CN114621491A - Method for preparing polyvinyl alcohol porous embolism microsphere - Google Patents
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
- C08J9/26—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof by elimination of a solid phase from a macromolecular composition or article, e.g. leaching out
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0036—Porous materials, e.g. foams or sponges
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2201/00—Foams characterised by the foaming process
- C08J2201/04—Foams characterised by the foaming process characterised by the elimination of a liquid or solid component, e.g. precipitation, leaching out, evaporation
- C08J2201/046—Elimination of a polymeric phase
- C08J2201/0464—Elimination of a polymeric phase using water or inorganic fluids
Abstract
The invention discloses a preparation method of polyvinyl alcohol porous embolism microsphere, relating to the field of medical embolism microsphere, wherein 300ml of alcohol with volume concentration of 35-95%, 5-50g of polyvinyl alcohol modifier, 0.5-20 g of pore-foaming agent and 0-3g of surfactant with HLB value between 8-18 are added into a 1000ml beaker, fully stirred, dissolved and dispersed for 30-300min to obtain dispersion phase A, and 200-600ml of oil phase B is slowly added into A; preparing 50-200ml of alkaline distilled water with the pH value of 8.0-10.5, slowly adding into the liquid under stirring, standing for layering, cleaning with ultrasonic wave, and oven drying. According to the invention, polyvinyl alcohol is firstly intensively modified by a chemical method, then microspheres are prepared by a physical method, and by utilizing the principle that polyvinyl alcohol modified substances have different solubilities in alcohols with different concentrations, colloidal droplets are firstly emulsified by a phase conversion method, then the droplets are solidified and formed by combining methods of phase separation and solvent replacement, and finally solvent replacement and colloid pore-forming are used to obtain the porous structure.
Description
Technical Field
The invention relates to the field of medical embolism microspheres, in particular to a method for preparing polyvinyl alcohol porous embolism microspheres.
Background
The drug-loaded embolism microsphere has good embolism function, can prolong the action time of the drug and tumor cells in the tumor cells because the drug-loaded embolism microsphere can be loaded with the chemotherapeutic drug with higher concentration, and has better use effect compared with the traditional iodized oil-chemotherapeutic drug mixed emulsion embolic agent. The microsphere embolization agent which is currently on the market at home and abroad comprises polyvinyl alcohol embolization microspheres, chitosan microspheres, sodium alginate microspheres, albumin microspheres, composite modified microspheres of the materials and the like. The microspheres made of different materials have different physicochemical properties such as resilience, expansion, adsorption, pressure resistance and the like. For example, sodium alginate microspheres are crosslinked by calcium ions, so that the brittleness and the resilience are poor, the microspheres are easily crushed after being conveyed by a catheter, and the drift risk of embolism is caused. The chitosan microspheres have certain degradation capability, but the compressive strength and the tensile strength of the expanded chitosan microspheres are poor, so that the chitosan microspheres cannot bear blood pressure impact, and the clinical application of the chitosan microspheres is limited. The polyvinyl alcohol embolism microsphere does not contain active groups, and before the medicine is loaded, the polyvinyl alcohol embolism microsphere needs to be activated or subjected to derivatization again, which is not beneficial to clinical operation. At present, a plurality of modification methods such as grafting, blending, copolymerization and the like are carried out on the polyvinyl alcohol embolism microsphere in the market, emulsification is carried out through physical means such as stirring, shearing, convection and the like, and the embolism microsphere is obtained by carrying out emulsion polymerization on emulsified liquid drops.
For example, publication No. CN113855848A provides a monodisperse boric acid crosslinked polyvinyl alcohol embolic microsphere, the matrix material of which is boric acid crosslinked polyvinyl alcohol, the preparation method comprises inputting the internal phase fluid into the injection tube of the microfluidic device, inputting the external phase fluid into the collection tube of the microfluidic device, forming a monodisperse water-in-oil emulsion in the collection tube, collecting the monodisperse water-in-oil emulsion with a container containing a collection liquid, initiating the polymerization reaction of polyvinyl alcohol and boric acid in the water phase of the droplets of the monodisperse water-in-oil emulsion in the alkaline environment provided by sodium hydroxide in the collection liquid, and after sufficient polymerization reaction, the monodisperse water-in-oil emulsion is converted into the monodisperse boric acid crosslinked polyvinyl alcohol embolic microsphere. The method adopts emulsion polymerization, the initiator and the cross-linking agent are difficult to completely clean, and the prepared embolism microsphere has low drug loading rate due to insufficient micropore porosity, poor microsphere mechanical property and the like.
