CN110559472A - Collagen-based medical adhesive and preparation method thereof - Google Patents
Collagen-based medical adhesive and preparation method thereof Download PDFInfo
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- CN110559472A CN110559472A CN201910858262.4A CN201910858262A CN110559472A CN 110559472 A CN110559472 A CN 110559472A CN 201910858262 A CN201910858262 A CN 201910858262A CN 110559472 A CN110559472 A CN 110559472A
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/102—Collagen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/06—Preparation of peptides or proteins produced by the hydrolysis of a peptide bond, e.g. hydrolysate products
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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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
Abstract
The invention provides a collagen-based medical adhesive, which comprises the following components: methylated collagen, a first component consisting of a first polymer and a first buffer, and a second component consisting of a second polymer and a second buffer. The invention utilizes the combination of natural biomaterial collagen and polyethylene glycol polymer, overcomes the problems of long time, poor biocompatibility and long curing time of the existing medical adhesive, and simultaneously, the collagen has good hemostatic effect and endows the adhesive with hemostatic performance.
Description
Technical Field
The invention belongs to the field of medical adhesives, and particularly relates to a collagen-based medical biological adhesive and a preparation method thereof.
Background
With the rapid development of modern medicine, the clinical requirements on surgical methods and auxiliary materials are higher and higher, so that the pain of patients is required to be relieved to the maximum extent, and the appearance can be perfectly recovered while the function is recovered. The medical adhesive is widely applied to clinic as a medical material which can replace surgical suture. Medical adhesives generally have adhesive functions and biocompatibility.
Currently, common medical adhesives can be classified into synthetic medical adhesives and natural medical adhesives, wherein the synthetic medical adhesives include α -cyanoacrylate adhesives, polyurethane adhesives, polyethylene glycol adhesives, and the like. Natural medical adhesives include fibrin glue, polysaccharide adhesives, and the like. However, synthetic medical adhesives are poorly biodegradable and release potentially toxic substances. The natural medical adhesive has the defects of poor mechanical property and long curing time. The US patent (US 6312725B 1) discloses a polyethylene glycol based adhesive with two different functional groups, which has a single component, resulting in a slow curing time and a longer degradation time of the adhesive.
disclosure of Invention
The invention aims to provide a medical adhesive with excellent biodegradability and adhesion performance and a preparation method thereof, aiming at the defects of the prior art.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
The invention provides a collagen-based medical adhesive, which comprises the following components: methylated collagen, a first component consisting of a first polymer and a first buffer, and a second component consisting of a second polymer and a second buffer.
Preferably, the first polymer is selected from one or more of four-arm N-hydroxysuccinimide propionate-based polyethylene glycol, four-arm N-hydroxysuccinimide succinate-based polyethylene glycol, four-arm N-hydroxysuccinimide glutarate-based polyethylene glycol, four-arm N-hydroxysuccinimide sebacate-based polyethylene glycol, two-arm N-hydroxysuccinimide propionate-based polyethylene glycol, two-arm N-hydroxysuccinimide succinate-based polyethylene glycol, two-arm N-hydroxysuccinimide glutarate-based polyethylene glycol, and two-arm N-hydroxysuccinimide sebacate-based polyethylene glycol.
Preferably, the molecular weight of the first polymer is 500 to 20000.
Preferably, the first polymer is a four-arm N-hydroxysuccinimide glutarate-based polyethylene glycol.
Preferably, the first polymer is a two-arm N-hydroxysuccinimide glutarate-based polyethylene glycol.
Preferably, a di-armed N-hydroxysuccinimide succinylated polyethylene glycol.
preferably, the first buffer solution is prepared from one or more of phosphate, carbonate, borate, phosphoric acid, acetic acid and hydrochloric acid, and the pH value of the first buffer solution is 2.0 ~ 6.5.
preferably, the first buffer solution is an anhydrous disodium hydrogen phosphate/disodium dihydrogen phosphate buffer solution, and the pH of the anhydrous disodium hydrogen phosphate/disodium dihydrogen phosphate buffer solution is 2.0-6.5.
preferably, the first buffer solution is an anhydrous disodium hydrogen phosphate/disodium dihydrogen phosphate buffer solution, and the pH of the anhydrous disodium hydrogen phosphate/disodium dihydrogen phosphate buffer solution is 5.8-6.0.
