CN116159178B - Small-particle-size embolism microsphere and preparation method thereof - Google Patents
Small-particle-size embolism microsphere and preparation method thereof Download PDFInfo
- Publication number
- CN116159178B CN116159178B CN202310409122.5A CN202310409122A CN116159178B CN 116159178 B CN116159178 B CN 116159178B CN 202310409122 A CN202310409122 A CN 202310409122A CN 116159178 B CN116159178 B CN 116159178B
- Authority
- CN
- China
- Prior art keywords
- polyvinyl alcohol
- microsphere
- reaction
- particle size
- embolic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
-
- 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
Abstract
The invention relates to small-particle-size embolic microspheres with narrow particle size distribution range and a preparation method thereof, belonging to the technical field of medical materials. The method comprises the following steps: adding water-soluble molecules containing unsaturated bonds and aldehyde or acetal structures and a first catalyst into a polyvinyl alcohol aqueous solution to react to prepare a polyvinyl alcohol embolism microsphere intermediate; adding the intermediate of the polyvinyl alcohol embolism microsphere, the cross-linking agent and the initiator into water for dissolution, then adding the solvent and the surfactant, and then stirring/uniformly mixing the mixture under inert gas atmosphere by using a homogenizing device for reaction; washing after the reaction is finished to obtain polyvinyl alcohol embolism microspheres; dissolving C3-C6 linear aldehyde in a solvent, adding polyvinyl alcohol embolism microsphere and a second catalyst, stirring for reaction, and cleaning after the reaction is finished to obtain the polyvinyl alcohol embolism microsphere with small particle size. The microsphere prepared by the invention has the particle size range of 5-40 microns, can be used for finer capillary embolism, and has the advantages of high drug carrying speed and longer drug release.
Description
Technical Field
The invention relates to a drug-loaded embolic microsphere, in particular to a small-particle-size embolic microsphere with a narrow particle size distribution range, and belongs to the technical field of medical materials.
Background
Interventional embolization has played an increasingly important role in clinical medicine in recent years, particularly in the treatment of tumors rich in blood vessels, such as liver cancer, and has become the first choice for the treatment of tumors that cannot be surgically resected. The drug-loaded embolic microsphere is one of the most common embolic carriers at present, and is paid more attention to the advantages of high targeting property to specific tissues and organs, good embolization, combination with chemotherapeutics, slow release of drugs and the like. The existing commercially available microspheres (such as DC Bead, callosphere and the like) have smooth surfaces, good elasticity and elasticity, good hydrophilicity and suspension property, are easy to guide along with blood flow, can block the whole section of blood vessels, can slowly release medicines at focus positions, maintain local effective medicine concentration for a long time, and generate remarkable cytotoxic effect on tumor cells.
Recent studies have shown that the use of embolic microspheres with small particle sizes (5-100 microns, especially 5-40 microns) can better embolize against capillaries at the target site, as the small size of these microspheres enables them to more precisely target the target vessel, which helps to increase the accuracy of embolization, and thus achieve better therapeutic results. However, the microsphere (such as the commercial microsphere) prepared by the prior art has the particle size range of 100-1000 microns, large particle size, wide particle size distribution and extremely low yield of small particle size microspheres, and the microsphere prepared by the method has the advantages of wide particle size range and nonuniform particle size, so that the drug loading speed of the microsphere is low, the embolism effect is poor, and the treatment of some tiny blood vessel parts is difficult.
Chinese patent CN114306724B discloses an embolism microsphere capable of slowly releasing medicine and a preparation method thereof, and the microsphere prepared by the method has good elasticity, medicine carrying property and slow release property, but has larger microsphere particle size, so that the application prospect is limited.
Chinese patent CN 106729953B describes a functional modified polyvinyl alcohol embolism microsphere and its preparation method, the microsphere can produce elastic deformation after modification and load antitumor drug. However, the embolic microsphere prepared by the method has the particle size range of 100-1000 microns, the microsphere has overlarge particle size and wide particle size distribution range, the microsphere is not fast enough to load the drug, the drug release speed is too fast, the embolic microsphere is inconvenient in clinical use, and local chemotherapy cannot be carried out in vivo for a long time.