The publication No. CN113797383A is to synthesize modified polyvinyl alcohol derivative, and the chemical reaction is carried out on the hydroxyl on the polyvinyl alcohol macromolecular chain by a ring-forming grafting agent to form a macromolecular hydrogel structure containing a stable six-membered ring and a functional side group containing double bonds, so as to obtain the modified polyvinyl alcohol derivative. The reaction system is divided into a dispersed phase and a continuous phase, wherein the dispersed phase consists of a modified polyvinyl alcohol derivative, a double-bond-containing micromolecule bridging agent, an ionic crosslinking agent and a first initiator; and the continuous phase consists of an oil-soluble solvent, a surfactant and a second initiator, the dispersed phase is dispersed in the continuous phase through a dispersing device, and the embolism particles are prepared through fluid shear force.
The publication No. CN112920450A discloses a preparation method of a drug-loaded porous polyvinyl alcohol embolization microsphere, which comprises the steps of adding an emulsifier into a continuous phase, uniformly stirring to obtain an oil phase, and then adding an aqueous solution dissolved with polyvinyl alcohol into the oil phase to obtain a water-in-oil emulsion; dripping the water-in-oil emulsion into a precooled organic solvent, cooling to obtain polyvinyl alcohol microspheres completely frozen into a solid state, and removing the organic solvent, and then sequentially dehydrating and cleaning the polyvinyl alcohol microspheres; adding the cleaned polyvinyl alcohol microspheres into a cross-linking agent for cross-linking, adding a catalyst, soaking a cross-linked product into glycine or lysine, taking out and cleaning to obtain cross-linked polyvinyl alcohol microspheres; soaking the crosslinked polyvinyl alcohol microspheres in deionized water to fully swell the crosslinked polyvinyl alcohol microspheres to obtain a polyvinyl alcohol microsphere suspension; adding a monomer containing vinyl and sulfonic groups or a monomer containing carboxyl into the polyvinyl alcohol microsphere suspension, adding an initiator, carrying out graft polymerization in a protective gas atmosphere, centrifuging and cleaning after polymerization is finished to obtain the polyvinyl alcohol microspheres grafted with sulfonic groups or grafted with carboxyl groups.
The No. CN109289081B discloses a preparation method of an anti-adhesion polyvinyl alcohol embolism microsphere, which comprises the steps of preparing a polyvinyl alcohol and charged natural polymer blending solution and an anti-adhesion polyvinyl alcohol microsphere, dropwise adding the blending solution into an organic dispersion phase of an emulsifier, adding diethyl ether, glutaraldehyde and hydrochloric acid, heating to 40-75 ℃, continuing to react for 3-8 h to crosslink and solidify into a microsphere, removing residual glutaraldehyde in the microsphere, and obtaining the anti-adhesion polyvinyl alcohol microsphere through centrifugal separation, washing and freeze drying;
the preparation method of the self-developing embolism microsphere with the authorization number of CN108114308B and high density elements comprises the steps of initiating biocompatible functionalized macromolecules through acetal/aldehyde/carboxylic acid of a cross-linking agent alkyl olefine acid derivative and sulfonic acid/carboxylic acid/sulfonate/carboxylate of the cross-linking agent alkyl olefine acid derivative through an initiator persulfate or persulfate and tetramethyl ethylene diamine, carrying out free radical reverse suspension polymerization crosslinking to form an intermediate of hydrogel, and then reacting with a compound with high density elements to prepare the self-developing embolism microsphere with the high density elements.
The preparation method of the polysaccharide-polyvinyl alcohol embolism microsphere with the authorization number of CN105148327B comprises the steps of preparing a blending liquid, emulsifying and crosslinking: the prepared aqueous blending liquid is divided into two parts, one part is the blending liquid for crosslinking and emulsification, and the other part is for standby. And dripping the cross-linking emulsion blend into an emulsifier and a dispersant, uniformly stirring, adding a cross-linking agent, injecting the standby blend into the cross-linking emulsion blend after cross-linking to form a cross-linking and uncross-linking particle blend solution, dripping isopropanol according to volume percentage, repeatedly washing, and drying to obtain the polysaccharide-polyvinyl alcohol embolism microsphere.