Preferably, the first buffer is an anhydrous disodium phosphate/phosphate buffer, and the pH of the first buffer is 3.95.
Preferably, the first buffer is a hydrochloric acid buffer, and the pH of the hydrochloric acid buffer is 4.0.
preferably, the first buffer solution is an anhydrous disodium hydrogen phosphate/disodium dihydrogen phosphate buffer solution, and the pH of the anhydrous disodium hydrogen phosphate/disodium dihydrogen phosphate buffer solution is 5.8-6.0.
Preferably, the second polymer is selected from one or more of four-arm mercapto polyethylene glycol, polyethylene imine, polyethylene oxide, polyvinyl alcohol, and copolymer of ethylene oxide and propylene oxide.
Preferably, the molecular weight of the second polymer is preferably in the range of 500 to 20000.
preferably, the second polymer is a four-arm thiol-polyethylene glycol.
Preferably, the second polymer is polyethyleneimine.
preferably, the second polymer is a copolymer of ethylene oxide and propylene oxide.
preferably, the second buffer solution is prepared from one or more of phosphate, carbonate, borate, phosphoric acid, acetic acid and hydrochloric acid, and the pH value of the second buffer solution is preferably 7.5 ~ 12.5.
preferably, the second buffer solution is a sodium dihydrogen phosphate dihydrate/anhydrous sodium carbonate buffer solution, and the pH value of the sodium dihydrogen phosphate dihydrate/anhydrous sodium carbonate buffer solution is 7.5-12.5.
preferably, the second buffer solution is a sodium dihydrogen phosphate/sodium carbonate buffer solution, and the pH value of the sodium dihydrogen phosphate/sodium carbonate is 9.6 ~ 9.9.
Preferably, the molar ratio of the reactive functional groups of the first and second components is 1: 1.
Preferably, the methylated collagen is prepared by the following method:
S1: preparing collagen powder: extracting collagen from animal skin, dissolving in pepsin, adding phosphoric acid solution, centrifuging, collecting precipitate, and oven drying to obtain collagen powder;
S2: preparation of methylated collagen: adding the collagen powder obtained in step S1 into methanol solution containing hydrochloric acid, stirring, dialyzing the collagen from acidic methanol, vacuum drying, sterilizing by gamma-ray radiation, and dissolving with water to obtain methylated collagen.
In another aspect of the present invention, there is provided a method for preparing the collagen-based medical adhesive, comprising the steps of:
s1: preparing collagen powder: extracting collagen from animal skin, dissolving in pepsin, adding phosphoric acid solution, centrifuging, collecting precipitate, and oven drying to obtain collagen powder;
S2: preparation of methylated collagen: adding the collagen powder obtained in the step S1 into a methanol solution containing hydrochloric acid, stirring, dialyzing and separating the collagen from acidic methanol, vacuum-drying, sterilizing by gamma-ray radiation, and dissolving with water to obtain a methylated collagen aqueous solution;
s3: formation of medical adhesive: and (3) mixing the methylated glue aqueous solution obtained in the step (S2) with a first component, then independently packaging, and independently packaging a second component to form the medical adhesive, wherein the first component consists of a first polymer and a first buffer solution, and the second component consists of a second polymer and a second buffer solution.
