CN114569782A - Hemostatic quick-setting spray and preparation method thereof - Google Patents

Hemostatic quick-setting spray and preparation method thereof Download PDF

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Publication number
CN114569782A
CN114569782A CN202210221447.6A CN202210221447A CN114569782A CN 114569782 A CN114569782 A CN 114569782A CN 202210221447 A CN202210221447 A CN 202210221447A CN 114569782 A CN114569782 A CN 114569782A
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hemostatic
hydrophilic
hydrophobic
polysaccharide
spray
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职康康
谭梓仪
曲乐丰
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Shanghai Changzheng Hospital
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Shanghai Changzheng Hospital
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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
    • A61L24/08—Polysaccharides
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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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    • 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
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
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    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
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    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
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    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
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Abstract

The invention discloses a hemostatic quick-setting spray and a preparation method thereof, wherein the spray contains hydrophilic-hydrophobic co-grafted polysaccharide conjugate, solvent and auxiliary agent; the hydrophilic-hydrophobic co-grafted polysaccharide conjugate and the solvent have both hydrophilicity and hydrophobicity and can react with all components in blood, so that blood gelatinization is promoted, the action time of the hemostatic material and the blood components is effectively shortened, and the healing of wounds is promoted; compared with the traditional mixed co-grafted polysaccharide conjugate, the hydrophilic and hydrophobic groups are distributed more uniformly due to the absence of a mixing step, so that the product performance is more stable; the spray is in the form of a spray, can be carried about, can be applied by only pressing a spray head when in use, is more convenient to use compared with sponges, dressing pastes, hemostatic powder and the like, has low requirement on the operating skill of an operator, and is more suitable for emergency occasions such as traffic accidents, war wounds, natural disaster events and the like.

Description

Hemostatic quick-setting spray and preparation method thereof
Technical Field
The invention relates to the field of medical consumables, in particular to a hemostatic quick-setting spray and a preparation method thereof.
Background
Blood is an essential substance for human survival, and the main barrier of the blood is skin tissue, and when the skin is damaged exogenously, the surface integrity of the skin tissue is damaged, so that a bleeding phenomenon occurs. Massive blood loss caused by trauma easily causes insufficient tissue perfusion, cell metabolic disorder and multi-organ failure, and further causes death; in the process of wound healing, fungal infection often occurs, which causes the wound condition to be further worsened.
In some emergencies such as car accidents, war wounds and natural disasters, the blood loss of the wounds is difficult to be systematically and timely cured due to condition limitation. Therefore, the hemostatic material which is convenient to prepare and use and can rapidly stanch blood can greatly reduce the disability rate and the death rate of patients with blood loss.
The existing hemostatic materials in the market at present mainly comprise a tourniquet, a natural sterile wound dressing, a synthetic hemostatic material, a compression bandage technology, a bioactive hemostatic material and the like, but all of the materials have certain defects. Such as tourniquets, can press local tissues during the hemostasis process to cause ischemia of the local tissues; the interaction of mineral zeolite in natural sterile wound dressing and blood generates heat, which causes local tissue damage; the thrombin in the biological active hemostatic material has the defects of immunogenic virus pollution, high price and the like.
The polysaccharide bioactive hemostatic material has the effects of promoting healing, stopping bleeding, absorbing moisture, keeping moisture and inhibiting the proliferation of silt marks, is rich in source, safe and non-toxic, good in biocompatibility and excellent in physical and chemical properties, is widely applied to the field of hemostasis in recent years, and most commonly used chitosan dressing is in the form of medical sponge, dressing paste or powder.
The conventional chitosan hemostatic sponge has the defect of lack of good adhesion with wound tissues, is mainly suitable for hemostasis of packed deep wounds, and is inconvenient to fix when surface wounds appear; the dressing paste needs to be repeatedly torn off and replaced in the replacement process, the wound surface is repeatedly damaged due to tearing in the replacement process, secondary damage is caused to the wound surface, the healing progress is influenced, and certain pain is brought to a patient; the hemostatic powder is not easy to be absorbed and needs to be fixed by external force. The three modes have certain requirements on the operation water level of an operator, training is required before use, and the use is very inconvenient.