A preparation method of polyvinyl alcohol embolism microsphere with the authorization number of CN104857576B comprises the steps of preparing a premixed solution of a polyvinyl alcohol aqueous solution and a cross-linking agent aqueous solution, and forming a discrete phase fluid by a catalyst aqueous solution; taking an organic solvent which is not mutually soluble with water as a continuous phase fluid, wherein the continuous phase fluid contains or does not contain a surfactant; and respectively pumping the discrete phase fluid and the continuous phase fluid into respective channels at respective constant flow rates, generating droplets with uniform particle size and controllable size at the intersection of the discrete phase fluid and the continuous phase fluid, further performing crosslinking reaction on polyvinyl alcohol, a crosslinking agent and a catalyst contained in the droplets, and completely curing to obtain crosslinked polyvinyl alcohol particles.
The microspheres prepared by the technical scheme disclosed above are basically chemically modified by introducing various chemical substances in the process of preparing the microspheres, or chemically reacted by crosslinking, modifying and the like in the process of emulsion polymerization. In order to obtain microspheres with better mechanical properties, polyvinyl alcohol with larger molecular weight is often used, the viscosity of the polyvinyl alcohol is larger, crosslinking modification is carried out in a water-in-oil system, and emulsion particles are easy to adhere. Therefore, the prior art has the problems of low yield, long production period, unstable microsphere size, complex production process, difficult removal of residual chemical substances, insufficient micropore porosity of the microspheres and the like. These problems lead to complicated processing techniques such as production and post-cleaning, while greatly increasing the cytotoxicity of the embolic particles. The product also has the problems that the drug-loading rate of the polyvinyl alcohol embolism microsphere is still lower, and the release of the chemotherapeutic drug in the blood vessel is quicker, so that the retention time of the drug in the target tumor tissue is short, the size of the microsphere cannot be accurately regulated and controlled, the target blood vessel cannot be completely embolized, and the clinical curative effect of the drug-loading microsphere embolization agent is greatly reduced by the factors.
Disclosure of Invention
The invention aims to provide a method for preparing polyvinyl alcohol porous embolism microspheres, which aims to solve the problems in the background technology.
In order to solve the technical problems, the invention provides the following technical scheme: a method for preparing polyvinyl alcohol porous embolism microsphere comprises the following steps:
a: preparation of the dispersed phase
Adding 300ml of alcohol with the volume concentration of 50-95%, 5-50g of polyvinyl alcohol modifier, 0.5-20 g of carbomer and 0-3g of surfactant with the HLB value of 8-18 into a 1000ml beaker, and fully stirring, dissolving and dispersing for 30-300min to obtain a dispersion phase A;
b: preparation of microsphere colloidal particles
Under the condition of stirring, slowly adding 200-600ml of oil phase B into the oil phase A to form an oil-in-water system, wherein the system gradually changes from a relatively transparent state to a turbid state along with the increase of the oil phase B to obtain microsphere adhesive droplets dispersed in the water-in-oil system;
c: curing treatment of microsphere colloidal particles
Preparing 50-200ml of alkaline distilled water with the pH value of 8.0-10.5, slowly adding the alkaline distilled water into the step b under the stirring state, and along with the increase of the adding amount, allowing microsphere liquid drops dispersed in the system to be in contact or collision with the water liquid drops, separating out polyvinyl alcohol modified substances in the microsphere liquid drops from pore-forming colloid due to the reduction of the solubility property, forming white microspheres, and changing the system from a turbid state to a milky color;
with the continuous increase of the amount of alkaline distilled water and the prolongation of time, the polyvinyl alcohol modified substance is completely precipitated and solidified and formed, the system is further subjected to phase transition from a water-in-oil system to an oil-in-water system, the microspheres are completely shaped and suspended in the water phase at the moment, then 200-600ml of distilled water is added, and the stirring is continued for 30-60 min;
d: treatment of porous microspheres
Standing the system obtained in the step c for 30-300min, layering the system, recovering an upper oil phase, filtering a lower water phase, soaking in water, and cleaning for 10-30min each time for 3-5 times by using ultrasonic waves;
e: post-processing treatment
Putting the microspheres subjected to the porous washing treatment in the step d into an oven, drying for 3-8 hours at the temperature of 45-65 ℃, and then grading, assembling, packaging and sterilizing to obtain the porous embolism microspheres.
