CN112826987A - Anti-adhesion gel and preparation method thereof - Google Patents

Anti-adhesion gel and preparation method thereof Download PDF

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CN112826987A
CN112826987A CN202110112042.4A CN202110112042A CN112826987A CN 112826987 A CN112826987 A CN 112826987A CN 202110112042 A CN202110112042 A CN 202110112042A CN 112826987 A CN112826987 A CN 112826987A
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weight
stirring
mixed system
water bath
sodium hyaluronate
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邹圣灿
王宝群
林莎莎
刘桂亭
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Qingdao Chenland Marine Bioengineering Co ltd
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Qingdao Chenland Marine Bioengineering Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/145—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/23—Carbohydrates
    • A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents

Abstract

The invention discloses an anti-adhesion gel and a preparation method thereof, belonging to the technical field of biological medicines; the anti-adhesion gel raw material comprises sodium hyaluronate, sodium alginate, soluble calcium salt solution, an isotonic regulator and deionized water; the mass ratio of the sodium hyaluronate, the sodium alginate, the soluble calcium salt solution, the isoosmotic adjusting agent and the deionized water is (1.0-10.0): (0.02-3.0): (5.0-30.0): (0.7-1.0): (56.0-94.0). The anti-adhesion gel has simple and safe formula, simple and easy preparation process, no pollutants such as waste liquid and the like in the whole preparation process, and is suitable for popularization and application.

Description

Anti-adhesion gel and preparation method thereof
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an anti-adhesion gel and a preparation method thereof.
Background
After the operation, the abnormal phenomenon of tissue and organ adhesion often occurs in the process of wound healing of a patient, wherein the incidence rate of the adhesion after the operation of the pelvic cavity and the abdominal cavity is 50-97 percent; the adhesion can cause intestinal obstruction, infertility, chronic pelvic cavity pain and other complications, and can also increase the incidence of reoperation, so that the prevention of postoperative adhesion is very necessary.
Adhesions are the result of the interaction of the inflammatory environment in the abdominal cavity, various adhesion factors, matrix metalloproteinases and the extracellular matrix of the peritoneum, and the mechanism of occurrence is complex; at present, the main measure for preventing tissue adhesion is to establish a physical barrier between surgical wound surfaces; however, the existing anti-adhesion gel preparation still has many defects, such as complex components, complex preparation process, unstable in vivo degradation (small molecular weight is easy to degrade, and derivatives after chemical modification are not easy to degrade), large addition amount of cross-linking agent and incomplete removal of residual part, which increases the use risk of the product.
Therefore, how to provide the anti-adhesion gel with simple and safe components, simple and easy preparation process, short preparation time and good biocompatibility is a problem to be solved in the field.
Disclosure of Invention
The invention discloses an anti-adhesion gel and a preparation method thereof, wherein the anti-adhesion gel is simple in components, can be prepared in a short time, and can obtain better viscosity under the condition of not using a cross-linking agent.
In order to achieve the purpose, the invention adopts the following technical scheme:
an anti-adhesion gel comprises sodium hyaluronate, sodium alginate, soluble calcium salt solution, isotonic regulator and deionized water;
the mass ratio of the sodium hyaluronate, the sodium alginate, the soluble calcium salt solution, the isoosmotic adjusting agent and the deionized water is (1.0-10.0): (0.02-3.0): (5.0-30.0): (0.7-1.0): (56.0-94.0).
The invention has simple formula and easily obtained materials, and does not contain any components which increase the potential use risk of the product, such as preservative, cross-linking agent and the like.
