CN109646711A - A kind of medical hemostatic closing is anti-to be adhered material - Google Patents
A kind of medical hemostatic closing is anti-to be adhered material Download PDFInfo
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- CN109646711A CN109646711A CN201910086935.9A CN201910086935A CN109646711A CN 109646711 A CN109646711 A CN 109646711A CN 201910086935 A CN201910086935 A CN 201910086935A CN 109646711 A CN109646711 A CN 109646711A
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- lysine
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- alanine
- tryptophan
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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
- A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
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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
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- Health & Medical Sciences (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention discloses a kind of closings of medical hemostatic to prevent being adhered material, forms line style function arm configuration by self assembly polypeptide unit and flexible material unit, function arm connects branch in multi-arm core, forms the hub-and-spoke configuration for having self-assembly ability.When in use, it by the self-assembly ability of self assembly polypeptide, is self-assembled into site of administration and is adhered coating for stereochemical structure hemostasis seals are anti-, coating has stronger mechanical strength, to reach better using effect.
Description
Technical field
The present invention relates to pharmaceutical technology field, in particular to a kind of medical hemostatic closing is anti-to be adhered material.
Background technique
In surgical operation, antibacterial, hemostasis are bases, and the reparation to bio-tissue, seam, bundle are two most basic behaviour
Make.This method is not only loaded down with trivial details laborious, and easily causes bleeding and new damage, brings more pains to patient;For those
It can not find the large area oozing of blood of blutpunkte, doctor also feels helpless.If can be replaced with gluing or part replaces suture, use
Glue spraying can stop thin vessels oozing of blood or closing cancer serosal surface, will be a revolution of surgical operation, in the last hundred years, people in order to
A kind of ideal medical adhesive is found, and has carried out unremitting effort.It is at present mostly medical alpha-cyanoacrylate system glue and fiber egg
White original class product, the problems such as there is cytotoxicity in varying degrees or use various risks caused by animal derived product.
With the continuous development of science and technology, in the Zhang Shuguang of Massachusetts Institute Technology in 1992 accidentally from Yeast protein
In have found can self assembly ion small peptide since, the research of self assembly peptide art is developed rapidly, and is applied successfully
To drug field, wherein just there is using self assembly polypeptide the application stopped blooding, promote wound healing.
And self assembly polypeptide used at present is traditional thread binding structure, formed polymeric material is in single layer sheet or sacculus more
Shape does not have strong chemical bond effect between lamella or sacculus, material is caused to be difficult to provide effective support.
Summary of the invention
Above-mentioned technical problem to be solved by this invention is to provide that a kind of medical hemostatic closing is anti-is adhered material, the present invention
Branch self assembly polypeptide is connect by building or using multi-arm active material, so that three-dimensional autonomous dress unit is formed, so that the strength of materials
Significantly promoted.To improve autonomous dress efficiency, flexible hydrodynamic form molecule interval is can be used between polypeptide in autonomous fill, and can be one
Multiple autonomous dress polypeptide units are designed on function arm, simple function arm and other a plurality of function arm reaction probabilities are improved, into one
Step promotes product strength.
The medical hemostatic closing prevents that be adhered material is made of multi-arm core (C) and z function arm (AnBm);
The function arm (AnBm) is connected by chemical bond with multi-arm core (C) structure;
Function arm (AnBm) quantity is z, and z value is 3-36;
The multi-arm core (C) by four arm polyethylene glycol, eight arm polyethylene glycol, silicon-hydrogen bond containing dissaving polymer or 2
It is a to be made of the cysteine of sulfide linkage crosslinking and its derivatives group structure.
Preferable, the autonomous dress polypeptide unit (A) and quantity that every function arm (AnBm) is n by quantity are m
Flexible material unit (B) be formed by connecting by random order;
The function arm (AnBm) is connected by chemical bond with multi-arm core (C) structure, is collectively constituted with multi-arm core (C)
(AnBm) z-C type structure or (An) z-C structure, the n be 1-99, m 1-198.