Preferably, the polyvinyl alcohol modified substance contains carboxyl in the side chain, and is one or more of polyvinyl glyoxylic acid, polyvinyl formal, polyvinyl acetal, polyvinyl glyoxal, polyvinyl glutaraldehyde and the like, or a mixed acetal substance of the polyvinyl glyoxylic acid and the polyvinyl formal, the polyvinyl acetal substance is water-insoluble alcohol-soluble polyvinyl acetal substance, and the total acetalization degree is between 35% and 75%.
Preferably, 5 to 50g of complete alcoholysis type polyvinyl alcohol with the average polymerization degree of 1000-2600-one-vinyl alcohol is added into 300g of water, the mixture is heated to 90 to 98 ℃ and stirred until the mixture is completely dissolved, hydrochloric acid or sulfuric acid is used for adjusting the pH value to be less than 2, 0.1 to 10g of glyoxylic acid, 0.5 to 15g of formaldehyde, 0 to 10g of acetaldehyde and 0 to 5g of glyoxal are dropwise added while stirring, the mixture is kept at the temperature of between 60 and 90 ℃ and reacts for 0.5 to 5 hours, the acetalization degree of the mixture is controlled to be between 30 and 60 percent, and when colloid is separated out from the water, calcium hydroxide or sodium hydroxide solution is dropwise added to neutralize the pH value of the system to be neutral;
repeatedly cleaning the product for 3-5 times by using 20-60% alcohol solution in a heating and cooling manner to obtain water-insoluble polyvinyl acetal;
the mass fraction of acetal is adjusted to be between 3.5 percent and 15 percent by alcohol solution, and the polyvinyl alcohol modified substance with side chain containing carboxyl is obtained.
Preferably, the polyvinyl alcohol modifier is polyvinyl formal sponge prepared by a gas foaming process or polyvinyl formal sponge produced by a starch filling pore-forming process.
Preferably, the polyvinyl alcohol-modified product is a polyvinyl formal resin or a polyvinyl formal acetal resin, and is obtained by further acetalizing glyoxylic acid under acidic conditions.
Preferably, the preparation steps of the polyvinyl alcohol modified product are as follows: taking 10g of polyvinyl acetal sponge or polyvinyl acetal resin, dispersing and soaking in 200ml of water, adjusting the pH to be less than 2, adding 0.1-3g of glyoxylic acid, reacting at 45-80 ℃ for 3-5 hours, taking out, cleaning and drying to obtain the polyvinyl acetal sponge or polyvinyl acetal resin.
Preferably, the polyvinyl alcohol is a complete alcoholysis type polyvinyl alcohol with the polymerization degree of 1000 to 2000.
Preferably, the polyvinyl alcohol modifier is polyvinyl acetal mixed aldehyde.
Furthermore, the pore-forming agent comprises at least one of sodium carboxymethylcellulose, sodium polyacrylate, carbomer and polyethylene glycol; the surfactant comprises anionic and nonionic surfactant, preferably polyoxyethylene ether nonionic surfactant; the oil phase is water insoluble and alcohol insoluble organic matter, preferably liquid paraffin.
A medical appliance containing polyvinyl alcohol porous embolism microsphere, the medical appliance comprises the polyvinyl alcohol porous embolism microsphere.
Compared with the prior art, the invention has the beneficial effects that:
1. firstly, polyvinyl alcohol is intensively modified by a chemical method, then microspheres are prepared by a physical method, and by utilizing the principle that polyvinyl alcohol modified substances have different solubilities in alcohol with different concentrations, colloidal droplets are emulsified by a phase conversion method, then the droplets are solidified and formed by combining methods of phase separation and solvent replacement, and finally, the porous structure is obtained by using solvent replacement and colloidal pore-forming. The technical scheme of the invention is obviously different from the traditional method for preparing the microspheres through emulsion polymerization or emulsion crosslinking reaction, so that the product of the invention has small chemical residue, and is simple and convenient.
