度为-10～50％，优选为5～47％。
对于上述医用水凝胶，在一种具体的实现方式中，所述医用水凝胶浸泡于水中后，浸泡液的pH值为7～9.5，优选7～8。
对于上述医用水凝胶，在一种具体的实现方式中，所述第一缓冲溶液的pH值为7.0～7.4或9.1～10.0，优选7.0～7.4；所述第二缓冲溶液的pH值为5.0～6.0或7.0～7.4，优选7.0～7.4。
本公开还提供了一种对于上述医用水凝胶的制备方法，包括以下步骤：
将所述第一组分溶于第一缓冲溶液中，得到第一混合液；
将所述第二组分溶于第二缓冲溶液中，得到第二混合液；
将所述第一混合液和第二混合液混合，得到医用水凝胶。
对于上述医用水凝胶的制备方法，在一种具体的实现方式中，所述第一混合液中，所述聚赖氨酸的浓度为1～50mg/mL，所述聚乙烯亚胺的浓度为1～50mg/mL；所述第二混合液中，所述四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯或其混合物的浓度为100～200mg/mL，所述第一混合液与所述第二混合液等体积混合，得到医用水凝胶。
对于上述医用水凝胶的制备方法，在一种具体的实现方式中，所述第二混合液中还包括显色剂，优选地，所述显色剂包括FD&C Blue#1、FD&C Blue#2、亚甲基蓝中的一种或几种。
本发明还提供一种医用水凝胶试剂盒，其包括本发明的医用水凝胶组合物以及用于溶解医用水凝胶组合物的各组分的缓冲溶液。
对于上述医用水凝胶试剂盒，在一种具体的实现方式中，所述医用水凝胶组合物的第一组分与第二组分是分开储存的；优选地，所述医用水凝胶组合物的第一组分中的聚赖氨酸和聚乙烯亚胺是分开储存的。
本发明还提供一种对于上述医用水凝胶在止血辅助物、防止肺部漏气或脑脊液渗漏制品、防粘连制品中的应用。
有益效果
在本公开中，所制备得到的医用水凝胶的溶胀度低，仅为-10％～50％，可应用在脑、脊椎以及周围神经分布密集的狭小部位。本公开制备得到的医用水凝胶的生物相容性好，且具有良好的抗菌性和生物降解性。另外，本公开的医用水凝胶也能够具备对组织也无刺激的效果。
根据下面参考附图对示例性实施例的详细说明，本公开的其它特征及方面将变得清楚。
附图说明
包含在说明书中并且构成说明书的一部分的附图与说明书一起示出了本公开的示例性实施例、特征和方面，并且用于解释本公开的原理。
图1示出细胞在实施例1的医用水凝胶I的浸提液中培养24h的生长状态；
图2示出细胞在实施例4的医用水凝胶IV的浸提液中培养24h的生长状态
图3示出五周解剖时大鼠皮下植入实施例4的医用水凝胶IV的降解情况；
图4示出五周解剖时大鼠皮下植入对比例4的医用水凝胶XI的降解情况；
图5示出五周解剖时大鼠皮下植入实施例4的医用水凝胶IV的部位组织切片图；
图6示出五周解剖时大鼠皮下植入对比例4的医用水凝胶XI的部位组织切片图；
图7示出将试验动物狗的硬脑膜切开的图片；
图8示出试验动物狗的硬脑膜缝合后的图片；
图9示出试验动物狗的硬脑膜缝合后注入医用水凝胶的图片；
图10示出试验动物狗的硬脑膜注胶后放回颅骨的图片；
图11示出喂养4周后，试验动物狗的硬脑膜的切口位置的愈合情况修复效果图。
具体实施方式
以下将参考附图详细说明本公开的各种示例性实施例、特征和方面。在这里专用的词“示例性”意为“用作例子、实施例或说明性”。这里作为“示例性”所说明的任何实施例不必解释为优于或好于其它实施例。
另外，为了更好地说明本公开，在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解，没有某些具体细节，本公开同样可以实施。在另外一些实例中，对于本领域技术人员熟知的方法、手段、器材和步骤未作详细描述，以便于凸显本公开的主旨。
本公开提供一种医用水凝胶组合物以及由该医用水凝胶组合物的不同组分反应获得的医用水凝胶。本公开的医用水凝胶组合物主要包括含有亲核试剂的第一组分和含有亲电试剂的第二组分，所述亲核试剂包括聚赖氨酸和聚乙烯亚胺(PEI)，所述亲电试剂包括四臂-聚乙二醇-琥珀酰亚胺戊二酸酯(4-arms-PEG-SG)、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯(4-arms-PEG-SS)、四臂-聚乙二醇-琥珀酰亚胺碳酸酯(4-arms-PEG-SC)中的一种或几种。