CN 106902716B describes a preparation method of small-particle size starch microsphere, said method uses polyvinylpyrrolidone solution as continuous phase, soluble starch solution as disperse phase, adopts high-speed shearing emulsifying machine to make emulsification so as to form double-aqueous emulsion, then utilizes starch retrogradation characteristic to make the starch solution droplet solidified into ball so as to obtain the invented small-particle size starch microsphere whose median particle size is less than 10 micrometers. However, the method is used for preparing the starch microsphere, the viscosity of the reactant is low, and the prepared microsphere has obvious aggregation phenomenon and no elasticity. The viscosity of the reactant for preparing the polyvinyl alcohol embolism microsphere is high, the microsphere cannot have agglomeration phenomenon, and good elasticity is required, so the method cannot be used for preparing the embolism microsphere.
Therefore, there is a need in the art to develop drug-loaded embolic microspheres with small particle size and narrow distribution range.
Disclosure of Invention
In order to overcome the defects of large particle size and wide particle size range of the traditional drug-loaded embolism microsphere, the invention provides a polyvinyl alcohol embolism microsphere with small particle size and a preparation method thereof. The polyvinyl alcohol embolism microsphere provided by the invention has the advantages of 5-40 microns of particle size range, small particle size and narrow distribution range, can be used for finer capillary embolism, has a faster medicine carrying speed, can release medicine more permanently, has excellent elasticity, and is more rapid and efficient to use.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the preparation method of the small-particle-size embolic microsphere is characterized by comprising the following steps of:
s1: adding water-soluble molecules containing unsaturated bonds and aldehyde or acetal structures and a first catalyst into a polyvinyl alcohol aqueous solution for reaction, adjusting the pH of a reaction system to 7-9 after the reaction is finished, and concentrating the solution to obtain a polyvinyl alcohol embolism microsphere intermediate; the weight average molecular weight of the polyvinyl alcohol is 55000-70000g/mol;
s2: adding the intermediate of the polyvinyl alcohol embolism microsphere prepared in the step S1, a cross-linking agent and an initiator into water for dissolution, adding a solvent and a surfactant, and then stirring/uniformly mixing the mixture under inert gas atmosphere by using a homogenizing device for reaction; washing after the reaction is finished to obtain polyvinyl alcohol embolism microspheres;
s3: C3-C6 linear aldehyde is dissolved in a solvent, the polyvinyl alcohol embolism microsphere prepared in the step S2 and a second catalyst are added, stirring reaction is carried out, and cleaning is carried out after the reaction is finished, so that the small-particle-size polyvinyl alcohol embolism microsphere is obtained.
Further, the water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure is N- (2, 2-dimethoxyethyl) -2-acrylamide or 4-acrylamidobutyraldehyde dimethyl acetal.
Further, the first catalyst is an inorganic acid, preferably at least one of concentrated hydrochloric acid, concentrated nitric acid or perchloric acid.
Further, the cross-linking agent is sodium 2-acrylamide-2-methylpropanesulfonate or potassium 3-sulfopropyl acrylate.
Further, the initiator is at least one of V-50 (azodiisobutylamidine hydrochloride), potassium persulfate and sodium persulfate.
Further, the solvent in the step S2 is at least one of liquid paraffin, ethyl acetate or butyl acetate; the surfactant is at least one of Tween 80 or cellulose acetate butyrate; the second catalyst is an organic acid.
Further, the concentration of the polyvinyl alcohol aqueous solution in the step S1 is 0.15-0.25g/mL; the concentration of the water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure in the aqueous polyvinyl alcohol solution described in step S1 is 4 to 6mg/mL, preferably 5mg/mL; the concentration of the first catalyst in the polyvinyl alcohol aqueous solution is 52-72mg/mL, preferably 62mg/mL; the concentrated solution is a solution concentrated to a viscosity of 1500cps.
Further, the concentration of the polyvinyl alcohol aqueous solution is preferably 0.2g/mL; the weight average molecular weight of the polyvinyl alcohol is preferably 65000g/mol.