2. The polyvinyl alcohol is subjected to glyoxylic acid condensation to obtain a carboxyl group with a side chain carrying negative charges, so that the interaction with a cationic drug is facilitated, and the drug slow-release time is prolonged.
3. In addition, the prepared porous microspheres have smooth surfaces, high dimensional stability and small surface friction; and the microporous structure is favorable for rapid drug permeation and drug loading increase, the surface layer can be partially gelated and swelled after imbibing, the mechanical property is stable, and the drug slow release time is long.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. 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.
The embodiment provides a method for preparing polyvinyl alcohol porous embolism microspheres, which comprises the following steps:
preparation of the dispersed phase
Adding 300ml of 60% alcohol, 50g of polyvinyl alcohol modifier, 0.5g of carbomer and 0.5g of peregal O25 into a 1000ml beaker, heating to 60 ℃, and fully stirring, dissolving and dispersing for 30min to obtain a dispersion phase A.
Carbomer is used as a pore-forming agent in this embodiment, and may be replaced with one or more of sodium carboxymethylcellulose, sodium polyacrylate, carbomer, polyethylene glycol, and the like.
The peregal O25 is used as a surfactant, and the surfactant in this example includes anionic and nonionic surfactants, preferably polyoxyethylene ether nonionic surfactants.
Preparation of microsphere colloidal particles
The principle is to prepare microsphere glue drops by switching from an oil-in-water system to a water-in-oil system.
Under the stirring condition of 400rpm, 400ml of liquid paraffin is slowly added into the A to form an oil-in-water system firstly, and the system gradually changes from a relatively transparent state to a turbid state along with the increase of the oil phase B to obtain microsphere glue droplets dispersed in the water-in-oil system.
Liquid paraffin is used as oil phase B in the present invention, and oil phase B may be other water-insoluble and alcohol-insoluble organic substances.
And (3) carrying out setting treatment on the microsphere glue drops, and separating out and forming polyvinyl alcohol modified substances in the microsphere glue drops by a physical method. 200ml of alkaline distilled water with the pH value of 10.5 is prepared and is slowly added into the microsphere glue drops in the step under the stirring state. With the increase of the adding amount, the microsphere liquid drops dispersed in the system contact or collide with the water liquid drops, and the polyvinyl alcohol modifier in the microsphere liquid drops is separated out from the carbomer colloid due to the reduction of the solubility property to form white microspheres, so that the system is changed into milky white from turbid. With the increase of the amount of alkaline distilled water and the extension of time, the polyvinyl alcohol modified substance is completely precipitated and solidified and formed, the system is further subjected to phase transition from a water-in-oil system to an oil-in-water system, the microspheres are completely shaped and suspended in the water phase at the moment, 500ml of distilled water is added, and the stirring is continued for 30-60 min.
The method comprises the following steps of performing pure physical change, namely, adding water to separate the polyvinyl alcohol modifier from carbomer to obtain microspheres by utilizing the physical characteristics of different dissolving properties of the polyvinyl alcohol modifier in the glue drops in alcohol-water mixed liquor in different proportion ranges, and completely separating out and shaping the polyvinyl alcohol modifier microspheres from the glue drops. The carbomer is embedded in the polyvinyl alcohol modifier microspheres in a colloid form because of good solubility in water and alcohol solution.
Carbomer is also called carbomer, is a high molecular polymer obtained by crosslinking pentaerythritol and the like with acrylic acid, is a very important rheology regulator, is an excellent gel matrix after alkali neutralization, has important purposes of thickening, suspending and the like, and is soluble in water and an alcohol-water system.
Treatment of porous microspheres
Standing the system obtained in the steps for 90min, layering the system, recovering the upper oil phase, filtering the lower water phase, soaking the filtered lower water phase in water, and cleaning the lower water phase by using ultrasonic waves for 3-5 times, wherein each time lasts for 10-30min, on one hand, residual alcohol in the solid microspheres is continuously replaced with water to enable the strength of the microspheres to tend to be stable, and on the other hand, carbomer glue embedded in the microspheres is gradually squeezed and cleaned to enable the microspheres to show a porous structure.
Post-processing treatment: placing the microspheres subjected to porous washing treatment into an oven, drying for 3-8 hours at 65 ℃, and then carrying out grading, assembling, packaging and sterilization to obtain the porous embolism microspheres.
