CN109985273B - Preparation method of polymer microsphere drug-loaded anticoagulant sustained-release dressing and application of polymer microsphere drug-loaded anticoagulant sustained-release dressing in preparation of anticoagulant sustained-release dressing - Google Patents

Preparation method of polymer microsphere drug-loaded anticoagulant sustained-release dressing and application of polymer microsphere drug-loaded anticoagulant sustained-release dressing in preparation of anticoagulant sustained-release dressing Download PDF

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CN109985273B
CN109985273B CN201910438649.4A CN201910438649A CN109985273B CN 109985273 B CN109985273 B CN 109985273B CN 201910438649 A CN201910438649 A CN 201910438649A CN 109985273 B CN109985273 B CN 109985273B
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anticoagulant
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CN109985273A (en
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高然
杨家赵
方诗元
王刚
羊政
杨功勋
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Anhui Chuangfu Medical Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0014—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0023—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents

Abstract

The invention discloses a preparation method of a polymer microsphere drug-loaded anticoagulant sustained-release dressing, which specifically comprises four steps of preparation of drug-loaded polymer gel microspheres, preparation of a polyvinyl alcohol carrier dressing solution, blending and coupling of the drug-loaded polymer gel microspheres and the polyvinyl alcohol carrier dressing solution, and foaming. Meanwhile, the invention discloses that the preparation method of the polymer microsphere drug-loaded anticoagulant sustained-release dressing is applied to preparation of the polymer microsphere drug-loaded anticoagulant sustained-release dressing. The polymer microsphere drug-loaded anticoagulant sustained-release dressing prepared by the preparation method disclosed by the invention solves the problem of negative pressure drainage wound-protecting material in the prior art. Because blood generates coagulation reaction in the aperture, the residue of blood clots can cause the aperture of the material and the blockage of the drainage tube, so that the application life of the negative pressure drainage wound protection material is greatly reduced. The invention discloses a polymer microsphere drug-loaded anticoagulant sustained-release dressing prepared by the preparation method.

Description

Preparation method of polymer microsphere drug-loaded anticoagulant sustained-release dressing and application of polymer microsphere drug-loaded anticoagulant sustained-release dressing in preparation of anticoagulant sustained-release dressing
Technical Field
The invention relates to preparation of an anticoagulant sustained-release dressing, in particular to a preparation method of a polymer microsphere drug-loaded anticoagulant sustained-release dressing and application of the polymer microsphere drug-loaded anticoagulant sustained-release dressing in preparation of the anticoagulant sustained-release dressing.
Background
Clinically, in the negative pressure drainage process, a wound protection material such as a foam dressing is often needed to be used, and the foam dressing is utilized to provide a closed environment for a wound surface or a wound cavity.
However, most of the negative pressure drainage wound-protecting materials disclosed in the prior art are made of polyurethane or polyvinyl alcohol materials, and a Pan's drainage tube is penetrated through the negative pressure drainage wound-protecting materials for drainage. Because blood is subjected to coagulation reaction in the pore diameter, the residual blood clots can cause the pore diameter of the material and the blockage of the drainage tube, so that the application life of the negative pressure drainage wound protection material is greatly reduced.
In the prior art, in order to solve the technical problems of blood coagulation and blockage, an anticoagulant cleaning solution is often coated and injected on a drainage tube, and the anticoagulation comprehensiveness of a drainage system cannot be ensured by the treatment modes, so that the long-acting performance of an inner hole of a material and the drainage tube is solved.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of a polymer microsphere drug-loaded anticoagulant sustained-release dressing and application of the polymer microsphere drug-loaded anticoagulant sustained-release dressing in preparation of the anticoagulant sustained-release dressing.