Preferably, the first polymer is selected from one or more of four-arm N-hydroxysuccinimide propionate-based polyethylene glycol, four-arm N-hydroxysuccinimide succinate-based polyethylene glycol, four-arm N-hydroxysuccinimide glutarate-based polyethylene glycol, four-arm N-hydroxysuccinimide sebacate-based polyethylene glycol, two-arm N-hydroxysuccinimide propionate-based polyethylene glycol, two-arm N-hydroxysuccinimide succinate-based polyethylene glycol, two-arm N-hydroxysuccinimide glutarate-based polyethylene glycol, and two-arm N-hydroxysuccinimide sebacate-based polyethylene glycol.
Preferably, the molecular weight of the first polymer is 500 to 20000.
preferably, the first buffer solution is prepared from one or more of phosphate, carbonate, borate, phosphoric acid, acetic acid and hydrochloric acid, and the pH value of the first buffer solution is 2.0 ~ 6.5.
Preferably, the second polymer is selected from one or more of four-arm mercapto polyethylene glycol, polyethylene imine, polyethylene oxide, polyvinyl alcohol, and copolymer of ethylene oxide and propylene oxide.
preferably, the molecular weight of the second polymer is preferably in the range of 500 to 20000.
preferably, the second buffer solution is prepared from one or more of phosphate, carbonate, borate, phosphoric acid, acetic acid and hydrochloric acid, and the pH value of the second buffer solution is preferably 7.5 ~ 12.5.
Preferably, the molar ratio of the reactive functional groups of the first and second components is 1: 1.
Compared with the prior art, the invention has the beneficial effects that:
The main raw materials of the invention are collagen and synthetic polyethylene glycol, both of which have good biocompatibility, and the collagen and the synthetic polyethylene glycol are physically mixed at the tissue action part to form the medical adhesive in situ through covalent crosslinking reaction. The medical adhesive material can be naturally degraded into micromolecules to be discharged out of the body after being kept in the organism for a certain time, so that secondary operation can be avoided, the pain of a patient is reduced, and the treatment cost is reduced. Meanwhile, the collagen is subjected to methylation treatment, so that the disease transmission risk caused by natural materials can be avoided.
The invention utilizes the combination of natural biomaterial collagen and polyethylene glycol polymer, overcomes the problems of long time, poor biocompatibility and long curing time of the existing medical adhesive, and simultaneously, the collagen has good hemostatic effect and endows the adhesive with hemostatic performance.
therefore, the medical adhesive of the invention plays an important role in the medical field and has wide application prospect.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The present invention will be described in detail with reference to the following embodiments.
the embodiment of the invention provides a collagen-based medical adhesive, which comprises the following components: methylated collagen, a first component consisting of a first polymer and a first buffer, and a second component consisting of a second polymer and a second buffer.
in the embodiment of the present invention, the first polymer is one or more selected from the group consisting of four-arm N-hydroxysuccinimide propionate-based polyethylene glycol, four-arm N-hydroxysuccinimide succinate-based polyethylene glycol, four-arm N-hydroxysuccinimide glutarate-based polyethylene glycol, four-arm N-hydroxysuccinimide sebacate-based polyethylene glycol, two-arm N-hydroxysuccinimide propionate-based polyethylene glycol, two-arm N-hydroxysuccinimide succinate-based polyethylene glycol, two-arm N-hydroxysuccinimide glutarate-based polyethylene glycol, and two-arm N-hydroxysuccinimide sebacate-based polyethylene glycol.
In this embodiment, the molecular weight of the first polymer is 500 to 20000.
In some embodiments, the first polymer is a four-arm N-hydroxysuccinimide glutarate-based polyethylene glycol.
In some embodiments, the first polymer is a two-arm N-hydroxysuccinimide glutarate-based polyethylene glycol.
in some embodiments, a two-armed N-hydroxysuccinimide succinylated polyethylene glycol.
in an embodiment of the invention, the first buffer solution is prepared from one or more of phosphate, carbonate, borate, phosphoric acid, acetic acid and hydrochloric acid, and the pH of the first buffer solution is 2.0 to 6.5. in some embodiments, the pH of the first buffer solution is 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.6, 1.6, 6.6, or 3.6.
in some embodiments, the first buffer is a disodium hydrogen phosphate/sodium dihydrogen phosphate dihydrate buffer having a pH of 5.8 ~ 6.0, and in some embodiments, the first buffer has a pH of 5.8, 5.9, or 6.0.