其中，所述第一组分和第二组分可以是分离的，在使用时将第一组分和第二组分混合。优选地，所述第一组分中的聚赖氨酸和聚乙烯亚胺(PEI)也是分离的，在使用之前几个小时或使用时将聚赖氨酸和聚乙烯亚胺(PEI)混合。
在实际应用的过程中，聚赖氨酸和聚乙烯亚胺(PEI)可以分别单独储存，使用前或使用时再溶解于同一溶剂中。为了使用方便，也可以将聚赖氨酸在溶剂中预先溶解的形式储存，例如可以溶解到少量的缓冲溶液中，使用前采用缓冲溶液进行稀释，也可以按照使用时的浓度溶解于缓冲溶液中储存。使用时，将溶解于缓冲溶液中的聚赖氨酸与 聚乙烯亚胺(PEI)混合。所述第二组分在使用前或使用时再溶解于溶剂中。本公开对所述的医用水凝胶组合物中的各组分的储存方式没有限制，所属技术领域人员可以根据需要，选择具体的储存方式，均在本公开的范围之内。
本公开的所述聚赖氨酸可以为ε-聚赖氨酸和/或聚-L-赖氨酸，所述聚赖氨酸的聚合度为20以上，优选25～35之间。本公开加入聚合度在20以上的聚赖氨酸，能够增大交联密度，使平衡溶胀度降低。其中，ε-聚赖氨酸的重均分子量优选为3000～5000Da，聚-L-赖氨酸的重均分子量优选为7500～300000Da，优选为100000～200000Da。所述聚乙烯亚胺(PEI)的数均分子量为1000～3500Da，优选为1500～2000Da。
其中，所述聚赖氨酸与所述聚乙烯亚胺的质量比为0.1～10。
本公开的医用水凝胶组合物的第二组分包含的四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯和四臂-聚乙二醇-琥珀酰亚胺碳酸酯的重均分子量均为2000～40000Da，优选为10000～20000Da。
一般而言，本公开所述的聚赖氨酸(包括ε-聚赖氨酸和聚-L-赖氨酸)，可以以其盐酸盐、氢溴酸盐或其他盐的形式存在，均在本公开所述范围内。
根据本公开的医用水凝胶组合物，所述医用水凝胶组合物负载有药物或活性因子。优选地，所述第一组分和/或第二组分中含有药物或活性因子。一般而言，所述药物可以是抗菌剂、抗炎症药物、抗癌药物等，用于防止/降低术后的感染风险或抑制癌细胞生长。所述活性因子可以是生长因子等，用于促进组织生长。
所述药物和/或活性因子的加入方式是：将药物和/或活性因子加入第一组分和/或第二组分中。一般而言，优选将药物添加至第二组分中。另外，通过化学改性方法，可以将药物接枝在第一组分中。
在另一实施方式中，本公开还提供一种医用水凝胶，其由本公开的医用水凝胶组合物的第一组分溶于第一缓冲溶液中，医用水凝胶组合物的第二组分溶于第二缓冲溶液中，然后再进行混合、反应后形成。
根据本公开的医用水凝胶，其中，所述医用水凝胶的溶胀度为-10～50％，优选为5～47％。
具体而言，本公开所述的医用水凝胶的溶胀度是指，当交联有效完成时医用水凝胶形成的时刻和将医用水凝胶以自由状态放在生理盐水或PBS溶液中24小时后的时刻(在该时间点可以合理地假设水凝胶已经达到了其平衡溶胀的状态)之间的体积或重量的变化。可以用以下公式表示：
溶胀度％＝[(在24h的重量-初始形成重量)/初始形成重量]×100％。
根据所述医用水凝胶组合物中的第一组分和第二组分混合后形成的医用水凝胶，将该医用水凝胶浸泡于水中时，所得到的浸泡液的pH值为7～9.5，优选7～8。
本公开所述的医用水凝胶的酸碱性(pH值)或所述浸泡液的pH值，是通过以下方法测得：将一定量医用水凝胶置于纯水中，纯水的重量为医用水凝胶的80倍，恒温37℃放置24h，测试浸泡液的pH值。
优选地，用于溶解所述亲核试剂的第一缓冲溶液的pH值为7.0～7.4或9.1～10.0，用于溶解所述亲电试剂的第二缓冲溶液的pH值为5.0～6.0或7.0～7.4。
溶解亲核试剂、亲电试剂使用的溶剂pH值对所制成的水凝胶的pH有较大影响。当用于溶解所述亲核试剂的缓冲溶液的pH值为7.0～7.4时，所制得的医用水凝胶接近中性，对组织的刺激性小，有利于细胞、组织的生长。当溶解亲核试剂和亲电试剂的缓冲溶液的pH值均为7.0～7.4时，所制得的医用水凝胶呈现中性，对组织和细胞没有刺激性，更适合细胞、组织的生长。