Based on the above, design a section can stanch fast and be suitable for convenient hemostasis spraying, is applicable to clinical incompressible class hemostasis scene.
Disclosure of Invention
In order to solve the technical problem of inconvenient use of the active hemostatic material, the invention aims to provide a hemostatic quick-setting spray, which adopts the technical scheme that:
a hemostatic and quick-setting spray comprises hydrophilic and hydrophobic co-grafted polysaccharide conjugate, solvent, and adjuvant.
The hydrophilic-hydrophobic co-grafted polysaccharide conjugate and the solvent have both hydrophilicity and hydrophobicity and can react with all components in blood, so that blood gelatinization is promoted, the action time of the hemostatic material and the blood components is effectively shortened, and the healing of wounds is promoted; compared with the traditional mixed co-grafted polysaccharide conjugate, the hydrophilic and hydrophobic groups are distributed more uniformly due to the absence of a mixing step, so that the product performance is more stable; the spray is in the form of a spray, can be carried about, can be applied by only pressing a spray head when in use, is more convenient to use compared with sponges, dressing pastes, hemostatic powder and the like, has low requirement on the operating skill of an operator, and is more suitable for emergency occasions such as traffic accidents, war wounds, natural disaster events and the like.
Specifically, the solvent is acetic acid, and the auxiliary agent is dimethyl ether, wherein the ratio of dimethyl ether: the polysaccharide conjugate containing the hydrophilic-hydrophobic co-grafted polysaccharide is 1: 9-3: 7, and the propelling effect is good at the moment.
More specifically, the polysaccharide conjugate of hydrophilic-hydrophobic co-grafting is prepared by performing hydrophobic and hydrophilic modification on polysaccharide macromolecules in an EDC/NHS system through coupling reaction in sequence.
EDC/NHS system is adopted for reaction, which can effectively promote crosslinking and enhance the stability of reaction products, and EDC and NHS can not enter the reaction products in the crosslinking process, but are converted into water-soluble urea derivatives, which are easy to wash and remove.
The preparation method of the hydrophilic-hydrophobic co-grafted polysaccharide conjugate in the hemostatic quick-setting spray comprises the following steps:
s1: hydrophobic modification
Adding a hydrophobic functional substance and EDC/NHS into a water-soluble polysaccharide solution, grafting the hydrophobic functional substance on a polysaccharide macromolecular main chain through a coupling reaction, and preparing a hydrophobically modified polysaccharide material through precipitation, washing and vacuum drying;
s2: hydrophilic modification
Adding hydrophilic functional substances and EDC/NHS into the hydrophobically modified polysaccharide material prepared in S1, grafting the hydrophilic functional substances on the hydrophobically modified polysaccharide macromolecular main chain through a coupling reaction, and dialyzing and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted polysaccharide conjugate.
Therefore, the polysaccharide macromolecule main chain has hydrophilic and hydrophobic functions at the same time, can generate synergistic action in the blood coagulation process, has action with whole blood components, and greatly enhances the hemostatic effect.
Further, the water-soluble polysaccharide in the steps S1 and S2 is one or more of chitosan, hydroxymethyl chitosan, carboxypropyl chitosan, chitosan oligosaccharide, sodium alginate, hyaluronic acid and aminodextran; the concentration of the polysaccharide is 10-50 mg/mL.
Further, the molar ratio of the polysaccharide dissolved in the step S1 to the added hydrophobic multifunctional substance is 5: 1-20: 1, the molar ratio of the polysaccharide dissolved in the step S2 to the hydrophilic multifunctional substance added is 1: 0.5-1: 2, the molar ratio of polysaccharide dissolved in S2 to coupling reaction activator EDC/NHS added was 1: 2: 2.
further, the hydrophobic substance in step S1 is one or more selected from n-octanoic acid, dodecanoic acid, hexadecanoic acid, octanoic anhydride, dodecanoic anhydride, hexadecanoic anhydride, n-octylamine, n-dodecylamine, n-hexadecylamine, and n-octadecylamine.