The invention utilizes the characteristics of a plurality of high polymer materials of alcohol-soluble water-insoluble, water-soluble alcohol-insoluble and limited miscibility in alcohol water, prepares modified polyvinyl alcohol microspheres with uniform particle size by using a phase inversion-based method through a prepared polyvinyl alcohol modifier in advance and skillfully utilizing the process of oil-in-water-in-oil-water-oil-in-water according to the physical performance characteristics of a modified polyvinyl alcohol high polymer system.
The porous microspheres prepared by the method have smooth surfaces, high dimensional stability and small surface friction; the present invention has microporous structure, and is favorable to fast medicine permeation and increased medicine carrying amount, and the surface layer after imbibing liquid may be partially gelated and swelled, and has stable mechanical performance, long medicine slow releasing time, high efficiency and capacity of raising yield.
The preparation process of the microsphere adopts the principle that polyvinyl alcohol modified substances have different solubilities in alcohol with different concentrations, firstly emulsifies the polyvinyl alcohol modified substances into droplets by a phase conversion method, solidifies and molds the droplets by combining a phase separation method and a solvent replacement method, and obtains a porous structure by using the solvent replacement method and colloid pore-forming method, and the processes are equal physical change processes.
The phase inversion method is one of the more effective methods for preparing polymer emulsion, and originally refers to the process of mutual inversion of continuous phases in a multi-component system under certain conditions, such as in an oil-in-water system, the continuous phase is converted from an aqueous phase to an oil phase, or in a water-in-oil system, the continuous phase is converted from an oil phase to an aqueous phase, in the phase conversion region, the interfacial tension of the system is the lowest, and the shearing force required for preparing the same particle size is the smallest, so that microspheres with smaller particle size can be obtained more easily.
In this embodiment, the side chain of the polyvinyl alcohol modified substance contains carboxyl, and is one or more of polyvinyl glyoxylic acid, polyvinyl formal, polyvinyl acetal, polyvinyl glyoxal, polyvinyl glutaraldehyde and the like, or a mixed acetal of the above substances, and is a water-insoluble alcohol-soluble polyvinyl acetal, and the total acetalization degree is between 35% and 75%. The polyvinyl alcohol modifier is prepared by the following steps:
adding 5-50g of complete alcoholysis type polyvinyl alcohol with average polymerization degree of 1000-2600-one-ion in 300g of water, heating to 90-98 ℃, stirring until the polyvinyl alcohol is completely dissolved, adjusting the pH value to be less than 2 by using hydrochloric acid or sulfuric acid, dropwise adding 0.1-10g of glyoxylic acid, 0.5-15g of formaldehyde, 0-10g of acetaldehyde and 0-5g of glyoxal while stirring, keeping the temperature at 60-90 ℃ for reaction for 0.5-5 hours, controlling the acetalization degree to be between 30-60%, and dropwise adding a calcium hydroxide or sodium hydroxide solution to neutralize the pH value of the system to be neutral when colloid is separated out from the water. Repeatedly cleaning the product for 3-5 times by using 20-60% alcohol solution in a heating and cooling manner to obtain water-insoluble polyvinyl acetal; the mass fraction of acetal is adjusted to be between 3.5 percent and 15 percent by alcohol solution, and the polyvinyl alcohol modified substance with side chain containing carboxyl is obtained.
Preferably, the polyvinyl alcohol is a complete alcoholysis type polyvinyl alcohol with the polymerization degree of 1000 to 2000.
Preferably, the polyvinyl alcohol modified substance is polyvinyl acetal mixed aldehyde, preferably glyoxylic acid and formal, can be mixed aldehyde of polyvinyl alcohol and glyoxylic acid and formaldehyde, and can also be polyvinyl alcohol which is firstly formal and then reacts with glyoxylic acid; or polyvinyl alcohol is firstly condensed with glyoxylic acid and then reacts with formaldehyde. Preferably the overall acetalization degree is between 45% and 65%.
Polyvinyl alcohol-modified products, particularly polyvinyl acetal-modified products, exhibit different solubility properties depending on the kind of acetal and the degree of acetal. The water-insoluble polyvinyl alcohol modified resin refers to the polyvinyl alcohol modified resin with different performances which can be obtained according to the different types and reaction degrees of the modified groups and can be dissolved in an alcohol aqueous solution, wherein in the process of substituting the hydroxyl group of the side chain of the polyvinyl alcohol by other groups, the water solubility of the product is reduced along with the improvement of the reaction degree, so that the product is separated out from the water. The invention uses acetal or graft modified polyvinyl alcohol product, which is water insoluble, but can be dissolved in 50% -95% ethanol solution, and has certain surface activity after being dissolved.