在又一种实施方式中，本公开还提供一种医用水凝胶的制备方法，
将第一组分溶于第一缓冲溶液中，得到第一混合液；
将第二组分溶于第二缓冲溶液中，得到第二混合液；
将第一混合液和第二混合液混合，得到医用水凝胶；
其中，所述第一组分包括聚赖氨酸和聚乙烯亚胺；所述第二组分包括四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯中的一种或几种。
本公开的医用水凝胶的制备方法中的第一混合液和第二混合液混合后，例如可以使用双联混合器混合，第一混合液中的亲核试剂(聚赖氨酸和聚乙烯亚胺)与第二混合液中的亲电试剂(四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯中的一种或几种)发生迈克尔加成反应，可以快速成胶，即生成本公开的医用水凝胶。该医用水凝胶具有低溶胀的优良性质，并且具有良好的生物相容性、降解性和抗菌效果。
优选地，用于溶解所述亲核试剂的第一缓冲溶液的pH值为7.0～7.4或9.1～10.0，用于溶解所述亲电试剂的第二缓冲溶液的pH值为5.0～6.0或7.0～7.4。进一步地，当用于溶解所述亲核试剂的第一缓冲溶液的pH值为7.0～7.4，得到的医用水凝胶呈中性。
优选地，在第一混合液中，所述聚赖氨酸浓度为1～50mg/mL，所述聚乙烯亚胺的 浓度为1～50mg/mL；在第二混合液中，所述四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯或其混合物的浓度为100～200mg/mL，所述第一混合液与所述第二混合液等体积混合，得到医用水凝胶。
根据本公开的医用水凝胶的制备方法，进一步地，可以在包含亲电试剂的第二混合液中加入蓝色显色剂，可选择的蓝色显色剂包括：FD&C Blue#1、FD&C Blue#2、亚甲基蓝等。
在又一种实施方式中，本公开还提供一种医用水凝胶试剂盒，其包括根据本公开所述的医用水凝胶组合物以及本公开的第一缓冲溶液和第二缓冲溶液。
根据本公开所述的医用水凝胶试剂盒，其包括：第一组分、第二组分、第一缓冲溶液和第二缓冲溶液，所述第一组分包括聚赖氨酸和聚乙烯亚胺；所述第二组分包括四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯中的一种或几种，其中，所述聚赖氨酸的聚合度为20以上，优选为25～35。
根据本公开所述的医用水凝胶试剂盒，其中，所述第一组分和第二组分可以是分开储存的，在使用时将第一组分和第二组分混合。优选地，所述第一组分中的亲核试剂聚赖氨酸和聚乙烯亚胺(PEI)也可以分开储存，在使用之前几个小时或使用时将聚赖氨酸和聚乙烯亚胺(PEI)混合。
在具体的医用水凝胶试剂盒中，聚赖氨酸和聚乙烯亚胺(PEI)可以分别单独储存，使用前或使用时再溶解于同一溶剂中。为了不同的使用需要，可以将聚赖氨酸预先溶解于第一缓冲溶液中储存，例如可以溶解到少量的第一缓冲溶液中，使用前进行稀释，也可以按照使用时的浓度溶解于第一缓冲溶液中储存。使用时，将溶解于第一缓冲溶液中的聚赖氨酸与未溶解的聚乙烯亚胺(PEI)混合。
另外，本公开的第二组分可以单独储存，使用前溶解于溶剂中。本公开对所述的医用水凝胶试剂盒中各组分的储存方式和使用方式没有限制，可以根据需要，选择适合的储存方式和使用方式。
在又一种实施方式中，本公开所述的医用水凝胶可用于止血辅助物、防止肺部漏气或脑脊液渗漏制品、防粘连制品等，如：动静脉重建缝线针眼封堵、硬脑膜缝合针眼封堵、硬脑膜重建贴合封堵、防止肺切除术后肺漏气、脊椎硬膜部位防粘连等应用中。
实施例
下面将结合实施例对本公开的实施方案进行详细描述，但是本领域技术人员将会 理解，下列实施例仅用于说明本公开，而不应视为限定本公开的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
4-arms-PEG-SG(北京键凯科技有限公司)、4-arms-PEG-SS(北京键凯科技有限公司)、4-arms-PEG-SC(北京键凯科技有限公司)、ε-聚赖氨酸(上海研拓生物科技有限公司)、聚-L-赖氨酸(上海纪宁实业有限公司)、聚乙烯亚胺(陶氏化学(中国)有限公司)、三赖氨酸(sigma公司)、4-arm-PEG-SH(北京键凯科技有限公司)。