The invention solves the technical problems through the following technical scheme:
a preparation method of a polymer microsphere drug-loaded anticoagulant sustained-release dressing comprises the following steps:
(1) preparing drug-loaded polymer gel microspheres:
adding the PVA acidic aqueous solution and the acetic acid solution of chitosan into a reactor, stirring, adding an anticoagulant during stirring, and fully stirring and dissolving to obtain a water phase A;
evenly mixing the Triton reagent and liquid paraffin to prepare an oil phase B;
dropwise adding the water phase A into the oil phase B, stirring and mixing materials in the dropwise adding process, continuously stirring after dropwise adding, adding a glutaraldehyde solution into a reaction system after stirring, heating to reflux, performing reflux reaction for 2 hours, adding isopropanol, standing, performing centrifugal separation, removing supernatant after centrifugal separation is finished, washing and pulping centrifugates with ether solvents, and filtering to obtain a filter cake, wherein the filter cake is the drug-loaded polymer gel microsphere;
(2) preparation of polyvinyl alcohol carrier dressing solution:
mixing corn starch and potato starch, adding water, stirring, and adding a defoaming agent to obtain a starch solution for later use;
mixing PVA with water, keeping the temperature for 2 hours at 95 ℃, dissolving the PVA during the heat preservation process, cooling to 72 ℃ after the dissolution is finished, adding the starch solution, stirring and mixing the materials, reducing the temperature of a reaction system during the stirring and mixing process, obtaining a polyvinyl alcohol carrier dressing solution when the temperature of the reaction system is reduced to 54 ℃, placing the polyvinyl alcohol carrier dressing solution under the constant temperature condition, and keeping the temperature for later use;
(3) blending and coupling the drug-loaded polymer gel microspheres and a polyvinyl alcohol carrier dressing solution:
adding the drug-loaded polymer gel microsphere solution prepared in the step (2) into the drug-loaded polymer gel microsphere prepared in the step (1), adding a formaldehyde solution, adding sulfuric acid when the temperature of a reaction system is reduced to 51 ℃, and adding the mixture into a negative-pressure drainage auxiliary material die after stirring;
(4) foaming:
and (4) placing the mould in the step (3) into an oven, reacting for 10h, controlling the temperature in the oven to be 62 ℃ in the reaction process, removing the mould after the reaction is finished to obtain a dressing, and washing the dressing to obtain the polymer microsphere drug-loaded anticoagulant slow-release dressing.
Preferably, the anticoagulant is any one or a mixture of two of heparin sodium, sodium citrate and ethylene diamine tetraacetic acid dipotassium.
Preferably, the Triton reagent is any one of Triton X-100, Triton X-114 and Triton X-45.
Preferably, the preparation method of the acidic aqueous solution of PVA in the step (1) is as follows:
mixing 1.67g of PVA with 100mL of water, heating to 90 ℃, preserving the temperature for 2h, adding 3.5mL of concentrated hydrochloric acid with the mass fraction of 33% into the PVA solution after the PVA is fully dissolved, and preparing into an acid PVA aqueous solution with the mass concentration of 1.67%;
the mass fraction of chitosan in the acetic acid solution of chitosan is 3%;
the addition amount of the acetic acid solution of the chitosan is 10mL, the addition amount of the isopropanol is 10mL, and after the isopropanol is added, the standing time is 10 min;
the mass fraction of the glutaraldehyde solution is 50%, the glutaraldehyde solution is added dropwise, and the addition amount of the glutaraldehyde solution is 0.55 mL.
Preferably, the preparation method of the oil phase B is as follows:
and uniformly mixing 4.5mL of Triton reagent with 60mL of liquid paraffin to obtain an oil phase B.
Preferably, the ether solvent is petroleum ether.
Preferably, in the step (2), the mass ratio of the corn starch to the potato starch is 2: 1.62, the total mass of the mixture is 3.62 g;
after mixing the corn starch and the potato starch, adding 10mL of water, stirring, and after uniformly stirring, adding 1.0g of defoaming agent to obtain a starch solution for later use;
the mixing mode of the PVA and the water is as follows: 10g of PVA were mixed with 60mL of water.
Preferably, the addition amount of the formaldehyde solution in the step (3) is 7mL, the addition amount of the sulfuric acid is 4.5mL, and after the sulfuric acid is added, the mixture is stirred for 15min and then added into the negative pressure drainage auxiliary material mold.
The invention also discloses application of the preparation method of the polymer microsphere drug-loaded anticoagulant sustained-release dressing in preparation of the anticoagulant sustained-release dressing.
Compared with the prior art, the invention has the following advantages:
the invention discloses a preparation method of a polymer microsphere drug-loaded anticoagulant sustained-release dressing, and solves the problem of negative pressure drainage wound-protecting materials in the prior art through the technical scheme disclosed by the invention. Because blood generates coagulation reaction in the aperture, the residue of blood clots can cause the aperture of the material and the blockage of the drainage tube, so that the application life of the negative pressure drainage wound protection material is greatly reduced. The invention discloses a polymer microsphere drug-loaded anticoagulant sustained-release dressing prepared by the preparation method.