In some embodiments, the first buffer is an anhydrous disodium phosphate/phosphate buffer having a pH of 3.95.
In some embodiments, the first buffer is a hydrochloric acid buffer having a pH of 4.0.
In the embodiment of the present invention, the second polymer is selected from one or more of four-arm thiol-polyethylene glycol, polyethyleneimine, polyethylene oxide, polyvinyl alcohol, and a copolymer of ethylene oxide and propylene oxide.
In the present embodiment, the molecular weight of the second polymer is preferably 500 to 20000.
In some embodiments, the second polymer is a four-arm thiol-polyethylene glycol.
In some embodiments, the second polymer is polyethyleneimine.
In some embodiments, the second polymer is a copolymer of ethylene oxide and propylene oxide.
in the embodiment of the invention, the second buffer solution is prepared from one or more of phosphate, carbonate, borate, phosphoric acid, acetic acid and hydrochloric acid, and the pH value of the second buffer solution is preferably 7.5 ~ 12.5.
in some embodiments, the second buffer is a monobasic sodium phosphate/anhydrous sodium carbonate buffer having a pH of 7.5 ~ 12.5, in some embodiments, the monobasic sodium phosphate/anhydrous sodium carbonate buffer has a pH of 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.12.12, 12.5, 11.12.5, 12.12.12, 12.5, 12.12.5, 12.12.12.12, 12.5, 12.12.12.5, 12.12.12.4, or 12.5.
in some embodiments, the second buffer is a sodium dihydrogen phosphate/sodium carbonate buffer having a pH of 9.6 ~ 9.9, in some embodiments, the pH of the sodium dihydrogen phosphate/sodium carbonate is 9.6, 9.7, 9.8, or 9.9.
In the embodiment of the invention, the molar ratio of the active functional groups of the first component to the second component is 1: 1.
in the embodiment of the invention, the methylated collagen is prepared by the following method:
S1: preparing collagen powder: extracting collagen from animal skin, dissolving in pepsin, adding phosphoric acid solution, centrifuging, collecting precipitate, and oven drying to obtain collagen powder;
S2: preparation of methylated collagen: adding the collagen powder obtained in step S1 into methanol solution containing hydrochloric acid, stirring, dialyzing the collagen from acidic methanol, vacuum drying, sterilizing by gamma-ray radiation, and dissolving with water to obtain methylated collagen.
In another aspect of the present invention, there is provided a method for preparing the collagen-based medical adhesive, comprising the steps of:
S1: preparing collagen powder: extracting collagen from animal skin, dissolving in pepsin, adding phosphoric acid solution, centrifuging, collecting precipitate, and oven drying to obtain collagen powder;
S2: preparation of methylated collagen: adding the collagen powder obtained in the step S1 into a methanol solution containing hydrochloric acid, stirring, dialyzing and separating the collagen from acidic methanol, vacuum-drying, sterilizing by gamma-ray radiation, and dissolving with water to obtain a methylated collagen aqueous solution;
s3: formation of medical adhesive: and (3) mixing the methylated glue aqueous solution obtained in the step (S2) with a first component, then independently packaging, and independently packaging a second component to form the medical adhesive, wherein the first component consists of a first polymer and a first buffer solution, and the second component consists of a second polymer and a second buffer solution.