Further, the hydrophilic substance in step S2 is one or more of 3, 4-dihydroxyphenylpropionic acid, 3,4, 5-trihydroxybenzoic acid, 4-carboxyphenylboronic acid, dopamine hydrochloride, and 3-aminophenylboronic acid hydrochloride.
The preparation method of the hemostatic quick-setting spray comprises the following steps: the preparation method comprises the steps of preparing the hydrophilic-hydrophobic co-grafted polysaccharide conjugate according to the method, dissolving the hydrophilic-hydrophobic co-grafted polysaccharide conjugate in acetic acid, using dimethyl ether as a propellant, co-injecting the hydrophilic-hydrophobic co-grafted polysaccharide conjugate into a pressure-resistant light handheld spray bottle, shaking the bottle for 10 seconds, and uniformly mixing to prepare the hemostatic spray.
The weight ratio of the hydrophilic-hydrophobic co-grafted polysaccharide conjugate to acetic acid in the hemostatic quick-setting spray is 1: 99.5-1: 98.
In the components, the volume ratio of the dimethyl ether to the hydrophilic-hydrophobic co-grafted polysaccharide conjugate is 1: 9-3: 7.
In production, the reaction substances can be selected according to actual needs so as to achieve the purpose of controlling the production cost.
By adopting the technical scheme, the invention has the following beneficial effects:
(1) the hemostatic material of the hemostatic quick-setting spray is hydrophilic-hydrophobic co-grafted polysaccharide conjugate, and can react with the whole blood component simultaneously, so that the action time of the hemostatic material and the blood component is effectively shortened, and the healing of wounds is promoted; compared with the traditional mixed co-grafted polysaccharide conjugate, the hydrophilic and hydrophobic groups are distributed more uniformly due to the absence of a mixing step, so that the product performance is more stable.
(2) The hemostatic quick-setting spray can be carried about, can be applied by pressing a spray head when in use, is more convenient to use compared with sponges, dressing pastes, hemostatic powder and the like, has low requirement on the operating skill of an operator, and is more suitable for emergency occasions such as traffic accidents, war wounds, natural disaster events and the like.
Detailed Description
In order to better understand the technical scheme, the technical scheme is described in detail in the following with reference to specific embodiments of the specification.
To make the objects, technical solutions and advantages of the embodiments of the present invention clearer and more fully described below with reference to the embodiments of the present invention, the detailed description of the embodiments of the present invention provided below is not intended to limit the scope of the claimed invention, but merely represents selected embodiments of the present invention. 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
2g of chitosan was dissolved in 100mL of 0.2M acetic acid and 100mL of ethanol was added followed by 364uL of caprylic anhydride and 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
dissolving 2g of hydrophobically modified chitosan in 100mL of 0.2M acetic acid, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 1.19g of 3, 4-dihydroxyphenyl propionic acid, 2.38g of EDC and 1.43g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted chitosan conjugate hemostatic quick-setting material;
2g of 1 wt% chitosan conjugate hemostatic quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as the propellant, according to dimethyl ether: chitosan conjugate hemostatic quick setting material 3:7 volume ratio were co-injected into a pressure-resistant light hand-held spray bottle, the jar was shaken for 10S and mixed well to make a hemostatic spray.