The polyvinyl alcohol modifier can also be polyvinyl formal sponge prepared by a gas foaming process, or polyvinyl formal sponge produced by a starch filled pore-forming process, or a product obtained by further performing an acetalization reaction with glyoxylic acid under an acidic condition by using a commercially available polyvinyl formal resin or polyvinyl formal acetal resin. The preparation method comprises the following steps: taking 10g of polyvinyl acetal sponge or polyvinyl acetal resin, dispersing and soaking in 200ml of water, adjusting the pH to be less than 2, adding 0.1-3g of glyoxylic acid, reacting at 45-80 ℃ for 3-5 hours, taking out, cleaning and drying to obtain the polyvinyl acetal sponge or polyvinyl acetal resin.
In this embodiment, polyvinyl alcohol is modified by a chemical method to obtain a polyvinyl alcohol modified substance constituting the polyvinyl alcohol porous embolization microsphere, and then the polyvinyl alcohol modified substance microsphere is prepared by a physical method.
The polyvinyl alcohol porous embolism microsphere can be made into various medical appliances.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A method for preparing polyvinyl alcohol porous embolism microsphere is characterized by comprising the following steps:
a: preparation of the dispersed phase
Adding 300ml of 35-95% alcohol by volume concentration, 5-50g of polyvinyl alcohol modifier, 0.5-20 g of pore-forming agent and 0-3g of surfactant with HLB value between 8 and 18 into a 1000ml beaker, and fully stirring, dissolving and dispersing for 30-300min to obtain a dispersion phase A;
b: preparation of microsphere colloidal particles
Under the condition of stirring, slowly adding 200-600ml of oil phase B into the oil phase A to form an oil-in-water system, wherein the system gradually changes from a relatively transparent state to a turbid state along with the increase of the oil phase B to obtain microsphere adhesive droplets dispersed in the water-in-oil system;
c: curing treatment of microsphere colloidal particles
Preparing 50-200ml of alkaline distilled water with the pH value of 8.0-10.5, slowly adding the alkaline distilled water into the step b under the stirring state, and along with the increase of the adding amount, the microsphere liquid drops dispersed in the system are contacted or collided with the water liquid drops, and polyvinyl alcohol modifiers in the microsphere liquid drops are separated out from the pore-forming agent colloid due to the reduction of the solubility property to form white microspheres, wherein the system is changed into milk white from turbid;
with the continuous increase of the amount of alkaline distilled water and the extension of time, the polyvinyl alcohol modifier is completely separated out and solidified and formed, the system is further subjected to phase transition from a water-in-oil system to an oil-in-water system, the microspheres are completely shaped and suspended in the water phase at the moment, then 200-600ml of distilled water is added, and the stirring is continued for 30-60 min;
d: porous treatment of microspheres
Standing the system obtained in the step c for 30-300min, layering the system, recovering an upper oil phase, filtering a lower water phase, soaking in water, and cleaning for 10-30min each time for 3-5 times by using ultrasonic waves;
e: post processing treatment
And d, putting the microspheres subjected to the porous washing treatment in the step d into an oven, drying for 3-8 hours at the temperature of 45-65 ℃, and then grading, matching, packaging and sterilizing to obtain the porous embolism microspheres.
2. The method for preparing porous embolism microsphere of polyvinyl alcohol in accordance with claim 1, wherein: the polyvinyl alcohol modified substance contains carboxyl in the side chain of the molecule, is one or more of polyvinyl glyoxylic acid and polyvinyl formal, polyvinyl acetal, polyvinyl glyoxal, polyvinyl glutaraldehyde and the like, or is a mixed acetal substance of the polyvinyl glyoxylic acid and the polyvinyl formal, is a water-insoluble alcohol-soluble polyvinyl acetal substance, and has the total acetalization degree of between 35 and 75 percent.