Drawings
FIG. 1 is a schematic diagram of the particle size distribution of drug-loaded polymer gel microspheres prepared in example 1 of the present invention; in FIG. 1, the number of microspheres is 285, the calculated mean particle size is 1.75 microns with a 2.18 variance;
fig. 2 is a data diagram of the drug release rate of the polymer microsphere drug-loaded anticoagulant sustained-release dressing prepared in example 1 of the present invention.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
A preparation method of a polymer microsphere drug-loaded anticoagulant sustained-release dressing comprises the following steps:
(1) preparing drug-loaded polymer gel microspheres:
10mL of PVA acidic aqueous solution is prepared (the preparation method of the PVA acidic aqueous solution is that 1.67g of PVA is mixed with 100mL of water, the temperature is raised to 90 ℃, the temperature is kept for 2h, after the PVA is fully dissolved, 3.5mL of concentrated hydrochloric acid with the mass fraction of 33% is added into the PVA solution to prepare the PVA acidic aqueous solution with the mass concentration of 1.67%) and 10mL of acetic acid solution of chitosan with the mass fraction of 3% are added into a reactor, the mixture is stirred, heparin sodium is added in the stirring process (the addition mode of the heparin sodium is that 2mL of injection with the activity unit of 25000U/mL is added), and after the mixture is fully stirred and dissolved, a water phase A is obtained;
uniformly mixing 4.5mL of TritonX-100 with 60mL of liquid paraffin to obtain an oil phase B;
dropwise adding the water phase A into the oil phase B, stirring and mixing materials in the dropwise adding process, continuously stirring after dropwise adding, dropwise adding 0.55mL of glutaraldehyde solution with the mass fraction of 50% into a reaction system after stirring, heating to reflux (the reflux temperature is 65 ℃), performing reflux reaction for 2 hours, adding 10mL of isopropanol, standing for 10min, performing centrifugal separation, removing supernatant after the centrifugal separation is finished, washing and pulping the centrifugate with an ether solvent, and filtering to obtain a filter cake, wherein the filter cake is the drug-loaded polymer gel microsphere.
Under the above conditions (acidity), chitosan reacts with the added glutaraldehyde solution in the following manner:
Figure BDA0002071362540000051
the dimers of chitosan are prepared according to the reaction mode disclosed by the formula I, and a reticular molecular structure is formed among the dimers of chitosan.
The reaction of PVA with added glutaraldehyde solution is carried out according to the following formula II:
Figure BDA0002071362540000061
through the reaction mode disclosed by the formula II, an acetal product is formed by PVA and added glutaraldehyde, and the acetal product and the dimer of the chitosan prepared by the reaction mode of the formula I continuously react to form a net-shaped molecular structure.
(2) Preparation of polyvinyl alcohol carrier dressing solution:
mixing corn starch and potato starch according to a mass ratio of 2: 1.62, adding 10mL of water, stirring, and adding 1g of defoaming agent to obtain a starch solution for later use, wherein the total mass of the mixture is 3.62 g;
mixing 10g of PVA with 60mL of water, keeping the temperature for 2h at 95 ℃, dissolving the PVA in the heat preservation process, cooling to 72 ℃ after the PVA is dissolved, adding a starch solution, stirring and mixing the materials, reducing the temperature of a reaction system in the stirring and mixing process, obtaining a polyvinyl alcohol carrier dressing solution when the temperature of the reaction system is reduced to 54 ℃, placing the polyvinyl alcohol carrier dressing solution under the constant temperature condition, and keeping the temperature for later use;
(3) blending and coupling the drug-loaded polymer gel microspheres and a polyvinyl alcohol carrier dressing solution:
adding the drug-loaded polymer gel microsphere solution prepared in the step (2) into the drug-loaded polymer gel microsphere prepared in the step (1), adding 7mL of formaldehyde solution, adding 4.5mL of sulfuric acid (the mass fraction of the sulfuric acid is 98%) when the reaction system is cooled to 51 ℃, stirring for 15min, and adding into a negative pressure drainage auxiliary material mold;
(4) foaming:
and (3) placing the mould in the step (3) into an oven, reacting for 10h, controlling the temperature in the oven to be 62 ℃ in the reaction process, removing the mould after the reaction is finished to obtain a dressing, and washing the dressing to obtain 10.75g of the polymer microsphere drug-loaded anticoagulant sustained-release dressing, wherein the diameter of the polymer microsphere drug-loaded anticoagulant sustained-release dressing is 8cm, and the thickness of the polymer microsphere drug-loaded anticoagulant sustained-release dressing is 1.0 cm.