Example 2
2g of chitosan was dissolved in 100mL of 0.2M acetic acid, and 100mL of ethanol was added, heated to 45 deg.C, followed by the addition of 0.2g of dodecanoic anhydride, and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
dissolving 2g of hydrophobically modified chitosan in 100mL of 0.2M acetic acid, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 1.19g of 3, 4-dihydroxyphenyl propionic acid, 2.38g of EDC and 1.43g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted chitosan conjugate hemostatic quick-setting material;
2g of 1 wt% chitosan conjugate hemostatic quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as the propellant, according to dimethyl ether: chitosan conjugate hemostatic quick setting material 3:7 volume ratio were co-injected into a pressure-resistant light hand-held spray bottle, the jar was shaken for 10S and mixed well to make a hemostatic spray.
Example 3
2g of chitosan was dissolved in 100mL of 0.2M acetic acid, and 100mL of ethanol was added, heated to 65 ℃, followed by the addition of 0.154g of dodecanoic anhydride, and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
dissolving 2g of hydrophobically modified chitosan in 100mL of 0.2M acetic acid, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then adding 1.19g of 3, 4-dihydroxyphenyl propionic acid, 2.38g of EDC and 1.43g of NHS in sequence, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted chitosan conjugate hemostatic quick-setting material;
2g of 1 wt% chitosan conjugate hemostatic quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as the propellant, according to dimethyl ether: chitosan conjugate hemostatic quick setting material 3:7 volume ratio were co-injected into a pressure-resistant light hand-held spray bottle, the jar was shaken for 10S and mixed well to make a hemostatic spray.
Example 4
2g of chitosan was dissolved in 100mL of 0.2M acetic acid, and 100mL of ethanol was added, heated to 65 ℃, followed by the addition of 0.154g of dodecanoic anhydride, and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
dissolving 2g of hydrophobically modified chitosan in 100mL of 0.2M acetic acid, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 1.17g of 3,4, 5-trihydroxybenzoic acid, 2.38g of EDC and 1.43g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted chitosan conjugate hemostatic quick-setting material;
2g of 1 wt% chitosan conjugate hemostatic quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as the propellant, according to dimethyl ether: chitosan conjugate hemostatic quick setting material-3: 7 volume ratio were co-injected into a pressure-resistant light hand-held spray bottle, the jar was shaken for 10S and mixed well to make a hemostatic spray.
Example 5
2g of chitosan was dissolved in 100mL of 0.2M acetic acid, and 100mL of ethanol was added, heated to 65 ℃, followed by the addition of 0.154g of dodecanoic anhydride, and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
dissolving 2g of hydrophobically modified chitosan in 100mL of 0.2M acetic acid, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, sequentially adding 1.03g of 4-carboxyphenylboronic acid, 2.38g of EDC and 1.43g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted chitosan conjugate hemostatic quick-setting material;
2g of 1 wt% chitosan conjugate hemostatic quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as the propellant, according to dimethyl ether: chitosan conjugate hemostatic quick setting material 3:7 volume ratio were co-injected into a pressure-resistant light hand-held spray bottle, the jar was shaken for 10S and mixed well to make a hemostatic spray.
Example 6
2g of chitosan was dissolved in 100mL of 0.2M acetic acid, and 100mL of ethanol was added, heated to 65 ℃, followed by the addition of 0.154g of dodecanoic anhydride, and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding 3mL of 5M sodium hydroxide to adjust the pH value to 10, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified chitosan;
dissolving 2g of hydrophobically modified chitosan in 100mL of 0.2M acetic acid, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 1.17g of 3,4, 5-trihydroxybenzoic acid, 2.38g of EDC and 1.43g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted chitosan conjugate hemostatic quick-setting material;
2g of 1 wt% chitosan conjugate haemostatic and quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as the propellant, according to the ratio of dimethyl ether: chitosan conjugate hemostatic quick setting material 3:7 volume ratio were co-injected into a pressure-resistant light hand-held spray bottle, the jar was shaken for 10S and mixed well to make a hemostatic spray.
