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 PDF

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Publication number
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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China
Prior art keywords
lysine
arg
ala
alanine
tryptophan
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CN201910086935.9A
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Inventor
李洪波
金海明
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QINGDAO ZHONGTENG BIOTECHNOLOGY Co Ltd
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QINGDAO ZHONGTENG BIOTECHNOLOGY Co Ltd
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Priority to CN201910086935.9A priority Critical patent/CN109646711A/en
Publication of CN109646711A publication Critical patent/CN109646711A/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10Polypeptides; Proteins
    • A61L24/108Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/04Materials 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)
  • Public Health (AREA)
  • 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

A kind of medical hemostatic closing is anti-to be adhered material
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.
CN201910086935.9A 2019-01-29 2019-01-29 A kind of medical hemostatic closing is anti-to be adhered material Pending CN109646711A (en)

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CN104399109A (en) * 2014-11-26 2015-03-11 沈伟 Gel hemostatic material composition and preparation method thereof
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CN101267831A (en) * 2005-04-25 2008-09-17 麻省理工学院 Compositions and methods for promoting hemostasis and other physiological activities
US20150359925A1 (en) * 2011-06-30 2015-12-17 Ethicon, Inc. Procoagulant Peptides and Their Derivatives and Uses Therefor
JP2015502991A (en) * 2011-11-04 2015-01-29 エージェンシー フォー サイエンス,テクノロジー アンド リサーチ Self-assembled composite ultra-small peptide polymer hydrogel
CN104399109A (en) * 2014-11-26 2015-03-11 沈伟 Gel hemostatic material composition and preparation method thereof
CN105085622A (en) * 2015-09-16 2015-11-25 中国石油大学(华东) Amphipathic self-assembly ultra-short peptide nano hemostatic material
CN107041967A (en) * 2016-11-29 2017-08-15 暨南大学 A kind of feature self-assembled nanometer polypeptide hydrogel material and its application in hemostatic material is prepared

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