Further, the concentrations of the intermediate of the polyvinyl alcohol embolic microsphere, the cross-linking agent, the initiator, the water and the surfactant in the solvent in the step S2 are respectively 0.15-0.18g/mL,0.03-0.05g/mL,0.7-1.75mg/mL,0.09-0.17g/mL and 0.07-0.09g/mL; preferably, 0.17g/mL,0.04g/mL,1.2mg/mL,0.12g/mL,0.08g/mL, respectively.
Further, the reaction temperature in the step S1 is 10-35 ℃ and the reaction time is 3-8 hours; the reaction temperature in the step S2 is 40-55 ℃ and the reaction time is 1-2h; the step S3 is carried out at room temperature.
Further, in the step S2, the homogenizing apparatus is an ultrasonic homogenizer with power of 1.0kW and frequency of 20kHz.
Further, the concentration of the solution of the linear aldehyde dissolved in the solvent in the step S3 is 0.05-0.1g/mL; the solvent is at least one of dimethyl sulfoxide, butyl acetate, ethyl acetate, n-heptane or cyclohexane; the second catalyst is at least one of methane sulfonic acid or trichloroacetic acid, and the concentration of the second catalyst is 0.06-0.14g/mL of solvent, preferably 0.10g/mL, and preferably methane sulfonic acid; the linear aldehyde is n-butyraldehyde, propionaldehyde or n-valeraldehyde, preferably n-butyraldehyde.
Further, the linear aldehyde in step S3: the mass ratio of the polyvinyl alcohol embolism microsphere is (1-2): 1.
the invention further protects the small-particle-size polyvinyl alcohol embolism microsphere prepared by the method, and the particle size range of the microsphere is 5-40 microns.
The invention has the following beneficial effects:
1. according to the method, linear aldehyde is added to react with the microsphere, the microsphere macromolecules are modified by linear alkane, hydrophobic molecules are connected to the polyvinyl alcohol skeleton, and the hydrophobicity is increased, so that the water content of the microsphere is reduced; so that the water content of the microsphere containing a large amount of water is obviously reduced, and the particle size of the microsphere is further reduced.
2. The small-particle-size embolic microsphere prepared by the method has high yield, more than 90 percent of microspheres have particle sizes ranging from 5 to 40 microns, small particle sizes, narrow distribution range and uniform particle sizes.
3. The embolic microsphere has the advantages of higher drug carrying speed and slower release speed; wherein, the drug loading rate in 3 minutes can reach about 90 percent, and the release rate in 28 days can reach 58.5 percent at the lowest.
4. The embolic microsphere has good mechanical property and high elasticity; the minimum elastic modulus can reach 2.5 MPa.
Drawings
FIG. 1 is a photograph of a microsphere microscope prepared in example 1 of the present invention.
Detailed Description
The following describes in further detail the embodiments of the present invention with reference to the drawings and examples. The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Example 1
S1, adding 100g of polyvinyl alcohol with weight average molecular weight of 65000 into 500mL of purified water, dissolving at 80 ℃, adding 2.5g N- (2, 2-dimethoxyethyl) -2-acrylamide and 70mL of 37wt% concentrated hydrochloric acid (with concentration of 62.16 mg/mL), reacting at 25 ℃ for 4 hours, adjusting pH of a system to 7.2 by using sodium hydroxide solution after the reaction is finished, and concentrating to viscosity of 1500cps to obtain a polyvinyl alcohol embolism microsphere intermediate;
s2, 10.2g of the microsphere intermediate prepared in the step S1, 2.4g of 2-acrylamide-2-methylpropanesulfonic acid sodium salt and 0.07g of V-50 initiator are completely dissolved in 7.2mL of deionized water. Adding 60mL of liquid paraffin and 4.8g of Tween 80, stirring with an ultrasonic homogenizer (power 1.0kW, frequency 20 kHz) under helium atmosphere, reacting at 47 ℃ for 1.5h, and washing with ethyl acetate, acetone and deionized water after the reaction is finished to obtain polyvinyl alcohol embolism microspheres;
s3, adding 1g of microspheres into 20mL of dimethyl sulfoxide solution in which 1.5g of n-butyraldehyde is dissolved, adding 1.5mL of methanesulfonic acid (the concentration is 0.10 g/mL), stirring at room temperature, reacting for 30 minutes, and washing with ethanol and deionized water to obtain small-particle-size polyvinyl alcohol embolism microspheres.