Example 7
2g of aminodextran was dissolved in 50mL of deionized water and 50mL of ethanol was added, the pH adjusted to 5.0, followed by 364uL of caprylic anhydride and 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified aminodextran;
dissolving 2g of hydrophobically modified aminodextran in 50mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 1.19g of 3, 4-dihydroxyphenyl propionic acid, 2.38g of EDC and 1.43g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic and hydrophobic co-grafted aminodextran conjugate hemostatic quick-setting material;
2g of 1 wt% aminodextran conjugate haemostatic quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as propellant, according to dimethyl ether: aminodextran conjugate hemostatic quick setting material 2: the 8 volume ratios were co-injected into a pressure-resistant light-weight hand-held spray bottle, which was shaken for 10 seconds and mixed uniformly to make a hemostatic spray.
Example 8
2g of aminodextran are dissolved in 50mL of deionized water and 50mL of ethanol are added, heated to 45 ℃ to adjust the pH to 5.0, followed by the addition of 0.2g of dodecanoic anhydride and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified aminodextran;
dissolving 2g of hydrophobically modified aminodextran in 50mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 1.19g of 3, 4-dihydroxyphenyl propionic acid, 2.38g of EDC and 1.43g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic and hydrophobic co-grafted aminodextran conjugate hemostatic quick-setting material;
2g of 1 wt% aminodextran conjugate haemostatic quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as propellant, according to dimethyl ether: aminodextran conjugate hemostatic quick setting material 2: the 8 volume ratios were co-injected into a pressure-resistant light-weight hand-held spray bottle, which was shaken for 10 seconds and mixed uniformly to make a hemostatic spray.
Example 9
2g of aminodextran are dissolved in 50mL of deionized water and 50mL of ethanol are added, heated to 65 ℃ and the pH is adjusted to 5.0, followed by the addition of 0.154g of dodecanoic anhydride and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified aminodextran;
dissolving 2g of hydrophobically modified aminodextran in 50mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 1.19g of 3, 4-dihydroxyphenyl propionic acid, 2.38g of EDC and 1.43g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic and hydrophobic co-grafted aminodextran conjugate hemostatic quick-setting material;
2g of 1 wt% aminodextran conjugate haemostatic quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as propellant, according to dimethyl ether: aminodextran conjugate hemostatic quick setting material 2: the 8 volume ratios were co-injected into a pressure-resistant light-weight hand-held spray bottle, which was shaken for 10 seconds and mixed uniformly to make a hemostatic spray.
Example 10
2g of aminodextran are dissolved in 50mL of deionized water and 50mL of ethanol are added, heated to 45 ℃ to adjust the pH to 5.0, followed by the addition of 0.2g of dodecanoic anhydride and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified aminodextran;
dissolving 2g of hydrophobically modified aminodextran in 50mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 1.17g of 3,4, 5-trihydroxybenzoic acid, 2.38g of EDC and 1.43g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic and hydrophobic co-grafted aminodextran conjugate hemostatic quick-setting material;
2g of 1 wt% aminodextran conjugate haemostatic quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as propellant, according to dimethyl ether: aminodextran conjugate hemostatic quick setting material 2: the 8 volume ratios were co-injected into a pressure-resistant light-weight hand-held spray bottle, which was shaken for 10 seconds and mixed uniformly to make a hemostatic spray.
Example 11
2g of aminodextran are dissolved in 50mL of deionised water and 50mL of ethanol are added, heated to 45 ℃ to adjust the pH to 5.0, followed by the addition of 0.2g of dodecanoic anhydride and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified aminodextran;
dissolving 2g of hydrophobically modified aminodextran in 50mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 1.02g of 4-carboxyphenylboronic acid, 2.38g of EDC and 1.43g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic and hydrophobic co-grafted aminodextran conjugate hemostatic rapid-setting material;
2g of 1 wt% aminodextran conjugate haemostatic quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as propellant, according to dimethyl ether: aminodextran conjugate hemostatic quick setting material ═ 2: the 8 volume ratios were co-injected into a pressure-resistant light-weight hand-held spray bottle, which was shaken for 10 seconds and mixed uniformly to make a hemostatic spray.