Preferable, the autonomous dress polypeptide unit is following sequence of one or more: Arg-Ala-day east
Propylhomoserin-alanine, lysine-valine, alanine-phenylalanine-threonine-cysteine-histidine-cysteine-essence
Propylhomoserin-arg-ser-cysteine-tyrosine-serine-threonine-glutamic acid-tyrosine-serine-tyrosine-
Glycine-threonine-cysteine-threonine-valine-methionine-glycine-Ile-Asn-group ammonia
Acid-Arg-Phe-cysteine-cysteine-leucine, Phe-Leu-Gly-Ala-are bright
Propylhomoserin-Phe-Lys-Ala-Leu-serine-histidine-Leucine-leucine, arg-leu-
Arg-arg-leu-Arg-Ala-Arg-Ala-Arg-Ala, Gly-Leu-
Trp-Trp-lysine-Ala-Trp-Trp-Ly-Ala-Trp-Trp-Ly-
Serine-leucine-Trp-Trp-arg-lys-arg-Lys-Arg-lysine-alanine,
Phenylalanine-phenylalanine-arginine-glycine-aspartic acid-phenylalanine, the-the third ammonia of glutamate-alanine-glutamic acid
Acid-lysine-alanine-lysine-ala-glu-ala-glu-alanine-lysine-alanine-relies ammonia
Acid-alanine, Arg-Ala-Asp-ala-arg-Ala-Asp-Ala-Gly-
Gly-Ala-Vitro By Serine/arginine-Ala-Asp-ala-arg-Ala-Asp-the third
Propylhomoserin, Arg-Ala-Asp-ala-arg-Ala-Asp-Ala-Gly-dried meat ammonia
Acid-Gly-Gly-Tyr-Arg-Ala-Asp-ala-arg-Ala-Asp-
Alanine, lysine-glutamic acid-threonine-Trp-Trp-glutamic acid-threonine-Trp-Trp-threonine-
Glutamic acid-tryptophan-Ser-Gln proline-lysine-lysine-lysine-arginine-lysine-figured silk fabrics ammonia
Acid, lysine-glutamic acid-threonine-tryptophan-Phe-Glu-threonine-tryptophan-phenylalanine-threonine-
Glutamic acid-tryptophan-Ser-Gln proline-lysine-lysine-lysine-arginine-lysine-figured silk fabrics ammonia
Acid, lysine-tryptophan-Phe-Glu-threonine-tryptophan-phenylalanine-threonine-glutamic acid-tryptophan-
Proline-lysine-Lys-Arg-lysine, Gly-Leu-tryptophan-Arg-Ala-leucine-
Tryptophan-arg-leu-Leu-Arg-Ser-leucine-tryptophan-arg-leu-leucine-
Tryptophan-Arg-Ala, Gly-Leu-Trp-Trp-arg-leu-Trp-Trp-
Arg-leu-arg-ser-tryptophan-Phe-A taug-leucine-tryptophan-phenylalanine-essence
Propylhomoserin-alanine, Ala-Ala-glutamate-alanine-Leu-Leu-lysine-Ala-His-the third
Propylhomoserin-glutamic acid-Leu-Leu-alanine-lysine-Ala-Ala-Gly-Gly-Gly-half
Cystine, alanine-Alanine-Alanine-Alanine-lysine-alanine-Alanine-Alanine-Alanine-lysine,
Trp-Ly-tryptophan-glutamic acid-Trp-Ly-tryptophan-glutamic acid-tryptophan, phenylalanine-rely ammonia
Acid-Phe-Glu-Phe-Lys-Phe-Glu, lysine-Trp-Ly-figured silk fabrics ammonia
Acid-lysine-valine-lysine-valine-lysine-valine-lysine-valine-lysine-valine-relies ammonia
Acid, Trp-Ly-valine-lysine-valine-lysine-valine-lysine-valine-lysine, paddy ammonia
Acid-tryptophan-glutamic acid-valine-glutamic acid-valine-glutamic acid-valine-glutamic acid-valine;
The flexible material unit by quantity be 1-85 amino acid form straight chain type peptide chain, polylactic acid, glucan, directly
Chain polyalkylene glycol, straight chain fatty, aliphatic alkyl chain or polyvinyl alcohol material are constituted.
Preferable, the autonomous dress polypeptide unit is the reverse sequence of aforementioned polypeptides sequence.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.
Embodiment one
The first step, synthetic peptide sequence: Arg-Ala-day east propylhomoserin-ala-arg-glycine-asparagus fern
Propylhomoserin-Arg-Ala-day east propylhomoserin-ala-arg-Gly-Asp-cysteine-arginine-is sweet
Propylhomoserin-Aspartic acid-Arginine-alanine-day east propylhomoserin-ala-arg-Gly-Asp-arginine-the third
Propylhomoserin-day east propylhomoserin-alanine.