实施例1
取0.5g的4-arms-PEG-SG(重均分子量15kDa，下同)溶于5mL的pH为5.60的酸性磷酸氢二钠缓冲溶液中，得到浓度为100mg/mL的溶液A；取20mg的ε-聚赖氨酸(重均分子量3500Da，聚合度25～35，下同)和80mg的聚乙烯亚胺(数均分子量1800Da，下同)溶于5mL的pH为9.90的碱性缓冲溶液中，得到浓度为20mg/mL的溶液B；将溶液A和溶液B通过双联混合器同等剂量喷出，形成医用水凝胶I。
实施例2
取0.5g的4-arms-PEG-SG溶于5mL的pH为5.60的酸性磷酸氢二钠缓冲溶液中，得到浓度为100mg/mL的溶液A；取50mg的ε-聚赖氨酸和50mg的聚乙烯亚胺溶于5mL的pH为7.4的生理盐水中，得到浓度为20mg/mL的溶液B；将溶液A和溶液B通过双联混合器同等剂量喷出，形成医用水凝胶II。
实施例3
取0.75g的4-arms-PEG-SG溶于5mL pH为5.60的酸性磷酸氢二钠缓冲溶液中，得到浓度为150mg/mL的溶液A，在溶液A中加入FD&C Blue#1显色剂；取100mg聚-L-赖氨酸(重均分子量150kDa，下同)和25mg的聚乙烯亚胺溶于5mL的pH为7.4的生理盐水中，得到浓度为25mg/mL的溶液B；将溶液A和溶液B通过双联混合器同等剂量喷出，形成医用水凝胶III。
实施例4
取0.5g的4-arms-PEG-SG溶于2.5mL的pH为7.4的生理盐水中，得到浓度为200mg/mL的溶液A，在溶液A中加入FD&C Blue#1显色剂；取10mg的ε-聚赖氨酸和90mg的聚乙烯亚胺溶于2.5mL的pH为7.4的生理盐水中，得到浓度为40mg/mL的溶液B；将溶液A和溶液B通过双联混合器同等剂量喷出，形成医用水凝胶IV。
实施例5
取0.25g的4-arms-PEG-SS(重均分子量15kDa，下同)溶于2.5mL的pH为7.4的生理盐水中，得到浓度为100mg/mL的溶液A，在溶液A中加入FD&C Blue#1显色剂；取5mg的ε-聚赖氨酸和45mg的聚乙烯亚胺溶于2.5mL的pH为7.4的生理盐水中，得到浓度为20mg/mL的溶液B；将溶液A和溶液B通过双联混合器同等剂量喷出，形成医用水凝胶V。
实施例6
取0.25g的4-arms-PEG-SS和0.25g的4-arms-PEG-SC(重均分子量15kDa，下同)溶于2.5mL的pH为5.60的酸性磷酸氢二钠缓冲溶液中，得到浓度为200mg/mL的溶液A，在溶液A中加入FD&C Blue#1显色剂；取100mg的聚-L-赖氨酸和25mg的聚乙烯亚胺溶于2.5mL的pH为7.4的生理盐水中，得到浓度为50mg/mL的溶液B；将溶液A和溶液B通过双联混合器同等剂量喷出，形成医用水凝胶VI。
实施例7
取0.5g的4-arms-PEG-SC溶于5.0mL的pH为7.4的生理盐水中，得到浓度为100mg/mL的溶液A，在溶液A中加入FD&C Blue#1显色剂；取60mg的ε-聚赖氨酸和90mg的聚乙烯亚胺溶于5.0mL的pH为7.4的生理盐水中，得到浓度为30mg/mL的溶液B；将溶液A和溶液B通过双联混合器同等剂量喷出，形成医用水凝胶VII。
对比例1
取0.5g的4-arm-PEG-SH(重均分子量15kDa)溶于2.5mL pH为6.0的磷酸二氢钠的缓冲溶液中，得到浓度为200mg/mL的溶液A；取0.5g的4-arms-PEG-SG溶于2.5mL pH为9.6的磷酸氢二钠—碳酸钠缓冲溶液中，得到浓度为200mg/mL的溶液B。将溶液A和溶液B通过双联混合器喷出，形成医用水凝胶VIII。
对比例2
使用购买的Duraseal注射器(所述注射器是双联注射器，其中包含有亲核试剂及用于溶解所述亲核试剂的缓冲溶液1，亲电试剂及用于溶解所述亲电试剂的缓冲溶液2，具体的所述亲核试剂是三赖氨酸，缓冲溶液1是pH约为10的硼酸盐缓冲溶液；所述亲电试剂是4-arm-PEG-SG，缓冲溶液2是pH约为4.5的磷酸盐缓冲溶液)，通过双联混合器将溶解在缓冲溶液1中的亲核试剂和溶解在缓冲溶液2中的亲电试剂同等剂量喷出，形成医用水凝胶IX。
对比例3