In an embodiment of the present invention, the first polymer is one or more selected from four-arm N-hydroxysuccinimide propionate-based polyethylene glycol, four-arm N-hydroxysuccinimide succinate-based polyethylene glycol, four-arm N-hydroxysuccinimide glutarate-based polyethylene glycol, four-arm N-hydroxysuccinimide sebacate-based polyethylene glycol, two-arm N-hydroxysuccinimide propionate-based polyethylene glycol, two-arm N-hydroxysuccinimide succinate-based polyethylene glycol, two-arm N-hydroxysuccinimide glutarate-based polyethylene glycol, and two-arm N-hydroxysuccinimide sebacate-based polyethylene glycol.
in this embodiment, the molecular weight of the first polymer in the above method is 500 to 20000.
in this embodiment, the first buffer solution is prepared from one or more of phosphate, carbonate, borate, phosphoric acid, acetic acid, and hydrochloric acid, and the pH of the first buffer solution is 2.0 to 6.5, and in some embodiments, the pH of the first buffer solution is 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.6, 1.6, or 2.
In this embodiment, the second polymer is selected from one or more of four-arm thiol-polyethylene glycol, polyethyleneimine, polyethylene oxide, polyvinyl alcohol, and copolymer of ethylene oxide and propylene oxide.
in this embodiment, the molecular weight of the second polymer in the above method is preferably 500 to 20000.
in this embodiment, the second buffer solution is prepared from one or more of phosphate, carbonate, borate, phosphoric acid, acetic acid, and hydrochloric acid, and the pH of the second buffer solution is preferably 7.5 ~ 12.5.
in some embodiments, the pH of the monobasic sodium phosphate dihydrate/anhydrous sodium carbonate buffer is 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, or 12.5.
in this example, the above method described a molar ratio of reactive functional groups of the first component and the second component of 1: 1.
The technical solution of the present invention will be illustrated with reference to the following specific examples:
Example 1:
The collagen-based medical adhesive of the embodiment is prepared by the following steps:
the collagen ~ based medical adhesive is prepared by extracting collagen from bovine dermis, dissolving the collagen in pepsin, purifying the collagen in a phosphoric acid solution with 0.2mol/L and pH =7.2 by using a neutralization reaction, centrifugally precipitating to finally obtain collagen with the concentration of 70mg/mL, drying the collagen into powder, adding the collagen into a 40mL methanol solution containing 0.1mol/L HCl, stirring for 4 days, dialyzing and separating the collagen from acidic methanol, drying in vacuum and sterilizing by gamma ~ ray radiation, dissolving a final product in an aqueous solution with the pH of 3 to finally obtain a methylated collagen solution, adding the methylated collagen into a four ~ arm N ~ hydroxysuccinimide glutarate ~ based polyethylene glycol with the molecular weight of 10000 and an anhydrous sodium hydrogen phosphate/sodium dihydrogen phosphate buffer solution with the pH of 2.0 ~ 6.5, and jointly acting the methylated collagen with a four ~ arm sulfhydryl ~ polyethylene glycol with the molecular weight of 10000 and an anhydrous sodium dihydrogen phosphate/anhydrous buffer solution with the pH of 7.5 ~ 12.5 on the same tissue site to form the collagen ~ based medical adhesive.
Example 2:
The collagen-based medical adhesive of the embodiment is prepared by the following steps:
extracting collagen from fish dermis, dissolving the collagen in pepsin, purifying the collagen in a phosphoric acid solution with 0.2mol/L and pH =7.2 by utilizing a neutralization reaction principle, centrifugally precipitating to obtain a collagen solution, drying the collagen solution into powder for 2 days, adding the collagen into 40mL of methanol solution containing 0.1mol/L HCl, stirring the solution for 4 days, separating the collagen from acidic methanol, drying the collagen in vacuum, sterilizing the collagen by gamma ~ ray radiation, dissolving the final product in an aqueous solution with pH =3 to obtain a methylated collagen solution, adding the methylated collagen into a buffer solution containing four ~ arm N ~ hydroxysuccinimide glutarate ~ based polyethylene glycol with a molecular weight of 20000 and anhydrous disodium hydrogen phosphate/sodium dihydrogen phosphate with a pH of 5.8 ~ 6.0, and then jointly acting the methylated collagen with four ~ arm sulfhydryl polyethylene glycol with a molecular weight of 20000 and sodium dihydrogen phosphate/sodium carbonate buffer solution with a pH of 9.6 ~ 9 on the same tissue part to form the collagen ~ based medical adhesive.