The microscopic image (40 times magnification) of the drug-loaded embolic microsphere prepared in this example is shown in fig. 1, and most microspheres have a particle size ranging from 5 to 40 microns, small particle size and narrow particle size distribution.
Example 2
S1, adding 110g of polyvinyl alcohol with weight average molecular weight of 68000 into 500mL of purified water, dissolving at 80 ℃, adding 2.7g N- (2, 2-dimethoxyethyl) -2-acrylamide and 74mL 37wt% of concentrated hydrochloric acid (with concentration of 65.71 mg/mL), reacting at 25 ℃ for 4 hours, adjusting pH of a system to 7.4 by using sodium hydroxide solution after the reaction is finished, and concentrating to viscosity of 1500cps to obtain a polyvinyl alcohol embolism microsphere intermediate;
s2, 10.5g of the microsphere intermediate prepared in the step S1, 2.8g of 2-acrylamide-2-methylpropanesulfonic acid sodium salt and 0.08g of V-50 initiator are completely dissolved in 8.5mL of deionized water. Then 60mL of liquid paraffin and 5g of Tween 80 are added, finally, an ultrasonic homogenizer is used for stirring (the power is 1.0kW, the frequency is 20 kHz) under the helium atmosphere, the reaction is carried out for 1.5 hours at 50 ℃, and after the reaction is finished, ethyl acetate, acetone and deionized water are used for washing, so that the polyvinyl alcohol embolism microsphere is obtained.
S3, adding 1g of microspheres into 20mL of dimethyl sulfoxide solution in which 1.5g of n-butyraldehyde is dissolved, adding 1.5mL of methanesulfonic acid (the concentration is 0.10 g/mL), stirring at room temperature, reacting for 30 minutes, and washing with ethanol and deionized water to obtain small-particle-size polyvinyl alcohol embolism microspheres.
Example 3
S1, adding 125g of polyvinyl alcohol with a weight average molecular weight of 70000 into 500mL of purified water, dissolving at 80 ℃, adding 3g N- (2, 2-dimethoxyethyl) -2-acrylamide and 80mL of 37wt% concentrated hydrochloric acid (with a concentration of 71.04 mg/mL), reacting at 30 ℃ for 3 hours, adjusting the pH of a system to 7.6 by using sodium hydroxide solution after the reaction is finished, and concentrating to a viscosity of 1500cps to obtain a polyvinyl alcohol embolism microsphere intermediate;
s2, 10.8g of the microsphere intermediate prepared in the step S1, 3g of 2-acrylamide-2-methylpropanesulfonic acid sodium and 0.095g of V-50 initiator are completely dissolved in 10.2mL of deionized water. Then 60mL of liquid paraffin and 5.4g of Tween 80 are added, finally, an ultrasonic homogenizer is used for stirring (the power is 1.0kW, the frequency is 20 kHz) under the helium atmosphere, the reaction is carried out for 1h at 55 ℃, and after the reaction is finished, ethyl acetate, acetone and deionized water are used for washing, so that the polyvinyl alcohol embolism microsphere is obtained.
S3, adding 1g of microspheres into 20mL of n-heptane solution in which 1g of propionaldehyde is dissolved, adding 2mL of methanesulfonic acid (with the concentration of 0.135 g/mL), stirring at room temperature, reacting for 30 minutes, and washing with ethanol and deionized water after the reaction is finished to obtain the small-particle-size polyvinyl alcohol embolism microspheres.