Example 12
2g of aminodextran are dissolved in 50mL of deionised water and 50mL of ethanol are added, heated to 65 ℃ to adjust the pH to 5.0, followed by the addition of 0.154g of dodecanoic anhydride and the addition of 2.38g of EDC and 1.43g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified aminodextran;
dissolving 2g of hydrophobically modified aminodextran in 50mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 1.19g of 3, 4-dihydroxyphenyl propionic acid, 2.38g of EDC and 1.43g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic and hydrophobic co-grafted aminodextran conjugate hemostatic quick-setting material;
2g of 1 wt% aminodextran conjugate haemostatic quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as propellant, according to dimethyl ether: aminodextran conjugate hemostatic quick setting material 2: the 8 volume ratios were co-injected into a pressure-resistant light-weight hand-held spray bottle, which was shaken for 10 seconds and mixed uniformly to make a hemostatic spray.
Example 13
2g of hyaluronic acid was dissolved in 50mL of deionized water and 50mL of ethanol was added to adjust the pH to 5.0, followed by 219uL of n-octylamine and 1.02g of EDC and 0.61g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified hyaluronic acid;
dissolving 2g of hydrophobically modified hyaluronic acid in 50mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 0.5g of dopamine hydrochloride, 1.02g of EDC and 0.61g of NHS, reacting overnight, dialyzing for 3 days with acidified deionized water, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted hyaluronic acid conjugate hemostatic quick-setting material;
2g of 1 wt% hyaluronic acid conjugate haemostatic and quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as propellant, according to the ratio of dimethyl ether: hyaluronic acid conjugate hemostatic quick-setting material ═ 1:9 volume ratio were co-injected into a pressure-resistant light-weight hand-held spray bottle, which was shaken for 10S and mixed uniformly to make a hemostatic spray.
Example 14
2g hyaluronic acid was dissolved in 50mL deionized water and 50mL ethanol was added, the pH adjusted to 5.0, followed by 219uL n-octylamine, 1.02g EDC and 0.61g NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified hyaluronic acid;
dissolving 2g of hydrophobically modified hyaluronic acid in 50mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 0.46g of 3-aminophenylboronic acid hydrochloride, 1.02g of EDC and 0.61g of NHS, reacting overnight, dialyzing for 3 days with acidified deionized water, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted hyaluronic acid conjugate hemostatic quick-setting material;
2g of 1 wt% hyaluronic acid conjugate haemostatic and quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as propellant, according to the ratio of dimethyl ether: hyaluronic acid conjugate hemostatic quick-setting material ═ 1:9 volume ratio were co-injected into a pressure-resistant light-weight hand-held spray bottle, which was shaken for 10S and mixed uniformly to make a hemostatic spray.
Example 15
2g of hyaluronic acid was dissolved in 50mL of deionized water and 50mL of ethanol was added to adjust the pH to 5.0, followed by 219uL of n-octylamine and 1.02g of EDC and 0.61g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified hyaluronic acid;
dissolving 1g of hydrophobically modified hyaluronic acid in 50mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, then sequentially adding 0.5g of dopamine hydrochloride, 1.02g of EDC and 0.61g of NHS, reacting overnight, dialyzing for 3 days with acidified deionized water, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted hyaluronic acid conjugate hemostatic quick-setting material;
2g of 1 wt% hyaluronic acid conjugate haemostatic and quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as propellant, according to the ratio of dimethyl ether: hyaluronic acid conjugate hemostatic quick-setting material ═ 1:9 volume ratio were co-injected into a pressure-resistant light-weight hand-held spray bottle, which was shaken for 10S and mixed uniformly to make a hemostatic spray.