Wherein " Arg-Ala-day east propylhomoserin-alanine " belongs to structure A and independently fills polypeptide unit, " alanine-essence
Propylhomoserin-glycine " belongs to structure B flexibility arm unit.
Second step, by being crosslinked with the crosslinking agent containing azobenzene group to two cysteine residues, two and half
Cystine is connected by disulfide bond and forms the multi-arm nuclear structure C with 4 arms.Purifying removal is carried out to cross-linking products
Crosslinking agent and unreacted group.
Third step, the condition for controlling illumination ultimately form so that azobenzene group may be implemented trans- to cis- transformation
The medical hemostatic closing that cross can be filled independently is anti-to be adhered material.
Embodiment two
The first step, synthetic peptide sequence: glutamic acid-tryptophan-glutamic acid-valine-glutamic acid-valine-glutamic acid-
Valine-glutamic acid-valine.
Second step, four arm polyglycols of oxidation, obtain four arm polyethylene glycol aldehyde radical derivatives.
Third step, under the conditions of pH5.0, by the first step, second step obtain product mix, active aldehyde radical can be by poly- second
Glycol is coupled on polypeptide, while using sodium cyanoborohydride as reducing agent, and polypeptide N-terminal amino is connect with polyethylene group.
Wherein " glutamic acid-tryptophan-glutamic acid-valine-glutamic acid-valine-glutamic acid-valine-glutamic acid-valine " belongs to
Polypeptide unit is independently filled in structure A, " polyethylene glycol " belongs to structure B flexibility arm unit.The Ji Wusi that four arm polyethylene glycol include
Alcohol structure composition multi-arm nuclear structure C.Purifying removal crosslinking agent and unreacted group are carried out to cross-linking products, obtaining cross can
The medical hemostatic closing independently filled is anti-to be adhered material.
Embodiment three
The first step, synthetic peptide sequence: Arg-Ala-day east propylhomoserin-Ala-His-histidine-group ammonia
Acid-histidine-histidine-histidine-Arg-Ala-day east propylhomoserin-Ala-His-histidine-histidine-group
Propylhomoserin-histidine-histidine.Wherein " Arg-Ala-day east propylhomoserin-alanine " belongs to structure A and independently fills polypeptide list
Member, " histidine-histidine-histidine-histidine-histidine-histidine " belong to structure B flexibility arm unit.
In eukaryon animal body, it is widely present histidine tag receptor, the tissue that flexible arm configuration is conducive to improve product is viscous
Attached effect.
Second step, by being crosslinked with the crosslinking agent containing azobenzene group to two cysteine residues, two and half
Cystine is connected by disulfide bond and forms the multi-arm nuclear structure C with 4 arms.Purifying removal is carried out to cross-linking products
Crosslinking agent and unreacted group.
Third step, the condition for controlling illumination ultimately form so that azobenzene group may be implemented trans- to cis- transformation
The medical hemostatic closing that cross can be filled independently is anti-to be adhered material.
Claims (3)
1. a kind of medical hemostatic closing is anti-to be adhered material, which is characterized in that the material is by multi-arm core (C) and z function arm
(AnBm) it constitutes;
The function arm (AnBm) is connected by chemical bond with multi-arm core (C) structure;
Function arm (AnBm) quantity is z, and z value is 3-36;
The multi-arm core (C) by four arm polyethylene glycol, eight arm polyethylene glycol, the dissaving polymer of silicon-hydrogen bond containing or 2 by
The cysteine and its derivatives group structure of sulfide linkage crosslinking are constituted;
The flexible material unit that the autonomous dress polypeptide unit (A) and quantity that every function arm (AnBm) is n by quantity are m
(B) it is formed by connecting by random order;
The function arm (AnBm) is connected by chemical bond with multi-arm core (C) structure, is collectively constituted with multi-arm core (C)
(AnBm) z-C type structure or (An) z-C structure, the n are 1-99, m 1-198.