Example 2
A preparation method of a polymer microsphere drug-loaded anticoagulant sustained-release dressing comprises the following steps:
(1) preparing drug-loaded polymer gel microspheres:
adding 10mL of PVA acidic aqueous solution (the preparation method of the PVA acidic aqueous solution is the same as that in example 1) and 10mL of acetic acid solution of chitosan with the mass fraction of 3% into a reactor, stirring, adding sodium citrate (controlling the final concentration of the sodium citrate to be 4.8mol/L) in the stirring process, and fully stirring and dissolving to obtain a water phase A;
uniformly mixing 4.5mL of TritonX-114 with 60mL of liquid paraffin to obtain an oil phase B;
dropwise adding the water phase A into the oil phase B, stirring and mixing materials in the dropwise adding process, continuously stirring after dropwise adding, dropwise adding 0.55mL of glutaraldehyde solution with the mass fraction of 50% into a reaction system after stirring, heating to reflux (the reflux temperature is 65 ℃), performing reflux reaction for 2 hours, adding 10mL of isopropanol, standing for 10min, performing centrifugal separation, removing supernatant after the centrifugal separation is finished, washing and pulping the centrifugate with an ether solvent, and filtering to obtain a filter cake, wherein the filter cake is the drug-loaded polymer gel microsphere.
Under the above conditions (acidic conditions), chitosan was reacted with the added glutaraldehyde solution in the same manner as in example 1:
PVA was reacted with the added glutaraldehyde solution in the same manner as in example 1:
(2) preparation of polyvinyl alcohol carrier dressing solution:
mixing corn starch and potato starch according to a mass ratio of 2: 1.62, adding 10mL of water, stirring, and adding 1g of defoaming agent to obtain a starch solution for later use, wherein the total mass of the mixture is 3.62 g;
mixing 10g of PVA with 60mL of water, keeping the temperature for 2h at 95 ℃, dissolving the PVA in the heat preservation process, cooling to 72 ℃ after the PVA is dissolved, adding a starch solution, stirring and mixing the materials, reducing the temperature of a reaction system in the stirring and mixing process, obtaining a polyvinyl alcohol carrier dressing solution when the temperature of the reaction system is reduced to 54 ℃, placing the polyvinyl alcohol carrier dressing solution under the constant temperature condition, and keeping the temperature for later use;
(3) blending and coupling the drug-loaded polymer gel microspheres and a polyvinyl alcohol carrier dressing solution:
adding the drug-loaded polymer gel microsphere solution prepared in the step (2) into the drug-loaded polymer gel microsphere prepared in the step (1), adding 7mL of formaldehyde solution, adding 4.5mL of concentrated sulfuric acid (the mass fraction of sulfuric acid is 98%) when the reaction system is cooled to 51 ℃, stirring for 15min, and adding into a negative pressure drainage auxiliary material mold;
(4) foaming:
and (3) placing the mould in the step (3) into an oven, reacting for 10h, controlling the temperature in the oven to be 62 ℃ in the reaction process, removing the mould after the reaction is finished to obtain a dressing, and washing the dressing to obtain 10.75g of the polymer microsphere drug-loaded anticoagulant sustained-release dressing, wherein the diameter of the polymer microsphere drug-loaded anticoagulant sustained-release dressing is 8cm, and the thickness of the polymer microsphere drug-loaded anticoagulant sustained-release dressing is 1.0 cm.