The wound surface can be separated, the healing of the peritoneum can be promoted, the dissolution of fiber can be enhanced, inflammation-causing factors can be eliminated, the occurrence of adhesion can be prevented, and the healing of the wound can be promoted by taking the sodium hyaluronate as the main component; sodium alginate can react with Ca2+Rapid generation of ion exchange reactionThe alginate gel with high strength is generated, and meanwhile, the alginate gel has good biocompatibility, biodegradability, hemostatic property, antibacterial property, healing promotion and other biological properties. The invention combines the two natural biological raw materials, and can prepare the anti-adhesion gel with better performance in a short time by properly adding the soluble calcium salt solution and the isotonic regulator, thereby effectively preventing postoperative tissue adhesion and promoting wound healing.
Preferably, the molecular weight of sodium hyaluronate is 100-.
Preferably, the soluble calcium salt solution concentration is 1-10% w/w, and the gel properties obtained are optimal within this concentration range.
Further preferably, the soluble calcium salt solution has a concentration of 2.5-5% w/w.
Preferably, the isotonicity adjusting agent is sodium chloride or glucose.
The preparation method of the anti-adhesion gel comprises the following steps:
(1) uniformly mixing deionized water and an isotonic regulator, and carrying out water bath at the temperature of 30-70 ℃ for 5-30min to obtain a mixed system I;
(2) adding sodium hyaluronate and sodium alginate into the mixed system I at the temperature of 30-70 ℃ in water bath, and stirring at the speed of 200-3000rpm for 0.17-1.5h to obtain a mixed system II;
(3) and (3) at the temperature of 30-70 ℃ in water bath, adding the soluble calcium salt solution into the mixed system II, and stirring at 200-3000rpm for 0.25-6h to prepare the anti-adhesion gel.
The preparation method is simple and short in time consumption, and the anti-adhesion gel with proper viscosity and enzymolysis resistance can be prepared by controlling the mixing process of the raw materials.
Preferably, in the step (1), deionized water and an isotonic regulator are uniformly mixed, and the mixture is subjected to heat preservation in a water bath at the temperature of 30-40 ℃ for 10min to obtain a mixed system I.
Preferably, the stirring condition in step (2) is 2500-.
Preferably, the stirring condition in step (3) is 500-600rpm for 30min, and the stirring process is carried out in a water bath at 30-40 ℃.
Preferably, the concentration of the soluble calcium salt solution in step (3) is 1-5% w/w, and the soluble calcium salt can be selected from calcium gluconate, calcium nitrate, calcium chlorate, calcium chloride and the like.
In conclusion, the anti-adhesion gel disclosed by the invention is simple and safe in formula, simple and feasible in preparation process, can be prepared within 1-2h, does not generate pollutants such as waste liquid and the like in the whole preparation process, and is suitable for popularization and application.
Drawings
FIG. 1 shows the pathological analysis of HE staining.
FIG. 2 is a schematic diagram of a sample with a failure made by changing the order of addition of osmolytes.
FIG. 3 is a schematic diagram showing a sample of failed product obtained by changing the stirring speed of calcium.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Weighing 86.0 parts by weight of deionized water, adding into a reaction vessel, adding 1.0 part by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in a water bath at 30 ℃ for 10min to obtain a mixed system I; then, under the temperature of 30 ℃ water bath, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 150wDa and 1.0 part by weight of sodium alginate powder into the mixed system I, and rapidly stirring at 2500rpm for 20min to obtain a mixed system II after the sodium hyaluronate powder and the sodium alginate powder are completely dissolved; and (3) keeping the temperature of the mixture in water bath at 30 ℃, adding the mixture into the mixture II in a weight ratio of 1: 9, rapidly stirring at 500rpm for 30min to obtain the composite anti-adhesion gel.
The stirring in the preparation process is electric stirring.
Example 2
Weighing 81.0 parts by weight of deionized water, adding into a reaction vessel, adding 1.0 part by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in a water bath at 30 ℃ for 10min to obtain a mixed system I; then, under the temperature of 30 ℃ water bath, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 150wDa and 1.0 part by weight of sodium alginate powder into the mixed system I, and rapidly stirring at 2500rpm for 20min to obtain a mixed system II after the sodium hyaluronate powder and the sodium alginate powder are completely dissolved; and (3) keeping the temperature of the mixture in water bath at 30 ℃, adding the mixture into the mixture II in a weight ratio of 3: 17, rapidly stirring at 500rpm for 30min to obtain the composite anti-adhesion gel.