取0.5g的4-arm-PEG-SG溶于2.5mL的pH为7.4的生理盐水中，得到浓度为200mg/mL的溶液A；取0.1g的聚乙烯亚胺溶于2.5mL的pH为7.4的生理盐水中，得到浓度为40mg/mL 的溶液B；将溶液A和溶液B通过双联混合器同等剂量喷出，形成医用水凝胶X。
对比例4
取0.5g的4-arm-PEG-SG溶于2.5mL的pH为6.0的磷酸二氢钠的缓冲溶液中，得到浓度为200mg/mL的溶液A；取0.1g的ε-聚赖氨酸溶于2.5mL的pH为9.6的磷酸氢二钠-碳酸钠缓冲溶液中，得到浓度为40mg/mL的溶液B。将溶液A和溶液B通过双联混合器同等剂量喷出，形成医用水凝胶XI。
测定实施例1-7制备得到的医用水凝胶I-VII以及对比例1-2制备得到的医用水凝胶VIII-IX的溶胀度，并且将上述医用水凝胶浸泡于纯水中，测定所得到的浸泡液的pH值。结果如下表1所示：
表1
测试对象 溶胀度 pH值
实施例1 21.61％ 9.10
实施例2 18.04％ 7.31
实施例3 7.37％ 7.44
实施例4 43.34％ 7.02
实施例5 37.92％ 7.15
实施例6 12.56％ 7.30
实施例7 40.68％ 7.21
对比例1 129.05％ 8.64
对比例2 198.30％ 8.55
从上述结果可以看出，本公开实施例1-7所制备得到的医用水凝胶I-VII的溶胀度远低于对比例1-2制备得到的医用水凝胶VIII-IX。在实施例1-7中，交联密度增大，溶胀度相比对比例1-2更低。
在实施例1和对比例1-2中溶解亲电试剂、亲核试剂的溶剂分别为酸性溶液、碱性溶液，其所对应的医用水凝胶的浸泡液均为碱性。在实施例2-7中，用于溶解亲核试剂的缓冲溶液为中性，制得的医用水凝胶的浸泡液为中性。上述结果表明溶解亲核试剂的溶剂为中性时，所制备的医用水凝胶的浸泡液为中性，更接近人体生理环境，因此该条件制备的医用水凝胶在使用时更安全。
细胞毒实验
根据标准GB/T16886.5-2005，通过浸提液接触培养细胞，对细胞形态、增殖观察，评价实施例1和实施例4所制备的医用水凝胶对体外细胞的毒性作用。
实验的具体过程为：实验组：用血清培养基按照0.1g/mL的比例浸提医用水凝胶， 所得到的浸提液定义为100％浓度的浸提液；将所述100％浓度的浸提液采用血清培养基进行梯度稀释，稀释后的浓度梯度为100％，50％和25％，采用所述浓度梯度的浸提液培养细胞；control组：仅采用血清培养基，其余细胞培养条件与实验组相同。分别采用实施例1的医用水凝胶I和实施例4的医用水凝胶IV进行浸提液的配制，浸提温度为(37士1)℃，浸提时间为(24±2)h，细胞培养条件：37℃无菌二氧化碳培养箱培养。
图1示出细胞在实施例1的医用水凝胶I的浸提液中培养24h的生长状态；图2示出细胞在实施例4的医用水凝胶IV的浸提液中培养24h的生长状态。由图1可知，实施例1的医用水凝胶I的浸提液与control组相比，医用水凝胶I的100％浓度的浸提液对L929细胞生长有较大影响，随着浸提液浓度的降低，细胞毒性呈减少趋势，细胞的生长状态接近control组细胞生长状态。
实施例1中所制备的医用水凝胶I呈碱性，证明了碱性的浸提液在一定程度上会影响细胞的生长。
由图2可知，细胞在医用水凝胶IV的100％浓度的浸提液中生长状态接近control组，随着浸提液浓度降低，细胞毒性呈减少趋势，细胞生长呈较好趋势，细胞的生长状态优于control组细胞生长状态。实施例4所制备的医用水凝胶IV呈中性，从而说明中性pH环境的浸提液对L929细胞生长无任何阻碍作用，中性的医用水凝胶在人体使用中更加安全。
抗菌性评价实验
使用琼脂扩散法进行抗菌性评价实验：取已灭菌的肉汤琼脂培养基溶化后倒入直径为10cm的平皿约20mL，待其凝固，得到琼脂平板。用灭菌棉签蘸取实验菌液均匀涂布于琼脂平板上，每块琼脂平板上涂布一种实验菌，然后用直径为10mm的无菌钢圈均匀打孔，每块打3个孔，去除孔内琼脂后将医用水凝胶或ε-聚赖氨酸注于孔中，每孔注入相同体积溶液形成的医用水凝胶或ε-聚赖氨酸，37℃恒温培养24h后取出，结果可以看出，在每个孔的外周均有一个未生长细菌的环，即为抑菌环。重复实验2次，并计算抑菌环有效直径的大小。
其中，抑菌环有效直径(mm)＝抑菌环实际直径(mm)-孔径(10mm)。