Example 3
A preparation method of a polymer microsphere drug-loaded anticoagulant sustained-release dressing comprises the following steps:
(1) preparing drug-loaded polymer gel microspheres:
adding 10mL of PVA acidic aqueous solution (the preparation method of the PVA acidic aqueous solution is the same as that in example 1) and 10mL of acetic acid solution of chitosan with the mass fraction of 3% into a reactor, stirring, adding dipotassium ethylenediamine tetraacetate (the final concentration of the dipotassium ethylenediamine tetraacetate is controlled to be 2.5mol/L) in the stirring process, and fully stirring and dissolving to obtain a water phase A;
uniformly mixing 4.5mL of TritonX-45 with 60mL of liquid paraffin to obtain an oil phase B;
dropwise adding the water phase A into the oil phase B, stirring and mixing materials in the dropwise adding process, continuously stirring after dropwise adding, dropwise adding 0.55mL of glutaraldehyde solution with the mass fraction of 50% into a reaction system after stirring, heating to reflux (the reflux temperature is 65 ℃), performing reflux reaction for 2 hours, adding 10mL of isopropanol, standing for 10min, performing centrifugal separation, removing supernatant after the centrifugal separation is finished, washing and pulping the centrifugate with an ether solvent, and filtering to obtain a filter cake, wherein the filter cake is the drug-loaded polymer gel microsphere.
Under the above conditions (acidic conditions), chitosan was reacted with the added glutaraldehyde solution in the same manner as in example 1:
PVA was reacted with the added glutaraldehyde solution in the same manner as in example 1:
(2) preparation of polyvinyl alcohol carrier dressing solution:
mixing corn starch and potato starch according to a mass ratio of 2: 1.62, adding 10mL of water, stirring, and adding 1g of defoaming agent to obtain a starch solution for later use, wherein the total mass of the mixture is 3.62 g;
mixing 10g of PVA with 60mL of water, keeping the temperature for 2h at 95 ℃, dissolving the PVA in the heat preservation process, cooling to 72 ℃ after the PVA is dissolved, adding a starch solution, stirring and mixing the materials, reducing the temperature of a reaction system in the stirring and mixing process, obtaining a polyvinyl alcohol carrier dressing solution when the temperature of the reaction system is reduced to 54 ℃, placing the polyvinyl alcohol carrier dressing solution under the constant temperature condition, and keeping the temperature for later use;
(3) blending and coupling the drug-loaded polymer gel microspheres and a polyvinyl alcohol carrier dressing solution:
adding the drug-loaded polymer gel microsphere solution prepared in the step (2) into the drug-loaded polymer gel microsphere prepared in the step (1), adding 7mL of formaldehyde solution, adding 4.5mL of concentrated sulfuric acid (the mass fraction of sulfuric acid is 98%) when the reaction system is cooled to 51 ℃, stirring for 15min, and adding into a negative pressure drainage auxiliary material mold;
(4) foaming:
and (3) placing the mould in the step (3) into an oven, reacting for 10h, controlling the temperature in the oven to be 62 ℃ in the reaction process, removing the mould after the reaction is finished to obtain a dressing, and washing the dressing to obtain 10.75g of the polymer microsphere drug-loaded anticoagulant sustained-release dressing, wherein the diameter of the polymer microsphere drug-loaded anticoagulant sustained-release dressing is 8cm, and the thickness of the polymer microsphere drug-loaded anticoagulant sustained-release dressing is 1.0 cm.
Example 4
A preparation method of a polymer microsphere drug-loaded anticoagulant sustained-release dressing comprises the following steps:
(1) preparing drug-loaded polymer gel microspheres:
adding 10mL of PVA acidic aqueous solution (the preparation method of the PVA acidic aqueous solution is the same as that in example 1) and 10mL of acetic acid solution of chitosan with the mass fraction of 3% into a reactor, stirring, adding a mixture of dipotassium ethylenediamine tetraacetate and sodium citrate (the molar ratio of the dipotassium ethylenediamine tetraacetate to the sodium citrate in the mixture is 1: 2) during stirring, and fully stirring and dissolving to obtain a water phase A;
uniformly mixing 4.5mL of TritonX-45 with 60mL of liquid paraffin to obtain an oil phase B;
dropwise adding the water phase A into the oil phase B, stirring and mixing materials in the dropwise adding process, continuously stirring after dropwise adding, dropwise adding 0.55mL of glutaraldehyde solution with the mass fraction of 50% into a reaction system after stirring, heating to reflux (the reflux temperature is 65 ℃), performing reflux reaction for 2 hours, adding 10mL of isopropanol, standing for 10min, performing centrifugal separation, removing supernatant after the centrifugal separation is finished, washing and pulping the centrifugate with an ether solvent, and filtering to obtain a filter cake, wherein the filter cake is the drug-loaded polymer gel microsphere.