The stirring in the preparation process is electric stirring.
Example 3
Weighing 86.0 parts by weight of deionized water, adding into a reaction vessel, adding 1.0 part by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in a water bath at 40 ℃ for 10min to obtain a mixed system I; then, under the temperature of 40 ℃ water bath, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 185wDa and 1.0 part by weight of sodium alginate powder into the mixed system I, and rapidly stirring at 3000rpm for 20min to obtain a mixed system II after the sodium hyaluronate powder and the sodium alginate powder are completely dissolved; and (3) keeping the temperature of the mixture in water bath at 40 ℃, adding the mixture into the mixture II in a weight ratio of 1: 9, and rapidly stirring the mixture for 30min at 500rpm in a 5.0% (w/w) calcium nitrate solution to fully mix the mixture to obtain the composite anti-adhesion gel.
The stirring in the preparation process is electric stirring.
Example 4
Weighing 76.0 parts by weight of deionized water, adding into a reaction vessel, adding 1.0 part by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in a water bath at 40 ℃ for 10min to obtain a mixed system I; then, under the temperature of 40 ℃ water bath, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 185wDa and 1.0 part by weight of sodium alginate powder into the mixed system I, and rapidly stirring at 3000rpm for 20min to obtain a mixed system II after the sodium hyaluronate powder and the sodium alginate powder are completely dissolved; and (3) keeping the temperature of the mixture in water bath at 40 ℃, adding the mixture into the mixture II in a weight ratio of 1: 4, rapidly stirring at 500rpm for 30min to obtain the composite anti-adhesion gel.
The stirring in the preparation process is electric stirring.
Example 5
Weighing 76.3 parts by weight of deionized water, adding into a reaction vessel, adding 1.0 part by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in a water bath at 40 ℃ for 10min to obtain a mixed system I; then, under the temperature of 40 ℃ water bath, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 150wDa and 0.7 part by weight of sodium alginate powder into the mixed system I, and rapidly stirring at 2500rpm for 20min to obtain a mixed system II after the sodium hyaluronate powder and the sodium alginate powder are completely dissolved; and (3) keeping the temperature of the mixture in water bath at 40 ℃, adding the mixture into the mixture II in a weight ratio of 1: 4, rapidly stirring at 600rpm for 30min to obtain the composite anti-adhesion gel.
The stirring in the preparation process is electric stirring.
Example 6
Weighing 76.3 parts by weight of deionized water, adding into a reaction vessel, adding 1.0 part by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in a water bath at 40 ℃ for 10min to obtain a mixed system I; and then, adding 2.0 parts by weight of sodium hyaluronate powder with the molecular weight of 200wDa and 0.7 part by weight of sodium alginate powder into the mixed system I at the temperature of 40 ℃ for water bath heat preservation, rapidly stirring at 3000rpm for 20min to completely dissolve the sodium hyaluronate powder and the sodium alginate powder to obtain a mixed system II, and adding the sodium hyaluronate powder and the mixed system II in a weight ratio of 1: 4, rapidly stirring at 600rpm for 30min to obtain the composite anti-adhesion gel.
The stirring in the preparation process is electric stirring.
Example 7
Weighing 82.0 parts by weight of deionized water, adding into a reaction vessel, adding 5.0 parts by weight of glucose, stirring for dissolving, and carrying out heat preservation in water bath at 40 ℃ for 10min to obtain a mixed system I; and then, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 185wDa and 1.0 part by weight of sodium alginate powder into the mixed system I at the temperature of 40 ℃ for water bath heat preservation, rapidly stirring at 3000rpm for 20min to completely dissolve the sodium hyaluronate powder and the sodium alginate powder to obtain a mixed system II, and adding the mixture I, which is mixed with the mixed system II in a weight ratio of 1: 9, rapidly stirring at 500rpm for 30min to obtain the composite anti-adhesion gel.