example 3:
The collagen-based medical adhesive of the embodiment is prepared by the following steps:
extracting collagen from bovine dermis, dissolving the collagen in pepsin, purifying the collagen in a phosphoric acid solution with 0.2mol/L and pH =5.5 by utilizing a neutralization reaction principle, centrifugally precipitating to obtain a collagen solution, drying the collagen solution into powder for 3 days, adding the collagen into 60mL of methanol solution containing 0.5mol/L HCl, stirring the mixture for 5 days, separating the collagen from acidic methanol, drying the collagen in vacuum, sterilizing the collagen by gamma-ray radiation, dissolving the final product in an aqueous solution with pH =4 to obtain a methylated collagen solution, adding the methylated collagen into a solution containing two-arm N-hydroxysuccinimide glutarate-based polyethylene glycol with a molecular weight of 10000 and anhydrous disodium hydrogen phosphate/phosphoric acid buffer with a pH of 3.95, and then jointly acting the methylated collagen with polyethyleneimine with a molecular weight of 10000 and a sodium dihydrogen phosphate/sodium carbonate buffer with a pH of 9.6-9.9 on the same tissue part to form the collagen-based medical adhesive.
Example 4:
the collagen-based medical adhesive of the embodiment is prepared by the following steps:
extracting collagen from bovine dermis, dissolving the collagen in pepsin, purifying the collagen in a phosphoric acid solution with 0.2mol/L and pH =7.2 by utilizing a neutralization reaction principle, centrifugally precipitating to obtain a collagen solution, drying the collagen solution into powder for 2 days, adding the collagen into 40mL of methanol solution containing 0.1mol/L HCl, stirring the solution for 4 days, separating the collagen from acidic methanol, drying the collagen in vacuum, sterilizing the collagen by gamma ~ ray radiation, dissolving the final product in an aqueous solution with pH =3 to obtain a methylated collagen solution, adding the methylated collagen into a buffer solution containing four ~ arm N ~ hydroxysuccinimide glutarate ~ based polyethylene glycol with a molecular weight of 20000 and anhydrous disodium hydrogen phosphate/sodium dihydrogen phosphate with a pH of 5.8 ~ 6.0, and then jointly acting the methylated collagen with four ~ arm sulfhydryl polyethylene glycol with a molecular weight of 20000 and sodium dihydrogen phosphate/sodium carbonate buffer solution with a pH of 9.6 ~ 9 on the same tissue site to form the collagen ~ based medical adhesive.
example 5:
The collagen-based medical adhesive of the embodiment is prepared by the following steps:
the collagen ~ based medical adhesive is formed by extracting collagen from bovine dermis, dissolving the collagen in pepsin, purifying the collagen in 1mol/L phosphoric acid solution with pH =7.2 by using a neutralization reaction principle, centrifugally precipitating to finally obtain collagen solution, drying the collagen solution into powder for 3 days, adding the collagen into 60mL methanol solution containing 1mol/L HCl, stirring the mixture for 5 days, separating the collagen from acidic methanol, drying the collagen in vacuum, sterilizing the collagen by gamma ~ ray radiation, dissolving the final product in aqueous solution with pH =3, finally obtaining methylated collagen solution, adding the methylated collagen into a buffer solution containing a dibasic N ~ hydroxysuccinimide succinate ~ based polyethylene glycol with molecular weight 20000 and hydrochloric acid with pH 4.0, and then jointly acting the methylated collagen ~ based medical adhesive on the same tissue site with ethylene oxide and propylene oxide copolymer with molecular weight 20000 and sodium dihydrogen phosphate/sodium carbonate buffer with pH 9.6 ~ 9.9.