结果判断：抑菌环有效直径小于10mm为低度敏感或耐药，抑菌环有效直径在10-15mm之间为中度敏感，抑菌环有效直径大于15mm为高度敏感。
由于ε-聚赖氨酸常态为粉末，遇水溶解，为了与本公开的医用水凝胶作更好的对比，ε-聚赖氨酸采用纸片法，即配制一定浓度的ε-聚赖氨酸溶液(40mg/mL)，将溶液滴在直径为8mm的纸片液上，晾干后将晾干的纸片置于营养琼脂平板中。
选择实施例4的医用水凝胶IV、实施例5的医用水凝胶V、对比例3-4的医用水凝胶X-XI以及ε-聚赖氨酸溶液进行抗菌实验，选用的菌种为金黄色葡萄球菌和大肠杆菌，浓度约为106cfu/mL。抑菌环有效直径的大小如下表2所示：
表2
实验对象 金黄色葡萄球菌/mm 大肠杆菌/mm
实施例4 11.5 10.2
实施例5 11.3 10.0
对比例3 9.2 9.0
对比例4 5.7 5.5
ε-聚赖氨酸 4.3 4.1
体外及体内降解实验
采用实施例4的医用水凝胶IV进行体外及体内降解实验，并在不同的时间点观察医用水凝胶IV的降解情况。其中，体外降解实验的方法如下：将实施例4中制备得到的溶液A和溶液B等体积注入直径为6mm，高为7mm的软管，制备得到水凝胶。取出水凝胶，将水凝胶放在透明玻璃瓶中并加入pH值为7.2±0.2的PBS缓冲溶液，完全浸没水凝胶，密封玻璃瓶，并将玻璃瓶放置在37±1℃恒温箱中，于实验后一周、三周、五周观察该水凝胶，并记录水凝胶的降解情况，结果如表3所示。
体内降解实验的方法如下：选健康的实验大鼠8只，随机分成4组，每组2只。然后麻醉大鼠，取实施例4的医用水凝胶IV植入大鼠腹部皮下，闭合创面，正常喂养。于手术后一周、三周、五周、三个月进行解剖(每个时间点随机选择一组进行解剖)，观察医用水凝胶IV在大鼠体内的降解情况。结果如表3所示：
表3
Figure PCTCN2017082425-appb-000001
注：“---”表示无数据。
按照上述体外降解实验和体内降解实验的方法，分别取实施例5的医用水凝胶V及实施例7的医用水凝胶VII进行体外降解实验和体内降解实验，结果与实施例4的观察结果 (表3)一致。
从实验结果可知，本公开的医用水凝胶在三周时仍能够保持着水凝胶的形态，五周时肉眼已看不到水凝胶，并且三个月时水凝胶已经完全降解。通常创面愈合需要一定的时间，组织粘连、脑脊液渗漏一般出现在手术后两周左右，本公开的水凝胶在三周时仍可以基本保持水凝胶的形态，有利于促进创面的愈合，降低组织粘连与脑脊液渗漏的风险。
体内降解对比实验
麻醉大鼠，分别取实施例4医用水凝胶IV和对比例4制备的医用水凝胶XI移入大鼠腹部皮下，闭合创面，于手术后三周、五周、八周进行解剖，观察医用水凝胶的降解情况。并取医用水凝胶附近的组织做组织切片，观察医用水凝胶与组织的生物相容性。并根据炎症与坏死评分标准表、以及纤维增生与修复评分标准进行综合评分，综合评分的计算方法为：综合评分＝(炎症与坏死评分的总计1)×2+(纤维增生与修复评分的总计2)，计算得到的总分即为综合评分，所述综合评分为仅限于植入物周围面积百分比总分。
其中，图3示出五周解剖时大鼠皮下植入实施例4的医用水凝胶IV的降解情况；图4示出五周解剖时大鼠皮下植入对比例4的医用水凝胶XI的降解情况。如图3所示，五周解剖时大鼠皮下植入部位有大量的增生毛细血管，皮下无积液，无坏死；已经无法找寻到实施例4的医用水凝胶IV，降解明显(图中黑色粒状物为缝线)。如图4所示，五周解剖时大鼠皮下植入部位仍旧可以看到对比例4的医用水凝胶XI的存在，并且材料降解不明显(图中黑色粒状物为缝线，囊肿部分为纤维囊包裹未降解的水凝胶)。
图5示出五周解剖时大鼠皮下植入实施例4的医用水凝胶IV的部位组织切片图(20×)。如图5所示，植入材料(实施例4的医用水凝胶IV)呈细颗粒状。植入材料周边可见少量纤维组织增生，其间可见少量淋巴细胞浸润(1-5个/PHF)，较多巨噬细胞浸润(5-10个/HPF)，较多毛细血管增生(4-7个/HPF)。植入材料周边可见细带状囊腔壁的纤维化囊腔形成。其炎症与坏死评分结果如表4所示，纤维增生与修复评分结果如表5所示，综合评分为9。
表4
Figure PCTCN2017082425-appb-000002
表5
