CN113577246B - Composition for preventing scar adhesion, postoperative anti-adhesion material and application - Google Patents
Composition for preventing scar adhesion, postoperative anti-adhesion material and application Download PDFInfo
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- CN113577246B CN113577246B CN202110880679.8A CN202110880679A CN113577246B CN 113577246 B CN113577246 B CN 113577246B CN 202110880679 A CN202110880679 A CN 202110880679A CN 113577246 B CN113577246 B CN 113577246B
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- buffer solution
- polyethylene glycol
- sodium hyaluronate
- conjugate
- adhesion
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
Abstract
The invention relates to a composition for preventing scar adhesion, a postoperative anti-adhesion material and application thereof. The epidural scar adhesion is an important cause of postoperative lumbar surgery failure syndrome, and the invention aims to provide a drug-loaded postoperative sealing material which can realize stable drug release while sealing wounds. The invention firstly provides a mitomycin C-IFN gamma-sodium hyaluronate conjugate for preventing scar adhesion, which can effectively inhibit scar tissue formation and slow down drug degradation speed, and the conjugate can obtain a sealing effect of low swelling and rapid solidification when being applied to polyethylene glycol sealant, is particularly suitable for spinal surgery such as laminectomy and the like, and has good clinical application value.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a composition for preventing scar adhesion, a postoperative anti-adhesion material containing the composition and application of the postoperative anti-adhesion material in spinal surgery.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Trauma to the muscle or ligament requires repair by scar tissue formation. After laminectomy or windowing, the dura mater contacts with the muscles and the residual edges of the vertebral plate, and dense scar tissues which are formed in the defect area of the vertebral plate are called laminectomy membranes in the process of wound repair. Scar tissue adheres to dura mater or nerve root, which can lead to traction and clamping of dura mater or nerve root, resulting in postoperative recurrence of symptoms. The scholars think that scar tissue can cause pain, and the inflammatory reaction of dura mater and nerve roots can also participate in adhesion, and the adhesion can cause nerve tissue dystrophic and abnormal conduction function, and is closely related to postoperative pain symptoms. Thus, epidural scar adhesions after laminectomy are an important factor in postoperative pain recurrence.
After the epidural formation, the difficulty of secondary operation is increased, and the treatment effect is poor. Therefore, prevention and reduction of post-epidural scar adhesions associated with intraspinal surgery has been a focus of research in spinal surgery. At present, the main modes of postoperative adhesion prevention in the field comprise modes of implantation of anti-adhesion materials, drug prevention and the like. The implanted anti-adhesion material has good biocompatibility and proper degradation time, and at present, mainly comprises hard materials such as tricalcium phosphate artificial vertebral plate, polyamide composite artificial vertebral plate and the like, membranous soft materials such as polylactic acid film and the like, fluid materials such as sodium hyaluronate, chitosan and the like, and biological materials such as autologous fat and the like. Among the above anti-adhesion materials, the anti-adhesion film has moderate flexibility and tissue compatibility, and has the defect that the film material is prepared in advance, the thickness is not changeable, and the degree of fit between certain complicated wound surface parts and tissues is low, so that the anti-adhesion effect is reduced. The anti-adhesion liquid of the chitosan has short degradation time, the anti-adhesion effect is not ideal at the wound surface part where long chronic inflammation exists, the anti-pressure capability is poor, the influence of the receptor site is large, and the anti-adhesion liquid is not suitable for preventing and treating adhesion of the nerve, surrounding tissues, tendons and other parts. In the drug prevention mode, drugs such as mitomycin C and the like are generally directly applied to an operation site, and the drug is short in retention time on a wound surface in the drug administration mode, so that an ideal treatment effect is difficult to obtain.
The hydrogel is used as a biocompatible material and is mainly used for postoperative anti-adhesion, hemostatic, filling of defective tissues, prevention of tissue fluid leakage, slow release of drugs and the like in medicine. The hydrogel sealing adhesive is present in the form of a liquid precursor without a fixed shape prior to gel formation and acts directly on the site of action by simple injection or application. This determines that the hydrogel sealant has good adaptability to the surgical wound surface and that the delivery means is simple and quick and easy to handle, while the unique properties of the amorphous liquid precursor also give it the ability to better contact the site of action and adhere more firmly.