Effect verification:
the collagen-based medical adhesive described in examples 1 to 5 was examined for curing time, lap-bond strength and in vitro degradation time, the medical adhesive prepared using the technical features disclosed in patent US6312725B1 was examined for curing time, lap-bond strength and in vitro degradation time as comparative example 1, and the medical adhesive prepared using the technical features disclosed in CN201610168941.5 was examined for curing time, lap-bond strength and in vitro degradation time as comparative example 2. The specific detection method comprises the following steps:
(1) Curing time: injecting the methylated collagen, the first component and the second component into a gel solidification tester (MD GT-II, Toyoyuan electronics Co., Ltd., Lingan) preheated to 37 ℃ through an injector, immediately timing until gel is formed (picking up the methylated collagen, the first component and the second component into gel with toothpicks), and recording the time for forming the gel.
(2) Lap-bond strength: detection was carried out according to the method defined in YY/T0729.1-2009.
(3) in vitro degradation time: the medical adhesive was placed in a fixed silicone tube to form a cylindrical adhesive with a diameter of 0.74cm and a length of 0.5 cm. The adhesive was placed in phosphate buffer at 37 ℃ isotonic with blood and pH 7.4 and observed daily until no visual observation was observed, and the time taken for the adhesive to degrade in vitro was recorded.
Collagen-based medical adhesives should meet the following characteristic criteria:
(1) the curing time is not more than 30 s;
(2) The lap-bond strength is not less than 20N/cm.
(3) the in vitro degradation time is 72 ~ 720 h.
Specific detection results are shown in table 1:
TABLE 1 comparison of the Properties of examples 1-5
| Experimental group | Curing time/s | Lap-bond strength/N/cm | Degradation time/h |
| example 1 | 16.5 | 23.5 | 127 |
| Example 2 | 18.7 | 22.1 | 135 |
| Example 3 | 13.0 | 27.1 | 158 |
| Example 4 | 11.2 | 28.3 | 212 |
| Example 5 | 12.3 | 26.1 | 261 |
| Comparative example 1 | 37.5 | 28.5 | 585 |
| Comparative example 2 | 21.3 | 18.5 | 498 |
As can be seen from table 1, the curing time, the lap-joint strength, and the in vitro degradation time of the collagen-based medical adhesive provided in the embodiment of the present invention all meet the characteristic indexes of the collagen-based medical adhesive, the characteristic indexes of the curing time and the degradation time of the collagen-based medical adhesive provided in the embodiment of the present invention are significantly superior to those of comparative example 1, the characteristic indexes of the lap-joint strength and the degradation time of the collagen-based medical adhesive provided in the embodiment of the present invention are significantly superior to those of comparative example 2, and compared with the prior art, the collagen-based medical adhesive provided in the embodiment of the present invention has outstanding substantive features and significant technical progress.
this summary merely illustrates some embodiments which are claimed, wherein one or more of the features recited in the claims can be combined with any one or more of the embodiments, and such combined embodiments are also within the scope of the present disclosure as if they were specifically recited in the disclosure.
Claims (10)
1. a collagen-based medical adhesive comprising the following components: methylated collagen, a first component consisting of a first polymer and a first buffer, and a second component consisting of a second polymer and a second buffer.
2. the collagen-based medical adhesive according to claim 1, wherein said first polymer is selected from one or more of four-armed N-hydroxysuccinimide propionate-based polyethylene glycol, four-armed N-hydroxysuccinimide succinate-based polyethylene glycol, four-armed N-hydroxysuccinimide glutarate-based polyethylene glycol, four-armed N-hydroxysuccinimide sebacate-based polyethylene glycol, two-armed N-hydroxysuccinimide propionate-based polyethylene glycol, two-armed N-hydroxysuccinimide succinate-based polyethylene glycol, two-armed N-hydroxysuccinimide glutarate-based polyethylene glycol, and two-armed N-hydroxysuccinimide sebacate-based polyethylene glycol.
3. The collagen-based medical adhesive according to claim 1, wherein the molecular weight of the first polymer is 500 to 20000.