Figure PCTCN2017082425-appb-000003
图6示出五周解剖时大鼠皮下植入对比例4的医用水凝胶XI的部位组织切片图(20×)。如图6所示，植入材料(对比例4的医用水凝胶XI)呈碎片状，内部疏松，可见较多成纤维细胞长入材料内部，残留材料面积百分比约为1-5％，与周围组织之间未见明显空隙。植入材料周边可见较多纤维组织增生，其间可见少量淋巴细胞浸润(1-5个/PHF)，较多巨噬细胞浸润(5-10个/HPF)，少量多核巨细胞浸润(1-2个/HPF)，较多毛细血管增生(4-7个/HPF)。植入材料周边可见中等厚带状的纤维囊形成，较大范围脂肪细胞浸润(21-40％)。其炎症与坏死评分结果如表6所示，纤维增生与修复评分结果如表7所示，炎症与纤维增生的综合评分为14。
表6
Figure PCTCN2017082425-appb-000004
表7
Figure PCTCN2017082425-appb-000005
由上述结果分析可知，实施例4的医用水凝胶IV与组织具有更好的生物相容性，并且在八周时实施例4的医用水凝胶IV在大鼠皮下已经降解完全，而对比例4的医用水凝胶XI仍然有部分未降解。
对机体来说，体内植入物作为异物，当其完成其特定目的之后，应该被取出或降解。人体大部分内科手术创伤后修复时间大致在1-8周，因此实施例4的医用水凝胶IV在降解时间上更适合临床使用。
硬脑膜缝合针眼封堵动物实验
将试验动物狗麻醉，将试验动物狗的左顶骨部位剖开，并取出3cm×2.5cm大小的颅 骨；将试验动物狗的左边硬脑膜切开，长度为2.0cm，并用缝合线(4-0尼龙线)缝合硬脑膜切口，针线之间的间隔2-3mm。并将实施例4的医用水凝胶IV注在缝合部位；待医用水凝胶IV凝固后，将取下的颅骨放回，缝合创面皮肤；饲养试验动物狗4周。
观察指标：(1)术后定性评估试验动物狗的行为是否正常，总的健康信息(如切口愈合情况，食欲，体重)，和可能脑脊液渗漏造成的不正常行为。(2)在将试验动物狗处死前，先使用腰椎穿刺包测定试验动物狗的颅内压，并记录数值，然后通过注射生理盐水增大颅内压，使颅内压增至200mm水柱，并保持至少5s，针眼部位有无脑脊液渗漏。(3)肉眼观察硬脑膜切口位置，医用水凝胶IV的降解和粘连(与脑组织)情况。
图7示出将试验动物狗的硬脑膜切开的图片；图8示出试验动物狗的硬脑膜缝合后的图片；图9示出试验动物狗的硬脑膜缝合后注入医用水凝胶的图片；图10示出试验动物狗的硬脑膜注胶后放回颅骨的图片；图11示出喂养4周后，试验动物狗的硬脑膜的切口位置的愈合情况修复效果图。如图7-11所示，由术后1-4周，受试动物狗的皮肤切口愈合正常，食欲和体重不出现明显差别，动物行为正常；术后4周时解剖，硬脑膜与上层组织无粘连；医用水凝胶肉眼不可见；当颅内压增至200mm水柱，在8s时，手术部位不出现脑脊液渗漏。
由上述实验可见，本公开中所成的医用水凝胶IV具有的低溶胀、呈中性、生物相容性好、可体内降解、具有抗菌效果，并且不会出现脑脊液渗漏。
以上所述，仅为本公开的具体实施方式，但本公开的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本公开揭露的技术范围内，可轻易想到变化或替换，都应涵盖在本公开的保护范围之内。因此，本公开的保护范围应以所述权利要求的保护范围为准。
实用性
根据本公开实施例所提供的医用水凝胶组合物，医用水凝胶及其制备方法与应用可应用于生物医药技术领域，尤其可以用于止血辅助物、防止肺部漏气或脑脊液渗漏制品、防粘连制品等，如：动静脉重建缝线针眼封堵、硬脑膜缝合针眼封堵、硬脑膜重建贴合封堵、防止肺切除术后肺漏气、脊椎硬膜部位防粘连等应用中。本公开制备得到的医用水凝胶的生物相容性好，且具有良好的抗菌性和生物降解性。另外，本公开的医用水凝胶也能够具备对组织也无刺激的效果。

Claims (19)

  1. 一种医用水凝胶组合物，其特征在于，包括第一组分和第二组分，所述第一组分包括聚赖氨酸和聚乙烯亚胺；所述第二组分包括四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯中的一种或几种，其中，所述聚赖氨酸的聚合度为20以上，优选为25～35。