Disclosure of Invention
Against the background of the above studies, the inventors believe that the gel adheres well to the surface of the site of action, itself having the effect of preventing scar adhesion. And the degradation time of the gel can be regulated and controlled, and the gel is hopeful to be used as a drug carrier to realize slow release of the drug until the wound surface heals. Therefore, the invention provides the drug-loaded gel which can be firmly adhered to wound tissues, realizes the stable release effect of the drug and can be used as a postoperative anti-adhesion sealing material.
Based on the technical purposes, the invention provides the following technical scheme:
in a first aspect of the invention, there is provided a composition for preventing scar adhesion comprising mitomycin C, an interferon and a polysaccharide; the polysaccharide is selected from dextran, chitin, chitosan, hyaluronic acid, cellulose, collagen, gelatin, fucan or mucopolysaccharide.
It is well known in the art that Interferon (IFN), which is a broad-spectrum antiviral agent, does not directly kill or inhibit viruses, but mainly produces antiviral proteins by cell surface receptor action, thus inhibiting replication of viruses, and at the same time, enhances the activities of natural killer cells (NK cells), macrophages and T lymphocytes, thus playing an immunoregulatory role and enhancing antiviral ability. Interferon is a group of active proteins (mainly glycoproteins) with multiple functions, a cytokine produced by monocytes and lymphocytes. They have broad-spectrum antiviral activity on the same cell, influence cell growth, differentiate, regulate immune function and other biological activities, and are the most main antiviral infection and antitumor biological products at present.
The research of the invention shows that the mitomycin C and the interferon can inhibit the formation of scar tissue. Among them, the interferon is preferably type I interferon, and IFN-beta is used in the scheme with better effect. The research of the composition shows that the composition has better scar formation inhibition effect by adopting the hyaluronic acid and mitomycin C and interferon to compound. The main disadvantage of using mitomycin C or hyaluronic acid as post-operative anti-adhesion material in the prior art is that the degradation rate is too high and the retention time of the drug on the wound surface is too short. The present invention contemplates the provision of a combination of the above-mentioned agents, wherein the active ingredients are covalently bound, which effectively slows down the degradation time of the active ingredients, and which has a significantly better capacity to inhibit scar tissue formation than the unbound mixed components.
In a second aspect of the invention there is provided the use of a composition according to the first aspect for the preparation of a post-operative anti-adhesion material.
Based on the good affinity and the drug slow release effect of the conjugate of the mitomycin C-IFN gamma-sodium hyaluronate of the first aspect, the conjugate has better application significance for the operation part with more dense nerve distribution such as epidural or meningeal. However, the degradation time of the conjugate is still insufficient to support wound healing, and the invention suggests that the conjugate is applied to a polymer postoperative sealing material to further increase the slow release effect. According to the invention, a polyethylene glycol hydrophilic sealing material is selected to design a postoperative anti-adhesion composite material, in the research process of the composite material, the inventor finds that the swelling effect and the gel forming speed can be effectively reduced by adopting a composite cross-linking agent, and further, the inventor adopts different solvent systems to dissolve the cross-linking agent, and through verification, the three-lysine and polyethylene imine composite effect is good, and the polyethylene imine can be dissolved in a polysaccharide solution to achieve a better mixing effect.
The hydrogel preparation has high coagulation speed and low swelling rate, is applied to the parts with dense nerve distribution such as vertebra, brain and the like, and can effectively reduce the compression effect on surrounding tissues and nerves. Has good prevention and treatment effects on common adhesion and scar complications after the epidural surgery, in particular to laminectomy.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a photograph of an in vitro degradation experiment of the present invention;
FIG. 2 is a photograph of a subcutaneous implantation experiment of hydrogel as described in example 1.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
As described in the background art, in order to solve the above technical problems, the present invention provides a composition for preventing scar adhesion, and an application of the composition in preparing postoperative anti-adhesion materials.