Under the above conditions (acidic conditions), chitosan was reacted with the added glutaraldehyde solution in the same manner as in example 1:
PVA was reacted with the added glutaraldehyde solution in the same manner as in example 1:
(2) preparation of polyvinyl alcohol carrier dressing solution:
mixing corn starch and potato starch according to a mass ratio of 2: 1.62, adding 10mL of water, stirring, and adding 1g of defoaming agent to obtain a starch solution for later use, wherein the total mass of the mixture is 3.62 g;
mixing 10g of PVA with 60mL of water, keeping the temperature for 2h at 95 ℃, dissolving the PVA in the heat preservation process, cooling to 72 ℃ after the PVA is dissolved, adding a starch solution, stirring and mixing the materials, reducing the temperature of a reaction system in the stirring and mixing process, obtaining a polyvinyl alcohol carrier dressing solution when the temperature of the reaction system is reduced to 54 ℃, placing the polyvinyl alcohol carrier dressing solution under the constant temperature condition, and keeping the temperature for later use;
(3) blending and coupling the drug-loaded polymer gel microspheres and a polyvinyl alcohol carrier dressing solution:
adding the drug-loaded polymer gel microsphere solution prepared in the step (2) into the drug-loaded polymer gel microsphere prepared in the step (1), adding 7mL of formaldehyde solution, adding 4.5mL of concentrated sulfuric acid (the mass fraction of sulfuric acid is 98%) when the reaction system is cooled to 51 ℃, stirring for 15min, and adding into a negative pressure drainage auxiliary material mold;
(4) foaming:
and (3) placing the mould in the step (3) into an oven, reacting for 10h, controlling the temperature in the oven to be 62 ℃ in the reaction process, removing the mould after the reaction is finished to obtain a dressing, and washing the dressing to obtain 10.75g of the polymer microsphere drug-loaded anticoagulant sustained-release dressing, wherein the diameter of the polymer microsphere drug-loaded anticoagulant sustained-release dressing is 8cm, and the thickness of the polymer microsphere drug-loaded anticoagulant sustained-release dressing is 1.0 cm.
Example 5
A preparation method of a polymer microsphere drug-loaded anticoagulant sustained-release dressing comprises the following steps:
(1) preparing drug-loaded polymer gel microspheres:
adding 10mL of PVA acidic aqueous solution (the preparation method of the PVA acidic aqueous solution is the same as that in example 1) and 10mL of acetic acid solution of chitosan with the mass fraction of 3% into a reactor, stirring, adding a mixture of heparin sodium and sodium citrate (the molar mass ratio of ethylene diamine tetraacetic acid dipotassium to sodium citrate in the mixture is 1: 2:1) during stirring, and fully stirring and dissolving to obtain a water phase A;
uniformly mixing 4.5mL of TritonX-45 with 60mL of liquid paraffin to obtain an oil phase B;
dropwise adding the water phase A into the oil phase B, stirring and mixing materials in the dropwise adding process, continuously stirring after dropwise adding, dropwise adding 0.55mL of glutaraldehyde solution with the mass fraction of 50% into a reaction system after stirring, heating to reflux (the reflux temperature is 65 ℃), performing reflux reaction for 2 hours, adding 10mL of isopropanol, standing for 10min, performing centrifugal separation, removing supernatant after the centrifugal separation is finished, washing and pulping the centrifugate with an ether solvent, and filtering to obtain a filter cake, wherein the filter cake is the drug-loaded polymer gel microsphere.