3. The method for preparing porous embolism microsphere with polyvinyl alcohol as claimed in claim 1 or 2, wherein the polyvinyl alcohol modifier is prepared by the following steps:
adding 5-50g of complete alcoholysis type polyvinyl alcohol with average polymerization degree of 1000-2600-one-ion in 300g of water, heating to 90-98 ℃, stirring until the polyvinyl alcohol is completely dissolved, adjusting the pH value to be less than 2 by using hydrochloric acid or sulfuric acid, dropwise adding 0.1-10g of glyoxylic acid, 0.5-15g of formaldehyde, 0-10g of acetaldehyde and 0-5g of glyoxal while stirring, keeping the temperature at 60-90 ℃ for reaction for 0.5-5 hours, controlling the acetalization degree to be between 30-60%, and dropwise adding a calcium hydroxide or sodium hydroxide solution to neutralize the pH value of the system to be neutral when colloid is separated out from the water;
repeatedly cleaning the product for 3-5 times by using 20-60% alcohol solution in a heating and cooling manner to obtain water-insoluble polyvinyl acetal;
the mass fraction of acetal is adjusted to be between 3.5 percent and 15 percent by alcohol solution, and the polyvinyl alcohol modified substance with side chain containing carboxyl is obtained.
4. The method for preparing porous embolism microsphere of polyvinyl alcohol in accordance with claim 1 or 2, wherein the polyvinyl alcohol modifier is polyvinyl formal sponge prepared by gas foaming process or polyvinyl formal sponge prepared by starch-filled pore-forming process.
5. The method for preparing porous embolism microsphere of polyvinyl alcohol in accordance with claim 1 or 2, wherein the polyvinyl alcohol modifier is polyvinyl formal resin or polyvinyl formal acetal resin, which is obtained by further acetalization with glyoxylic acid under acidic condition.
6. The method for preparing porous embolism microsphere with polyvinyl alcohol according to claim 5, wherein the polyvinyl alcohol modifier is prepared by the following steps: taking 10g of polyvinyl acetal sponge or polyvinyl acetal resin, dispersing and soaking in 200ml of water, adjusting the pH to be less than 2, adding 0.1-3g of glyoxylic acid, reacting at 45-80 ℃ for 3-5 hours, taking out, cleaning and drying to obtain the polyvinyl acetal sponge or polyvinyl acetal resin.
7. The method for preparing porous embolism microsphere of polyvinyl alcohol in accordance with claim 3, wherein: the polyvinyl alcohol is completely alcoholysis type polyvinyl alcohol with the polymerization degree of 1000-2000.
8. The method for preparing porous embolism microsphere of polyvinyl alcohol according to claim 2, characterized in that: the polyvinyl alcohol modifier is polyvinyl acetal mixed aldehyde.
9. The method for preparing porous embolism microsphere of polyvinyl alcohol in accordance with claim 2, wherein: the pore-forming agent comprises at least one of sodium carboxymethylcellulose, sodium polyacrylate, carbomer and polyethylene glycol; the surfactant comprises anionic and nonionic surfactant, and oil phase B is water insoluble and alcohol insoluble organic matter.
10. A medical device containing polyvinyl alcohol porous embolism microsphere is characterized in that: the medical device comprising the porous embolizing microspheres of the polyvinyl alcohol type according to claim 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20100065500A1 (en) * | 2006-12-01 | 2010-03-18 | Institute of Process Engineering, Chinese Academy of Science | Super-macroporous polymeric microspheres and preparation method thereof |
| CN103977458A (en) * | 2014-05-28 | 2014-08-13 | 南京弗来明医疗器械有限公司 | Polyhydroxyl polymer embolized microsphere and preparation process thereof |
| CN113801367A (en) * | 2021-09-17 | 2021-12-17 | 苏州永沁泉智能设备有限公司 | Porous hydrogel microsphere and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20100065500A1 (en) * | 2006-12-01 | 2010-03-18 | Institute of Process Engineering, Chinese Academy of Science | Super-macroporous polymeric microspheres and preparation method thereof |
| CN103977458A (en) * | 2014-05-28 | 2014-08-13 | 南京弗来明医疗器械有限公司 | Polyhydroxyl polymer embolized microsphere and preparation process thereof |
| CN113801367A (en) * | 2021-09-17 | 2021-12-17 | 苏州永沁泉智能设备有限公司 | Porous hydrogel microsphere and preparation method thereof |
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