In a first aspect of the invention, there is provided a composition for preventing scar adhesion comprising mitomycin C, an interferon and a polysaccharide; the polysaccharide is selected from dextran, chitin, chitosan, hyaluronic acid, cellulose, collagen, gelatin, fucan or mucopolysaccharide.
In a more effective version of the composition according to the first aspect, the polysaccharide is selected from the group consisting of chitosan, cellulose, dextran, chitosan and sodium hyaluronate.
In a preferred embodiment, the polysaccharide is chitosan, dextran or sodium hyaluronate.
Among them, sodium hyaluronate itself has a good effect of inhibiting scar tissue and has an ideal biocompatibility. In a further preferred embodiment, the polysaccharide is sodium hyaluronate.
Preferably, the interferon IFNγ is a type I interferon, further, IFN- β.
In one embodiment of the above preferred embodiment, the composition is a conjugate of mitomycin C-IFN gamma-sodium hyaluronate, and the covalent bond between mitomycin C, IFN gamma and sodium hyaluronate is formed by cross-linking with a cross-linking agent, wherein the cross-linking agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) or N-hydroxysuccinimide (NHS).
In a specific embodiment, the mitomycin C-IFN gamma-sodium hyaluronate conjugate is prepared as follows: dissolving sodium hyaluronate in PBS buffer solution with pH of 6.5, adding EDC, and stirring at low speed for 25-35 min to activate sodium hyaluronate; adding mitomycin C and IFNgamma into the activated sodium hyaluronate buffer solution, and stirring for 6-10 hours at room temperature to obtain the mitomycin C-IFNgamma-sodium hyaluronate conjugate; after the reaction is completed, the product can be purified by dialysis or elution and the like.
In a second aspect of the invention there is provided the use of a composition according to the first aspect for the preparation of a post-operative anti-adhesion material.
Preferably, the postoperative anti-adhesion material is one of a film preparation, a liquid preparation and a gel preparation.
Further, the postoperative anti-adhesion material is a hydrogel, and the hydrogel is a cross-linked product of polyethylene glycol activated ester.
In the above embodiment, the hydrogel preparation comprises polyethylene glycol active ester, mitomycin C-IFN gamma-sodium hyaluronate conjugate, crosslinking agent and buffer solution.
The polyethylene glycol activating ester is selected from four-arm polyethylene glycol succinimide succinate (4-arm-PEG-SS), four-arm polyethylene glycol succinimide glutarate (4-arm-PEG-SG), four-arm polyethylene glycol succinimide sebacate (4-arm-PEG-SSeb), six-arm polyethylene glycol succinimide succinate (6-arm-PEG-SS), six-arm polyethylene glycol succinimide glutarate (6-arm-PEG-SG), six-arm polyethylene glycol succinimide sebacate (6-arm-PEG-SSeb), eight-arm polyethylene glycol succinimide succinate (8-arm-PEG-SS), eight-arm polyethylene glycol succinimide glutarate (8-arm-PEG-SG) or eight-arm polyethylene glycol succinimide sebacate (8-arm-PEG-SSeb). The molecular weight is 3000-20000 dalton.
The cross-linking agent is selected from one or a combination of polylysine and polyethyleneimine.
In a better embodiment, the cross-linking agent is a combination of polylysine and polyethyleneimine.
Further, the polylysine is trilysine, tetrapolylysine or pentapolylysine.
Preferably, the buffer solution comprises an acidic buffer solution and an alkaline buffer solution, wherein the pH value of the acidic buffer solution is 3-5, and the acidic buffer solution is one or more of a phthalic acid buffer solution, a phosphoric acid buffer solution, a citric acid buffer solution or an acetic acid buffer solution; the pH value of the alkaline buffer solution is 9-11, and further, the alkaline buffer solution is one or more of phosphate buffer solution, barbital sodium buffer solution, tris buffer solution, boric acid buffer solution, glycine buffer solution and carbonic acid buffer solution.