The stirring in the preparation process is electric stirring.
Comparative example 1
Weighing 97.0 parts by weight of deionized water, adding into a reaction vessel, adding 1.0 part by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in water bath at 30 ℃ for 10min to obtain a mixed system I; and then 2.0 parts by weight of sodium hyaluronate powder with the molecular weight of 150wDa is added into the mixed system I at the temperature of 30 ℃ water bath, and the mixed system I is rapidly stirred for 20min at 2500rpm, so that gel is obtained after the sodium hyaluronate powder is completely dissolved.
The stirring in the preparation process is electric stirring.
Comparative example 2
Weighing 87.0 parts by weight of deionized water, adding the deionized water into a reaction container, adding 1.0 part by weight of sodium chloride, stirring to dissolve, and carrying out heat preservation in a water bath at 30 ℃ for 10min to obtain a mixed system I; and then, adding 2.0 parts by weight of sodium hyaluronate powder with the molecular weight of 150wDa into the mixed system I at the temperature of 30 ℃ water bath, quickly stirring at 2500rpm for 20min to obtain a mixed system II after completely dissolving the sodium hyaluronate powder, and adding the mixture of sodium hyaluronate powder and the mixed system II in a weight ratio of 1: 9, rapidly stirring at 500rpm for 30min to obtain composite gel.
The stirring in the preparation process is electric stirring.
Comparative example 3
Weighing 96.0 parts by weight of deionized water, adding into a reaction vessel, adding 1.0 part by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in water bath at 30 ℃ for 10min to obtain a mixed system I; and then, adding 2.0 parts by weight of sodium hyaluronate powder with the molecular weight of 150wDa and 1.0 part by weight of sodium alginate powder into the mixed system I at the temperature of 30 ℃ in water bath, and rapidly stirring at 2500rpm for 20min to completely dissolve the sodium hyaluronate powder and the sodium alginate powder to obtain the composite gel.
The stirring in the preparation process is electric stirring.
Comparative example 4
Dissolving sodium hyaluronate dry powder with the molecular weight of 150wDa in sodium hydroxide solution with the mass concentration of 10%, adding adipic acid dihydrazide with the weight of 0.01% of the weight of the sodium hyaluronate dry powder, and preserving the heat at 35 ℃ for 5 hours to obtain gel X; pressing the gel X at 500MPa for 1 min; adjusting the pH value of the pressed gel X to be neutral, adding a phosphate buffer solution, and swelling for 18h at 40 ℃; and cooling the swollen gel X to-4 ℃, and carrying out heat preservation treatment for 1h to obtain the sodium hyaluronate gel.
Comparative example 5
Weighing 86.0 parts by weight of deionized water, adding into a reaction vessel, adding 1.0 part by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in a water bath at 40 ℃ for 10min to obtain a mixed system I; then, under the temperature of 40 ℃ water bath, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 38wDa and 1.0 part by weight of sodium alginate powder into the mixed system I, and rapidly stirring at 3000rpm for 20min to obtain a mixed system II after the sodium hyaluronate powder and the sodium alginate powder are completely dissolved; and (3) keeping the temperature of the mixture in water bath at 40 ℃, adding the mixture into the mixture II in a weight ratio of 1: 9, and rapidly stirring the mixture for 30min at 500rpm in a 5.0% (w/w) calcium nitrate solution to fully mix the mixture to obtain the composite anti-adhesion gel.
The stirring in the preparation process is electric stirring.