Under the above conditions (acidic conditions), chitosan was reacted with the added glutaraldehyde solution in the same manner as in example 1:
PVA was reacted with the added glutaraldehyde solution in the same manner as in example 1:
(2) preparation of polyvinyl alcohol carrier dressing solution:
mixing corn starch and potato starch according to a mass ratio of 2: 1.62, adding 10mL of water, stirring, and adding 1g of defoaming agent to obtain a starch solution for later use, wherein the total mass of the mixture is 3.62 g;
mixing 10g of PVA with 60mL of water, keeping the temperature for 2h at 95 ℃, dissolving the PVA in the heat preservation process, cooling to 72 ℃ after the PVA is dissolved, adding a starch solution, stirring and mixing the materials, reducing the temperature of a reaction system in the stirring and mixing process, obtaining a polyvinyl alcohol carrier dressing solution when the temperature of the reaction system is reduced to 54 ℃, placing the polyvinyl alcohol carrier dressing solution under the constant temperature condition, and keeping the temperature for later use;
(3) blending and coupling the drug-loaded polymer gel microspheres and a polyvinyl alcohol carrier dressing solution:
adding the drug-loaded polymer gel microsphere solution prepared in the step (2) into the drug-loaded polymer gel microsphere prepared in the step (1), adding 7mL of formaldehyde solution, adding 4.5mL of concentrated sulfuric acid (the mass fraction of sulfuric acid is 98%) when the reaction system is cooled to 51 ℃, stirring for 15min, and adding into a negative pressure drainage auxiliary material mold;
(4) foaming:
and (3) placing the mould in the step (3) into an oven, reacting for 10h, controlling the temperature in the oven to be 62 ℃ in the reaction process, removing the mould after the reaction is finished to obtain a dressing, and washing the dressing to obtain 10.75g of the polymer microsphere drug-loaded anticoagulant sustained-release dressing, wherein the diameter of the polymer microsphere drug-loaded anticoagulant sustained-release dressing is 8cm, and the thickness of the polymer microsphere drug-loaded anticoagulant sustained-release dressing is 1.0 cm.
Example 6
And (3) performance detection:
carrying out particle size distribution detection on the drug-loaded polymer gel microspheres prepared in the embodiment 1 of the invention;
the slow release detection of the polymer microsphere medicine-carrying anticoagulant dressing prepared in the embodiment 1 of the invention is carried out as follows:
the particle size distribution result of the gel microspheres is shown in figure 1, and the detection result of the drug sustained release is shown in figure 2;
the particle size distribution detection method comprises the following steps:
a hot type polarization microscope is adopted, observation is carried out when a natural light path is not heated, the diameter of the microsphere is measured by using a microscope with a ruler, and 285 samples are calculated according to the particle size of the microsphere.
As can be seen from fig. 1: the microsphere prepared by the method has good dispersity and the average grain diameter of 1.7 microns. The drug-loaded microspheres have uniform size distribution, and are beneficial to uniform release of drugs.
Wherein, the particle size of the microsphere is calculated according to the following formula:
Figure BDA0002071362540000131
in the above formula: diRepresents: the particle size of a single microsphere; n represents: the number of microspheres; d represents: average particle size of microspheres; DP represents: dispersity (dispersity is used to measure the dispersibility of microspheres).
The drug sustained release detection method comprises the following steps:
the polymer microsphere drug-loaded anticoagulant sustained-release dressing prepared in the embodiment 1 is loaded on a negative pressure drainage device (the dressing is arranged on a drainage tube) according to a mode disclosed by the prior art, a valve on the negative pressure drainage device is adjusted, the drainage operation is carried out according to the speed of 1000mL/h of sterile water in the first 2h, the drainage liquid is collected, the drainage operation is carried out according to the speed of 1000mL/h of sterile water in the last 6h, the concentration of the drug is measured by the collection liquid (high performance liquid chromatography), and the elution speed of the drainage drug is calculated.