In an embodiment with a better effect in the above preferred technical solution, the polylysine is trilysine, and the trilysine and the polyethylenimine are respectively placed in different dissolution systems: the polylysine is placed in a buffer and the polyethylenimine is dissolved in a polysaccharide solution.
In other specific embodiments, antioxidants, colorants, or other drugs are also included in the hydrogel formulation.
In a fourth aspect, the present invention provides a sealant kit for use in surgery, the kit comprising the scar adhesion prevention composition of the first aspect.
Preferably, the kit further comprises polyethylene glycol activated ester, a cross-linking agent or a buffer solution.
Preferably, the kit further comprises a syringe and a mixing device.
In the clinical treatment process, the gel preparation is quickly prepared after operation, and has important significance for reducing the wound infection probability. The skilled in the art is motivated to adopt hydrogel mixing and spraying devices, such as syringes, spray heads and the like, to realize the rapid mixing and smearing effects of the raw materials.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail below with reference to specific examples and comparative examples.
Example 1
In this example, a mitomycin C-IFN gamma-sodium hyaluronate conjugate is provided, wherein the molecular weight of the sodium hyaluronate is 5kDa, and the preparation method of the mitomycin C-IFN gamma-sodium hyaluronate conjugate is as follows:
dissolving sodium hyaluronate in PBS buffer solution with pH of 6.5, adding appropriate amount of EDC, and stirring at low speed at room temperature for 30min to activate carboxyl group of sodium hyaluronate. And (3) dissolving mitomycin C and IFN gamma in PBS buffer solution, slowly adding the mixture into activated sodium hyaluronate under the stirring condition, stirring for 8 hours at room temperature after the dripping is finished, purifying the conjugate by adopting a PBS dialysis mode, and freeze-drying the purified product for later use.
Example 2
In this example, a mitomycin C-IFN gamma-sodium hyaluronate conjugate is provided, wherein the molecular weight of the sodium hyaluronate is 10kDa, and the preparation method of the mitomycin C-IFN gamma-sodium hyaluronate conjugate is as follows:
dissolving sodium hyaluronate in PBS buffer solution with pH of 6.0, adding appropriate amount of EDC, and stirring at low speed at room temperature for 35min to activate carboxyl group of sodium hyaluronate. Dissolving mitomycin C and IFNgamma in PBS buffer solution, slowly adding into activated sodium hyaluronate under stirring, stirring for 10 hours at room temperature after dripping, eluting by column chromatography to obtain the mitomycin C-IFNgamma-sodium hyaluronate conjugate, and freeze-drying the purified product for later use.
Example 3
In this example, a mitomycin C-IFN gamma-sodium hyaluronate conjugate is provided, wherein the molecular weight of the sodium hyaluronate is 10kDa, and the preparation method of the mitomycin C-IFN gamma-sodium hyaluronate conjugate is as follows:
sodium hyaluronate was dissolved in PBS buffer at pH6.0, and after addition of EDC, the sodium hyaluronate was stirred at low speed for 25 minutes at room temperature to activate the carboxyl group of sodium hyaluronate. Dissolving mitomycin C and IFNgamma in PBS buffer solution, slowly adding into activated sodium hyaluronate under stirring, stirring for 10 hours at room temperature after dripping, eluting by column chromatography to obtain the mitomycin C-IFNgamma-sodium hyaluronate conjugate, and freeze-drying the purified product for later use.
Example 4
In this embodiment, a post-operation anti-adhesion material is provided, the anti-adhesion material is a polyethylene glycol hydrogel preparation, and the components and the proportions of the hydrogel preparation are as follows:
(a) Four arm polyethylene glycol succinimidyl succinate 0.4g, mitomycin C-IFN gamma sodium hyaluronate conjugate 0.25g;
(b) Trilysine (10 g/L) -borate buffer (65 mM) 2.5ml, ph=9.8;
(c) 8-7-0.1 mL of sodium hyaluronate (molecular weight 2000) in mass fraction;
(d) Phosphate buffer (1.5 mM) 2.4ml, ph=4.0.
The preparation method of the hydrogel comprises the following steps: mixing the (a) and the (d) to obtain a solution A, mixing the (B) and the (c) to obtain a solution B, and mixing the solution A and the solution B to obtain the gel preparation.