  2. 根据权利要求1所述的医用水凝胶组合物，其特征在于，在所述第一组分中，所述聚赖氨酸与所述聚乙烯亚胺的质量比为0.1～10。
  3. 根据权利要求1或2所述的医用水凝胶组合物，其特征在于，所述聚赖氨酸为ε-聚赖氨酸和/或聚-L-赖氨酸。
  4. 根据权利要求3所述的医用水凝胶组合物，其特征在于，所述ε-聚赖氨酸的重均分子量为3000～5000Da。
  5. 根据权利要求3所述的医用水凝胶组合物，其特征在于，所述聚-L-赖氨酸的重均分子量为7500～300000Da，优选100000～200000Da。
  6. 根据权利要求1-5任一项所述的医用水凝胶组合物，其特征在于，所述聚乙烯亚胺的数均分子量为1000～3500Da，优选为1500～2000Da。
  7. 根据权利要求1-6任一项所述的医用水凝胶组合物，其特征在于，所述四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯和四臂-聚乙二醇-琥珀酰亚胺碳酸酯的重均分子量均为2000～40000Da，优选为10000～20000Da。
  8. 根据权利要求1-7任一项所述的医用水凝胶组合物，其特征在于，所述医用水凝胶组合物负载有药物或活性因子，优选地，所述第一组分和/或第二组分中含有药物或活性因子。
  9. 一种医用水凝胶，其由权利要求1-8任一项所述的医用水凝胶组合物的第一组分和第二组分反应后形成；优选地，所述医用水凝胶由所述第一组分和所述第二组分在缓冲溶液中反应后形成。
  10. 根据权利要求9所述的医用水凝胶，其特征在于，所述医用水凝胶由所述第一组分溶于第一缓冲溶液中，所述第二组分溶于第二缓冲溶液中，然后混合、反应后形成。
  11. 根据权利要求9或10所述的医用水凝胶，其特征在于，所述医用水凝胶的溶胀度为-10～50％，优选为5～47％。
  12. 根据权利要求9-11任一项所述的医用水凝胶，其特征在于，所述医用水凝胶浸泡于水中后，浸泡液的pH值为7～9.5，优选7～8。
  13. 根据权利要求9-12任一项所述的医用水凝胶，其特征在于，所述第一缓冲溶液 的pH值为7.0～7.4或9.1～10.0，优选7.0～7.4；所述第二缓冲溶液的pH值为5.0～6.0或7.0～7.4，优选7.0～7.4。
  14. 一种根据权利要求9-13任一项所述的医用水凝胶的制备方法，其特征在于，包括以下步骤：
    将所述第一组分溶于第一缓冲溶液中，得到第一混合液；
    将所述第二组分溶于第二缓冲溶液中，得到第二混合液；
    将所述第一混合液和第二混合液混合，得到医用水凝胶。
  15. 根据权利要求14所述的医用水凝胶的制备方法，其特征在于，所述第一混合液中，所述聚赖氨酸的浓度为1～50mg/mL，所述聚乙烯亚胺的浓度为1～50mg/mL；所述第二混合液中，所述四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯或其混合物的浓度为100～200mg/mL；所述第一混合液与所述第二混合液等体积混合，得到医用水凝胶。
  16. 根据权利要求14或15所述的医用水凝胶的制备方法，其特征在于，所述第二混合液中还包括显色剂，优选地，所述显色剂包括FD&C Blue#1、FD&C Blue#2、亚甲基蓝中的一种或几种。
  17. 一种医用水凝胶试剂盒，其特征在于，其包括权利要求1-8任一项所述的医用水凝胶组合物以及用于溶解医用水凝胶组合物的各组分的缓冲溶液。
  18. 根据权利要求17所述的医用水凝胶试剂盒，其特征在于，所述医用水凝胶组合物的第一组分与第二组分是分开储存的；优选地，所述医用水凝胶组合物的第一组分中的聚赖氨酸和聚乙烯亚胺是分开储存的。
  19. 一种根据权利要求9-13任一项所述的医用水凝胶在止血辅助物、防止肺部漏气或脑脊液渗漏制品、防粘连制品中的应用。
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CN112225912A (zh) * 2020-10-19 2021-01-15 上海瑞凝生物科技有限公司 可降解医用水凝胶

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