Example 16
2g of sodium alginate was dissolved in 100mL of deionized water and 100mL of ethanol was added followed by 837uL of n-octylamine, the pH adjusted to 3.4 and 1.94g of EDC and 1.16g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified sodium alginate;
dissolving 1g of hydrophobically modified sodium alginate in 100mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, sequentially adding 0.96g of dopamine hydrochloride, 1.94g of EDC and 1.16g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted sodium alginate conjugate hemostatic quick-setting material;
2g of 1 wt% sodium alginate conjugate haemostatic and quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as the propellant, according to the ratio of dimethyl ether: sodium alginate conjugate hemostatic quick setting material 1:9 volume ratio were co-injected into a pressure-resistant light-weight hand-held spray bottle, which was shaken for 10S and mixed uniformly to make a hemostatic spray.
Example 17
2g of sodium alginate was dissolved in 100mL of deionized water and 100mL of ethanol was added followed by 837uL of n-octylamine, the pH adjusted to 3.4 and 1.94g of EDC and 1.16g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified sodium alginate;
dissolving 1g of hydrophobically modified sodium alginate in 100mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, sequentially adding 0.88g of 3-aminophenylboronic acid hydrochloride, 1.94g of EDC and 1.16g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted sodium alginate conjugate hemostatic quick-setting material;
2g of 1 wt% sodium alginate conjugate haemostatic and quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as the propellant, according to the ratio of dimethyl ether: sodium alginate conjugate hemostatic quick setting material 1:9 volume ratio were co-injected into a pressure-resistant lightweight hand-held spray bottle, the jar was shaken for 10 seconds and mixed well to make hemostatic spray.
Example 18
2g of sodium alginate was dissolved in 100mL of deionized water and 100mL of ethanol was added followed by 837uL of n-octylamine, the pH adjusted to 3.4 and 1.94g of EDC and 1.16g of NHS. Reacting overnight, adding excessive acetone for precipitation, filtering, washing with water and ethanol for 5 times, and drying in a vacuum oven to obtain hydrophobically modified sodium alginate;
dissolving 2g of hydrophobically modified sodium alginate in 100mL of deionized water, introducing nitrogen for 10 minutes, adjusting the pH to 5.0, sequentially adding 0.96g of dopamine hydrochloride, 1.94g of EDC and 1.16g of NHS, reacting overnight, dialyzing with acidified deionized water for 3 days, and freeze-drying to obtain the hydrophilic-hydrophobic co-grafted sodium alginate conjugate hemostatic quick-setting material;
2g of 1 wt% sodium alginate conjugate haemostatic and quick setting material was dissolved in acetic acid, with dimethyl ether (DME) as the propellant, according to the ratio of dimethyl ether: sodium alginate conjugate hemostatic quick setting material 1:9 volume ratio were co-injected into a pressure-resistant light-weight hand-held spray bottle, which was shaken for 10S and mixed uniformly to make a hemostatic spray.
And (3) hemostasis test:
after the rabbit is successfully anesthetized by intravenous injection of 25% urethane anesthetic (1g/kg) at the ear margin, the abdominal cavity of the rabbit is opened, and the liver of the rabbit is fully exposed. A wound surface of 0.5cm length by 0.5cm depth was prepared with a sharp knife at a distance of about 1cm from the edge of the lobe of the liver. The time to hemostasis(s) was recorded and the mass of wound bleeding (m2-m1) was calculated, giving table 1:
TABLE 1 statistical table comparing hemostasis time and bleeding amount of different hemostatic materials
Figure BDA0003537566730000111
Figure BDA0003537566730000121
As can be seen from the above table, the hemostatic speed spray prepared by the invention has far shorter hemostatic time than the traditional hemostatic material, has lower bleeding amount than the traditional hemostatic material, and shows excellent performance.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention, and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A hemostatic and quick-setting spray is characterized in that: comprises a hydrophilic-hydrophobic co-grafted polysaccharide conjugate, a solvent and an auxiliary agent.
2. The styptic spray according to claim 1, wherein: the solvent is acetic acid, and the auxiliary agent is dimethyl ether.