Comparative example 6
Weighing 77.0 parts by weight of deionized water, adding into a reaction container, and carrying out water bath heat preservation at 40 ℃ for 10 min; then, under the temperature of 40 ℃ water bath, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 200wDa and 1.0 part by weight of sodium alginate powder, and rapidly stirring at 3000rpm for 20min to obtain a mixed system I after the sodium hyaluronate powder and the sodium alginate powder are completely dissolved; and (3) keeping the temperature of the mixture in water bath at 40 ℃, adding the mixture into the mixture I in a weight ratio of 1: 4, rapidly stirring at 500rpm for 30min to obtain the composite anti-adhesion gel.
The stirring in the preparation process is electric stirring.
Comparative example 7
Weighing 76.6 parts by weight of deionized water, adding into a reaction vessel, adding 0.4 part by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in a water bath at 40 ℃ for 10min to obtain a mixed system I; then, under the temperature of 40 ℃ water bath, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 200wDa and 1.0 part by weight of sodium alginate powder into the mixed system I, and rapidly stirring at 3000rpm for 20min to obtain a mixed system II after the sodium hyaluronate powder and the sodium alginate powder are completely dissolved; and (3) keeping the temperature of the mixture in water bath at 40 ℃, adding the mixture into the mixture II in a weight ratio of 1: 4, rapidly stirring at 500rpm for 30min to obtain the composite anti-adhesion gel.
Comparative example 8
Weighing 75.0 parts by weight of deionized water, adding into a reaction vessel, adding 2.0 parts by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in water bath at 40 ℃ for 10min to obtain a mixed system I; then, under the temperature of 40 ℃ water bath, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 200wDa and 1.0 part by weight of sodium alginate powder into the mixed system I, and rapidly stirring at 3000rpm for 20min to obtain a mixed system II after the sodium hyaluronate powder and the sodium alginate powder are completely dissolved; and (3) keeping the temperature of the mixture in water bath at 40 ℃, adding the mixture into the mixture II in a weight ratio of 1: 4, rapidly stirring at 500rpm for 30min to obtain the composite anti-adhesion gel.
And (3) verification test:
1. the anti-blocking gels prepared in examples 1 to 7 and comparative examples 1 to 8 were subjected to pH (0631 in the general of the year 2015 in pharmacopoeia of the people's republic of china), viscosity (0633 in the general of the year 2015 in the pharmacopoeia of the people's republic of china), intrinsic viscosity (0632 in the general of the year 2015 in the pharmacopoeia of the people's republic of china), enzymatic hydrolysis performance, and cytotoxicity (GB/T16886.5), and the results of the tests are shown in table 1.
TABLE 1 anti-adhesion gel determination results Table
Figure BDA0002919270140000081
Figure BDA0002919270140000091
As can be seen from the table above, the gel of the example can be prepared in a short time, and has high viscosity and good enzymolysis resistance; the gels in comparative examples 1, 2, 3 and 5 had lower viscosity and poorer enzymatic resistance; the gel in the comparative example 4 has high viscosity and good enzymolysis resistance, but has high cytotoxicity and potential use risk due to the addition of the cross-linking agent; the gels of comparative examples 6, 7 and 8 do not meet the requirements with respect to osmotic pressure. In conclusion, the anti-adhesion gel with good performance, safety and no cytotoxicity can be prepared in a short time by combining the sodium hyaluronate, the sodium alginate, the calcium and the osmotic pressure regulator under the condition of not adding the cross-linking agent.
2. In vivo degradation and local reaction test
The samples from example 1 were taken and tested according to the method for muscle implantation as specified in GB/T16886.6-2015, using rabbits as the animal. No abnormality is found in the tissue structure of the implanted part of the muscle by visual observation of the test sample and the negative control. Histopathological examination showed that the samples and negative control 7d were slightly irritant, and 14d and 28d were both non-irritant. The muscle implantation 7d sample was gel-like, 14d was gel-like and the volume decreased from the previous one, and the test sample was not found at 28d (fig. 1). The in vivo degradation absorption rate of the material is predicted to be matched with the treatment period of biological tissues, and the anti-adhesion can be effectively carried out.