Example 5
In this embodiment, a post-operation anti-adhesion material is provided, the anti-adhesion material is a polyethylene glycol hydrogel preparation, and the components and the proportions of the hydrogel preparation are as follows:
(a) Six-arm polyethylene glycol succinimidyl succinate 0.4g, mitomycin C-IFN gamma sodium hyaluronate conjugate 0.25g;
(b) Trilysine (10 g/L) -borate buffer (65 mM) 2.5ml, ph=9.8;
(c) 8-7-0.1 mL of sodium hyaluronate (molecular weight 2000) in mass fraction;
(d) Phosphate buffer (1.5 mM) 2.4ml, ph=4.0.
The preparation method of the hydrogel comprises the following steps: mixing the (a) and the (d) to obtain a solution A, mixing the (B) and the (c) to obtain a solution B, and mixing the solution A and the solution B to obtain the gel preparation.
Example 6
In this embodiment, a drug-loaded surgical sealant is provided, where the components and proportions of the hydrogel in the surgical sealant are as follows:
(a) Six-arm polyethylene glycol succinimide sebacate 0.45g, mitomycin C-IFN gamma-sodium hyaluronate conjugate 0.2g;
(b) Trilysine (15 g/L) -borate buffer (65 mM) 2.5ml, ph=9.8;
(c) Polyethylene imine (molecular weight 1800) with mass fraction of 10% -chitosan 5% -water solution of 0.1mL;
(d) Phosphate buffer (1.5 mM) 2.4ml, ph=4.0.
The preparation method of the hydrogel comprises the following steps: mixing the (a) and the (d) to obtain a solution A, mixing the (B) and the (c) to obtain a solution B, and mixing the solution A and the solution B to obtain the gel preparation.
Comparative example 1
In this comparative example, a mixed solvent of mitomycin C, IFN gamma and sodium hyaluronate was provided, and equal amounts of mitomycin C, IFN gamma and sodium hyaluronate in example 1 were added to a PBS solution and stirred for 30 minutes to mix them uniformly.
Comparative example 2
In this comparative example, a mixed solvent of mitomycin C, IFN gamma and chitosan was provided, and equal amounts of mitomycin C, IFN gamma and chitosan in example 1 were added to a PBS solution and stirred for 30 minutes to mix them uniformly.
Comparative example 3
In this comparative example, a mitomycin C, IFN gamma and chitosan conjugate was provided, and the same dosage of sodium hyaluronate as in example 1 was replaced with chitosan of the same molecular weight to produce a mitomycin C-IFN gamma-chitosan conjugate.
Comparative example 4
In this embodiment, a post-operation anti-adhesion material is provided, the anti-adhesion material is a polyethylene glycol hydrogel preparation, and the components and the proportions of the hydrogel preparation are as follows:
(a) Four arm polyethylene glycol succinimidyl succinate 0.4g, mitomycin C-IFN gamma sodium hyaluronate conjugate 0.25g;
(b) Trilysine (10 g/L) -borate buffer (65 mM) 2.5ml, ph=9.8;
(c) 8% -0.1 mL of polyethyleneimine (molecular weight 2000) mass fraction;
(d) Phosphate buffer (1.5 mM) 2.4ml, ph=4.0.
The preparation method of the hydrogel comprises the following steps: mixing the (a) and the (d) to obtain a solution A, mixing the (B) and the (c) to obtain a solution B, and mixing the solution A and the solution B to obtain the gel preparation.
Comparative example 5
In this embodiment, a post-operation anti-adhesion material is provided, the anti-adhesion material is a polyethylene glycol hydrogel preparation, and the components and the proportions of the hydrogel preparation are as follows:
(a) Four arm polyethylene glycol succinimidyl succinate 0.4g, mitomycin C-IFN gamma sodium hyaluronate conjugate 0.25g;
(b) Trilysine (10 g/L) -borate buffer (65 mM) 2.5ml, ph=9.8;
(c) Phosphate buffer (1.5 mM) 2.4ml, ph=4.0.