2. medical hemostatic closing according to claim 1 is anti-to be adhered material, which is characterized in that the autonomous dress polypeptide unit
It is following sequence of one or more: Arg-Ala-day east propylhomoserin-alanine, lysine-valine, alanine-benzene
Alanine-threonine-cysteine-histidine-cysteine-Arg-Arg-serine-cysteine-tyrosine-
Serine-threonine-Glu-Tyr-Ser-Tyr-glycine-threonine-cysteine-threonine-figured silk fabrics ammonia
Acid-methionine-glycine-Ile-Asn-- half Guang ammonia of histidine-Arg-Phe-cysteine
Acid-leucine, Phe-Leu-Gly-Ala-Ile-Phe-lysine-Ala-Leu-
Serine-histidine-Leucine-leucine, arg-leu-arg-arg-leu-Arg-Ala-
Arg-Ala-Arg-Ala, Gly-Leu-Trp-Trp-lysine-Ala-Trp-
Trp-Ly-Ala-Trp-Trp-Ly-serine-leucine-Trp-Trp-arginine-
Lys-Arg-Lys-Arg-lysine-alanine, phenylalanine-phenylalanine-arginine-glycine-day
Aspartic acid-phenylalanine, glutamate-alanine-glutamate-alanine-lysine-alanine-lysine-alanine-paddy ammonia
Acid-ala-glu-alanine-lysine-alanine-lysine-alanine, Arg-Ala-Asp-the third
Propylhomoserin-Arg-Ala-Asp-Ala-Gly-Gly-Ala-Vitro By Serine/arginine-alanine-
Asp-Ala-Arg-Ala-Asp-alanine, Arg-Ala-Asp-alanine-
Arg-Ala-Asp-Ala-Gly-proline-the-the third ammonia of Gly-Gly-Tyr-Arg
Acid-Asp-Ala-Arg-Ala-Asp-alanine, lysine-glutamic acid-threonine-tryptophan-
Tryptophan-glutamic acid-threonine-Trp-Trp-threonine-glutamic acid-tryptophan-Ser-Gln dried meat ammonia
Acid-lysine-lysine-Lys-Arg-lysine-valine, lysine-glutamic acid-threonine-tryptophan-phenylpropyl alcohol
Propylhomoserin-glutamic acid-threonine-tryptophan-phenylalanine-threonine-glutamic acid-tryptophan-Ser-Gln dried meat ammonia
Acid-lysine-lysine-Lys-Arg-lysine-valine, lysine-tryptophan-Phe-Glu-Soviet Union
Propylhomoserin-tryptophan-phenylalanine-threonine-glutamic acid-tryptophan-proline-lysine-Lys-Arg-lysine,
Gly-Leu-tryptophan-Arg-Ala-leucine-tryptophan-arg-leu-leucine-arginine-
Serine-leucine-tryptophan-arg-leu-leucine-tryptophan-Arg-Ala, Gly-Leu-
Trp-Trp-arg-leu-Trp-Trp-arg-leu-arg-ser-tryptophan-
Phe-A taug-leucine-tryptophan-Phe-A taug-alanine, Ala-Ala-glutamic acid-the third
Propylhomoserin-Leu-Leu-lysine-Ala-His-ala-glu-Leu-Leu-alanine-relies
Propylhomoserin-Ala-Ala-Gly-Gly-Gly-cysteine, alanine-Alanine-Alanine-Alanine-
Lysine-alanine-Alanine-Alanine-Alanine-lysine, Trp-Ly-tryptophan-glutamic acid-tryptophan-
Lysine-tryptophan-glutamic acid-tryptophan, Phe-Lys-Phe-Glu-Phe-Lys-
Phe-Glu, lysine-Trp-Ly-valine-lysine-valine-lysine-valine-rely ammonia
Acid-valine-lysine-valine-lysine-valine-lysine, Trp-Ly-valine-lysine-figured silk fabrics ammonia
Acid-lysine-valine-lysine-valine-lysine, glutamic acid-tryptophan-glutamic acid-valine-glutamic acid-figured silk fabrics ammonia
Acid-glutamic acid-valine-glutamic acid-valine;
The flexible material unit is that straight chain type peptide chain, polylactic acid, glucan, straight chain that 1-85 amino acid forms gather by quantity
Ethylene glycol, straight chain fatty, aliphatic alkyl chain or polyvinyl alcohol material are constituted.
3. medical hemostatic closing according to claim 1 is anti-to be adhered material, which is characterized in that the autonomous dress polypeptide unit
For the reverse sequence of polypeptide sequence described in claim 2.
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