3. Verification of the influence of the addition timing of the osmotic pressure regulator on the gel preparation
Weighing 82.0 parts by weight of deionized water, adding the deionized water into a reaction container, preserving heat in a water bath at 40 ℃ for 10min, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 185wDa and 1.0 part by weight of sodium alginate powder, and rapidly stirring at 3000rpm for 20min to obtain a mixed system I after completely dissolving the sodium hyaluronate; then, at the temperature of 40 ℃ water bath, adding 1.0 part by weight of sodium chloride into the mixed system I to completely dissolve the sodium chloride to obtain a mixed system II; and (3) keeping the temperature of the mixture in water bath at 40 ℃, adding the mixture into the mixture II in a weight ratio of 1: 9 (5.0% (w/w) calcium chloride solution) and stirred rapidly at 500rpm for 30min to mix thoroughly. The stirring in the preparation process is electric stirring.
The results of the test are shown in FIG. 2, and it was found that insoluble particulate matter was present in the prepared sample, thereby causing the test to fail.
4. Verification of the Effect of the stirring Process on gel preparation
Weighing 86.0 parts by weight of deionized water, adding into a reaction vessel, adding 1.0 part by weight of sodium chloride, stirring for dissolving, and carrying out heat preservation in a water bath at 30 ℃ for 10min to obtain a mixed system I; then, under the temperature of 30 ℃ water bath, adding 2.0 parts by weight of sodium hyaluronate powder with molecular weight of 150wDa and 1.0 part by weight of sodium alginate powder into the mixed system I, and rapidly stirring at 3500rpm for 20min to obtain a mixed system II after the sodium hyaluronate powder and the sodium alginate powder are completely dissolved; and (3) keeping the temperature of the mixture in water bath at 30 ℃, adding the mixture into the mixture II in a weight ratio of 1: 9 (1.0% (w/w) calcium chloride solution) was rapidly stirred at 100rpm or 2000rpm for 30min to thoroughly mix. The stirring in the preparation process is electric stirring.
As shown in FIG. 3, even if the stirring speed is too slow or too fast, a homogeneous gel system is not obtained, which results in failure of the test.
The parts by weight in the examples in this specification are merely to show the proportional relationship of the weight of each raw material, and those skilled in the art can determine the actual weight of each part according to the related relationship of the parts by weight.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to the above-described embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (5)

1. An anti-adhesion gel, which is characterized in that,
the raw materials comprise sodium hyaluronate, sodium alginate, soluble calcium salt solution, an isotonic regulator and deionized water;
the mass ratio of the sodium hyaluronate, the sodium alginate, the soluble calcium salt solution, the isoosmotic adjusting agent and the deionized water is (1.0-10.0): (0.02-3.0): (5.0-30.0): (0.7-1.0): (56.0-94.0).
2. The anti-blocking gel according to claim 1,
the molecular weight of the sodium hyaluronate is 100-200 wDa.
3. The anti-blocking gel according to claim 1,
the concentration of the soluble calcium salt solution is 1-10% w/w.
4. The anti-blocking gel according to claim 1,
the isotonic regulator is sodium chloride or glucose.
5. The process for preparing an anti-blocking gel according to any one of claims 1 to 4, characterized in that it comprises the following steps:
(1) uniformly mixing deionized water and an isotonic regulator, and carrying out water bath at the temperature of 30-70 ℃ for 5-30min to obtain a mixed system I;
(2) adding sodium hyaluronate and sodium alginate into the mixed system I at the temperature of 30-70 ℃ in water bath, and stirring at the speed of 200-3000rpm for 0.17-1.5h to obtain a mixed system II;
(3) and (3) at the temperature of 30-70 ℃ in water bath, adding the soluble calcium salt solution into the mixed system II, and stirring at 200-3000rpm for 0.25-6h to prepare the anti-adhesion gel.
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