As can be seen from fig. 2: the polymer microsphere drug-loaded anticoagulant sustained-release dressing prepared by the invention shows better drug sustained-release characteristics.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (9)

1. A preparation method of a polymer microsphere drug-loaded anticoagulant sustained-release dressing is characterized by comprising the following steps:
(1) preparing drug-loaded polymer gel microspheres:
adding the PVA acidic aqueous solution and the acetic acid solution of chitosan into a reactor, stirring, adding an anticoagulant during stirring, and fully stirring and dissolving to obtain a water phase A;
evenly mixing the Triton reagent and liquid paraffin to prepare an oil phase B;
dropwise adding the water phase A into the oil phase B, stirring and mixing materials in the dropwise adding process, continuously stirring after dropwise adding, adding a glutaraldehyde solution into a reaction system after stirring, heating to reflux, performing reflux reaction for 2 hours, adding isopropanol, standing, performing centrifugal separation, removing supernatant after centrifugal separation is finished, washing and pulping centrifugates with ether solvents, and filtering to obtain a filter cake, wherein the filter cake is the drug-loaded polymer gel microsphere;
(2) preparation of polyvinyl alcohol carrier dressing solution:
mixing corn starch and potato starch, adding water, stirring, and adding a defoaming agent to obtain a starch solution for later use;
mixing PVA with water, keeping the temperature for 2 hours at 95 ℃, dissolving the PVA during the heat preservation process, cooling to 72 ℃ after the dissolution is finished, adding the starch solution, stirring and mixing the materials, reducing the temperature of a reaction system during the stirring and mixing process, obtaining a polyvinyl alcohol carrier dressing solution when the temperature of the reaction system is reduced to 54 ℃, placing the polyvinyl alcohol carrier dressing solution under the constant temperature condition, and keeping the temperature for later use;
(3) blending and coupling the drug-loaded polymer gel microspheres and a polyvinyl alcohol carrier dressing solution:
adding the polyvinyl alcohol carrier dressing solution prepared in the step (2) into the drug-loaded polymer gel microspheres prepared in the step (1), adding a formaldehyde solution, adding sulfuric acid when the temperature of a reaction system is reduced to 51 ℃, and adding the sulfuric acid into a negative-pressure drainage auxiliary material die after stirring;
(4) foaming:
and (4) placing the mould in the step (3) into an oven, reacting for 10h, controlling the temperature in the oven to be 62 ℃ in the reaction process, removing the mould after the reaction is finished to obtain a dressing, and washing the dressing to obtain the polymer microsphere drug-loaded anticoagulant slow-release dressing.
2. The preparation method of the polymer microsphere drug-loaded anticoagulant sustained-release dressing according to claim 1, wherein the anticoagulant is any one or a mixture of two of heparin sodium, sodium citrate and ethylene diamine tetraacetic acid dipotassium.
3. The method for preparing the polymer microsphere drug-loaded anticoagulant sustained-release dressing according to claim 2, wherein the Triton reagent is any one of Triton X-100, Triton X-114 and Triton X-45.
4. The preparation method of the polymer microsphere drug-loaded anticoagulant sustained-release dressing according to claim 3, wherein the preparation method of the PVA acidic aqueous solution in the step (1) is as follows:
mixing 1.67g of PVA with 100mL of water, heating to 90 ℃, preserving heat for 2 hours, adding 3.5mL of concentrated hydrochloric acid with the mass fraction of 33% into the PVA solution after the PVA is fully dissolved, and preparing into an acid PVA aqueous solution;
the mass fraction of chitosan in the acetic acid solution of chitosan is 3%;
the addition amount of the acetic acid solution of the chitosan is 10mL, the addition amount of the isopropanol is 10mL, and after the isopropanol is added, the standing time is 10 min;
the mass fraction of the glutaraldehyde solution is 50%, the glutaraldehyde solution is added in a dropwise manner, and the dropwise adding amount of the glutaraldehyde solution is 0.55 mL.
5. The preparation method of the polymeric microsphere drug-loaded anticoagulant sustained-release dressing according to claim 4, wherein the preparation method of the oil phase B comprises the following steps:
and uniformly mixing 4.5mL of Triton reagent with 60mL of liquid paraffin to obtain an oil phase B.
6. The method for preparing the polymer microsphere drug-loaded anticoagulant sustained-release dressing according to claim 4, wherein the ether solvent is petroleum ether.
7. The preparation method of the polymeric microsphere drug-loaded anticoagulant sustained-release dressing according to claim 4, wherein in the step (2), the mass ratio of corn starch to potato starch is 2: 1.62, the total mass of the mixture is 3.62 g;
after mixing the corn starch and the potato starch, adding 10mL of water, stirring, and after uniformly stirring, adding 1.0g of defoaming agent to obtain a starch solution for later use;
the mixing mode of the PVA and the water is as follows: 10g of PVA were mixed with 60mL of water.
8. The preparation method of the polymer microsphere drug-loaded anticoagulant sustained-release dressing according to claim 4, wherein the addition amount of the formaldehyde solution in the step (3) is 7mL, the addition amount of the sulfuric acid is 4.5mL, and after the sulfuric acid is added, the mixture is stirred for 15min and then added into a negative pressure drainage auxiliary material mold.
9. The application of the preparation method of the polymer microsphere drug-loaded anticoagulant sustained-release dressing according to any one of claims 1 to 8 in preparation of the anticoagulant sustained-release dressing.
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