The preparation method of the hydrogel comprises the following steps: mixing the components (a) and (c), injecting into the component (b), and injecting into the wound surface to be sealed after mixing.
The invention aims at examining the scar inhibition effect of the mitomycin C-IFN gamma-sodium hyaluronate conjugate, and the examination method comprises the following steps of measuring the content of collagen fibers in rat epidural scar tissues: healthy mature Wistar rats are selected, standard operation is carried out according to lumbar laminectomy after anesthesia, the rats are placed in prone position after anesthesia, operation incision is positioned in the back side, spinous process and vertebral lamina are removed after skin, fascia and muscle are separated, and the window is closed after operation. The compositions described in examples 1-3 and comparative examples 1-3, respectively, were placed on the wound surface. Three days after operation, continuously drenching antibiotics for treatment, killing the rats 14 days after operation, taking epidural adhesion scar tissues, and detecting the content of hydroxyproline in the scar tissues through ultraviolet absorbance after drying so as to detect the content of collagen fibers, wherein the detection results are shown in the following table 1:
TABLE 1
| Group of | Hyp content μg/mg sample | In vitro degradation time (d) |
| Example 1 | 1.19±0.11 | 3.4 |
| Example 2 | 1.27±0.24 | 4.1 |
| Example 3 | 1.08±0.41 | 4.2 |
| Comparative example 1 | 1.53±0.14 | 1.2 |
| Comparative example 2 | 1.88±0.31 | 0.8 |
| Comparative example 3 | 1.69±0.34 | 1.5 |
From the results of the table, the conjugate form provided by the invention can effectively prolong the stay time of the medicine in the wound and effectively prolong the action time of the medicine. As can be seen from the measurement of the hydroxyproline content, the conjugate form can effectively inhibit the formation of collagen fibers in scar tissues, and the conjugate prepared by adopting the mixture form or other polysaccharides cannot achieve the effect. In the research process of the invention, the effect of hyaluronic acid combination cannot be realized by testing various polysaccharides such as dextran, gelatin and the like.
The present invention was also directed to the detection of in vitro degradation time, swelling rate and gel forming rate of the hydrogels described in examples 4 to 6 in the following examples, and the specific detection method is as follows:
in vitro degradation time: spraying the hydrogel into a conical flask, weighing, adding physiological saline according to 0.1g/mL, covering a bottle stopper, sealing by a sealing film, putting into a shaking incubator at 37+/-1 ℃, and observing the gel disappearance time.
Detection of swelling Rate: the hydrogel prepared above is weighed and moved into a grinding triangular flask, added into 7.4 phosphate buffer solution (the formula of the phosphate buffer solution is that 1.36g of monopotassium phosphate is weighed, 79mL of 0.1mol/mL of sodium hydroxide solution is added, and the solution is diluted to 200mL of water to obtain the phosphate buffer solution with the pH of 7.4) which is preheated to 37+/-1 ℃, the grinding triangular flask is placed into a 37+/-1 ℃ incubator, samples are taken out every few hours, surface moisture is absorbed by filter paper, and the weighing is finished until the weight is no longer increased. The gel swell ratio was calculated as follows.
Swelling ratio= (mass of sample after swelling-sampling amount) ×100%/sampling amount.