3. A haemostatic spray according to claim 2, characterised in that: the preparation steps of the hydrophilic-hydrophobic co-grafted polysaccharide conjugate are as follows:
s1: hydrophobic modification
Adding a hydrophobic functional substance and EDC/NHS into a water-soluble polysaccharide solution, grafting the hydrophobic functional substance on a polysaccharide macromolecular main chain through a coupling reaction, and preparing a hydrophobically modified polysaccharide material through precipitation, washing and vacuum drying;
s2: hydrophilic modification
Adding a hydrophilic functional substance and EDC/NHS into the hydrophobically modified polysaccharide material prepared in S1, grafting the hydrophilic functional substance on the hydrophobically modified polysaccharide macromolecular main chain through a coupling reaction, and dialyzing and freeze-drying to prepare the hydrophilic-hydrophobic co-grafted polysaccharide conjugate.
4. A haemostatic and rapid setting spray according to claim 3, characterised in that: the water-soluble polysaccharide in the steps S1 and S2 is one or more of chitosan, hydroxymethyl chitosan, carboxypropyl chitosan, chitosan oligosaccharide, sodium alginate, hyaluronic acid and aminodextran; the polysaccharide concentration is 10-50 mg/mL.
5. A haemostatic and rapid setting spray according to claim 3, characterised in that: the molar ratio of the polysaccharide dissolved in the step S1 to the added hydrophobic multifunctional substance is 5: 1-20: 1, the molar ratio of the polysaccharide dissolved in the step S2 to the hydrophilic multifunctional substance added is 1: 0.5-1: 2, the molar ratio of polysaccharide dissolved in S2 to coupling reaction activator EDC/NHS added was 1: 2: 2.
6. a haemostatic and rapid-setting spray according to claim 3, characterised in that: the hydrophobic substance in step S1 is one or more selected from n-octanoic acid, dodecanoic acid, hexadecanoic acid, octanoic anhydride, dodecanoic anhydride, hexadecanoic anhydride, n-octylamine, n-dodecylamine, n-hexadecylamine, and n-octadecylamine.
7. A haemostatic and rapid-setting spray according to claim 3, characterised in that: the hydrophilic substance in step S2 is one or more of 3, 4-dihydroxyphenyl propionic acid, 3,4, 5-trihydroxybenzoic acid, 4-carboxyphenylboronic acid, dopamine hydrochloride, and 3-aminophenylboronic acid hydrochloride.
8. The preparation method of the hemostatic quick-setting spray according to claim 3, wherein the preparation method comprises the following steps: the method of claim 3, wherein the polysaccharide conjugate is prepared by co-grafting the hydrophilic and hydrophobic polysaccharide conjugates in acetic acid, co-injecting the co-grafted polysaccharide conjugates in acetic acid using dimethyl ether as a propellant into a pressure-resistant lightweight hand-held spray bottle, shaking the bottle for 10 seconds, and mixing to form a hemostatic spray.
9. The hemostatic spray according to claim 8, wherein the hemostatic spray comprises: the weight ratio of the hydrophilic-hydrophobic co-grafted polysaccharide conjugate to acetic acid is 1: 99.5-1: 98.
10. The hemostatic spray according to claim 8, wherein the hemostatic spray comprises: the volume ratio of the dimethyl ether to the hydrophilic-hydrophobic co-grafted polysaccharide conjugate is 1: 9-3: 7.
CN202210221447.6A 2022-03-09 2022-03-09 Hemostatic quick-setting spray and preparation method thereof Withdrawn CN114569782A (en)

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Publication number Priority date Publication date Assignee Title
WO2023165469A1 (en) * 2022-03-02 2023-09-07 上海交通大学 Polysaccharide conjugate hemostatic material, preparation method therefor and use thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023165469A1 (en) * 2022-03-02 2023-09-07 上海交通大学 Polysaccharide conjugate hemostatic material, preparation method therefor and use thereof

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