4. the collagen-based medical adhesive according to claim 1, wherein the first buffer solution is prepared from one or more of phosphate, carbonate, borate, phosphoric acid, acetic acid and hydrochloric acid, and the pH of the first buffer solution is 2.0-6.5.
5. the collagen-based medical adhesive according to claim 1, wherein the second polymer is selected from one or more of the group consisting of tetra-arm mercapto polyethylene glycol, polyethylene imine, polyethylene oxide, polyvinyl alcohol, copolymers of ethylene oxide and propylene oxide.
6. The collagen-based medical adhesive according to claim 1, wherein the molecular weight of the second polymer is preferably 500 to 20000.
7. the collagen-based medical adhesive according to claim 1, wherein the second buffer solution is prepared from one or more of phosphate, carbonate, borate, phosphoric acid, acetic acid and hydrochloric acid, and the pH of the second buffer solution is preferably 7.5-12.5.
8. The collagen-based medical adhesive according to claim 1, wherein the molar ratio of the active functional groups of the first component and the second component is 1: 1.
9. The collagen-based medical adhesive according to claim 1, wherein the methylated collagen is prepared by the following method:
S1: preparing collagen powder: extracting collagen from animal skin, dissolving in pepsin, adding phosphoric acid solution, centrifuging, collecting precipitate, and oven drying to obtain collagen powder;
s2: preparation of methylated collagen: adding the collagen powder obtained in step S1 into methanol solution containing hydrochloric acid, stirring, dialyzing the collagen from acidic methanol, vacuum drying, sterilizing by gamma-ray radiation, and dissolving with water to obtain methylated collagen.
10. A method of preparing a collagen-based medical adhesive according to any one of claims 1 to 9, comprising the steps of:
S1: preparing collagen powder: extracting collagen from animal skin, dissolving in pepsin, adding phosphoric acid solution, centrifuging, collecting precipitate, and oven drying to obtain collagen powder;
S2: preparation of methylated collagen: adding the collagen powder obtained in the step S1 into a methanol solution containing hydrochloric acid, stirring, dialyzing and separating the collagen from acidic methanol, vacuum-drying, sterilizing by gamma-ray radiation, and dissolving with water to obtain a methylated collagen aqueous solution;
S3: formation of medical adhesive: in use, the methylated glue aqueous solution obtained in step S2 is mixed with a first component and a second component at the site of action to form the medical adhesive, the first component being composed of a first polymer and a first buffer solution, and the second component being composed of a second polymer and a second buffer solution.
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| US6312725B1 (en) * | 1999-04-16 | 2001-11-06 | Cohesion Technologies, Inc. | Rapid gelling biocompatible polymer composition |
| US20060062768A1 (en) * | 2004-09-23 | 2006-03-23 | Olexander Hnojewyj | Biocompatible hydrogel compositions |
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| CN105778124A (en) * | 2012-09-28 | 2016-07-20 | 山东赛克赛斯药业科技有限公司 | Biodegradable medicine hydrogel and preparation method and application thereof |
| CN109568641A (en) * | 2018-12-27 | 2019-04-05 | 山东百多安医疗器械有限公司 | A kind of medical closed glue and preparation method thereof can promote wound healing |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6312725B1 (en) * | 1999-04-16 | 2001-11-06 | Cohesion Technologies, Inc. | Rapid gelling biocompatible polymer composition |
| US20060062768A1 (en) * | 2004-09-23 | 2006-03-23 | Olexander Hnojewyj | Biocompatible hydrogel compositions |
| CN105778124A (en) * | 2012-09-28 | 2016-07-20 | 山东赛克赛斯药业科技有限公司 | Biodegradable medicine hydrogel and preparation method and application thereof |
| CN104399109A (en) * | 2014-11-26 | 2015-03-11 | 沈伟 | Gel hemostatic material composition and preparation method thereof |
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Application publication date: 20191213 |