And (3) detecting the gel forming time: connecting the first injector (a) with the powder bottle (c), injecting liquid into the powder bottle to dissolve polyethylene glycol derivative, pumping the liquid back to the first injector after dissolution, injecting 0.5mL of liquid into a test tube, putting a magnet, putting the test tube on a magnetic stirrer to enable the magnet to rotate, then rapidly injecting the liquid in 0.5mL of the second injector into the test tube, starting timing, and stopping timing when observing that the magnet stops rotating or the speed is obviously changed, wherein the timing is the gel forming time. The test results are shown in Table 2 below:
TABLE 2
| Group of | Time per second of gel formation | Swelling ratio/% | In vitro degradation time/d |
| Example 4 | 0.67 | 0.85 | 7.8 |
| Example 5 | 0.75 | 0.97 | 8.1 |
| Example 6 | 0.88 | 0.78 | 7.9 |
| Comparative example 4 | 1.23 | 2.15 | 6.4 |
| Comparative example 5 | 1.58 | 3.14 | 5.4 |
In order to verify the safety performance of the hydrogel product, the hydrogel prepared in the examples 4-6 is implanted under the skin of New Zealand white rabbits, and the time for degradation of the hydrogel product in a biocompatible organism is examined. Experimental rabbits were anesthetized with 8mg ketamine plus sodium pentobarbital (0.2 mg/kg) by intraperitoneal injection, and hydrogel was injected subcutaneously at the back of the rabbits, 1mL at each site. Rabbits were observed every 2 weeks after the operation, and the skin of the injection site was taken after the rabbits were sacrificed to observe the envelope condition. As shown in figure 2, after cutting the skin of the rabbit at 2 weeks, the injection point can be observed to have a thin transparent coating, the coating is soft, and a small amount of capillary blood vessel hyperplasia is generated, so that the hydrogel product provided by the invention has good biocompatibility. The in vivo degradation time of the hydrogels described in examples 4-6 was 8-12 weeks.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. A conjugate for preventing scar adhesion, which is characterized in that the conjugate is a conjugate of mitomycin C-IFN-beta-sodium hyaluronate, and mitomycin C, IFN-beta and sodium hyaluronate are combined through covalent bonds;
the preparation method of the mitomycin C-IFN-beta-sodium hyaluronate conjugate comprises the following steps: adding sodium hyaluronate into PBS buffer solution with pH of 6.5, uniformly mixing, adding EDC, and stirring at a low speed for 25-35 min to activate sodium hyaluronate; adding mitomycin C and IFN-beta into the activated sodium hyaluronate buffer solution, and stirring for 6-10 hours at room temperature to obtain the mitomycin C-IFN-beta-sodium hyaluronate conjugate; after the reaction is completed, the product is purified by dialysis or elution.
2. Use of the conjugate of claim 1 for the preparation of a post-operative anti-adhesion material.
3. The use according to claim 2, wherein the postoperative anti-adhesion material is a gel preparation, and the raw materials of the gel preparation are polyethylene glycol-based activated ester, mitomycin C-IFN-beta-sodium hyaluronate conjugate, cross-linking agent and buffer;
the polyethylene glycol activating ester is selected from one of four-arm polyethylene glycol succinimide succinate, four-arm polyethylene glycol succinimide glutarate, four-arm polyethylene glycol succinimide sebacate, six-arm polyethylene glycol succinimide succinate, six-arm polyethylene glycol succinimide glutarate, six-arm polyethylene glycol succinimide sebacate, eight-arm polyethylene glycol succinimide succinate, eight-arm polyethylene glycol succinimide glutarate and eight-arm polyethylene glycol succinimide sebacate, and the molecular weight is 3000-20000 daltons;
the cross-linking agent is a combination of trilysine and polyethyleneimine.
4. The use according to claim 3, wherein the buffer solution comprises an acidic buffer solution and an alkaline buffer solution, wherein the pH value of the acidic buffer solution is 3-5, and the buffer solution is one of a phthalic acid buffer solution, a phosphoric acid buffer solution, a citric acid buffer solution and an acetic acid buffer solution;
the pH value of the alkaline buffer solution is 9-11, and the alkaline buffer solution is one of phosphate buffer solution, barbital sodium buffer solution, tris buffer solution, boric acid buffer solution, glycine buffer solution and carbonic acid buffer solution.
5. The use according to claim 3, wherein the trilysine and the polyethylenimine are placed in separate dissolution systems: the trilysine is placed in a buffer solution, and the polyethyleneimine is dissolved in a sodium hyaluronate solution.
6. A sealant kit for use in surgery, comprising the scar adhesion prevention conjugate of claim 1.
7. The surgical sealant kit according to claim 6, further comprising the polyethylene glycol-based activated ester and the cross-linking agent according to claim 3, the buffer according to claim 4, a syringe and a mixing device.
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