Example 4
S1, adding 75g of polyvinyl alcohol with weight average molecular weight of 60000 into 500mL of purified water, dissolving at 80 ℃, adding 2g N- (2, 2-dimethoxyethyl) -2-acrylamide and 60mL of 37wt% concentrated hydrochloric acid (with concentration of 53.28 mg/mL), reacting at 15 ℃ for 6 hours, adjusting pH of a system to 7.5 by using sodium hydroxide solution after the reaction is finished, and concentrating to viscosity of 1500cps to obtain a polyvinyl alcohol embolism microsphere intermediate;
s2, 9g of the microsphere intermediate prepared in the step S1, 1.8g of 2-acrylamide-2-methylpropanesulfonic acid sodium and 0.042g of V-50 initiator are completely dissolved in 5.4mL of deionized water. Then 60mL of liquid paraffin and 4.2g of Tween 80 are added, finally, an ultrasonic homogenizer is used for stirring (the power is 1.0kW, the frequency is 20 kHz) in helium atmosphere, the reaction is carried out for 2 hours at 40 ℃, and after the reaction is finished, ethyl acetate, acetone and deionized water are used for washing, so that the polyvinyl alcohol embolism microsphere is obtained.
S3, adding 1g of microspheres into 20mL of cyclohexane solution in which 2g of n-valeraldehyde is dissolved, adding 1mL of methanesulfonic acid (the concentration is 0.0675 g/mL), stirring at room temperature, reacting for 30 minutes, and washing with ethanol and deionized water after the reaction is finished, thus obtaining the small-particle-size polyvinyl alcohol embolism microspheres.
Example 5
S1, adding 100g of polyvinyl alcohol with weight average molecular weight of 60000 into 500mL of purified water, dissolving at 80 ℃, adding 2.5g of 4-acrylamidobutyraldehyde dimethyl acetal and 31.6mL of 68wt% concentrated nitric acid (with concentration of 61.12 mg/mL), reacting at 25 ℃ for 4 hours, adjusting pH of a system to 7.2 by using sodium hydroxide solution after the reaction is finished, and concentrating to viscosity of 1500cps to obtain a polyvinyl alcohol embolism microsphere intermediate;
s2, 10.2g of the microsphere intermediate prepared in the step S1, 2.4g of 3-sulfopropyl potassium acrylate and 0.07g of potassium persulfate initiator are completely dissolved in 7.2mL of deionized water. 60mL of ethyl acetate and 4.8g of cellulose acetate butyrate (weight average molecular weight 65000 g/mol) are added, finally, an ultrasonic homogenizer is used for stirring (power 1.0kW, frequency 20 kHz) in a helium atmosphere, the reaction is carried out for 1.5 hours at 47 ℃, and after the reaction is finished, the polyvinyl alcohol embolism microsphere is obtained by washing with ethyl acetate, acetone and deionized water.
S3, adding 1g of microspheres into 20mL of cyclohexane solution in which 2g of n-hexanal is dissolved, adding 1.5mL of trichloroacetic acid (the concentration is 0.10 g/mL), stirring at room temperature, reacting for 30 minutes, and washing with ethanol and deionized water to obtain the small-particle-size polyvinyl alcohol embolism microspheres.
Example 6
S1, adding 110g of polyvinyl alcohol with weight average molecular weight of 60000 into 500mL of purified water, dissolving at 80 ℃, adding 2.7g of 4-acrylamidobutyraldehyde methylal and 60mL of 72wt% perchloric acid (with concentration of 61.12 mg/mL), reacting at 25 ℃ for 4 hours, adjusting pH of a system to 7.5 by using sodium hydroxide solution after the reaction is finished, and concentrating to viscosity of 1500cps to obtain a polyvinyl alcohol embolism microsphere intermediate;
s2, 10.5g of the microsphere intermediate prepared in the step S1, 2.8g of 3-sulfopropyl potassium acrylate and 0.08g of sodium persulfate initiator are completely dissolved in 8.5mL of deionized water. Then 60mL butyl acetate and 5g cellulose acetate butyrate (weight average molecular weight 65000 g/mol) are added, finally an ultrasonic homogenizer is used for stirring (power 1.0kW, frequency 20 kHz) in helium atmosphere, the reaction is carried out for 1.5 hours at 50 ℃, and after the reaction is finished, ethyl acetate, acetone and deionized water are used for washing, thus obtaining the polyvinyl alcohol embolism microsphere.
S3, adding 1g of microspheres into 20mL of dimethyl sulfoxide solution in which 1g of hexanal is dissolved, adding 1mL of trichloroacetic acid (the concentration is 0.0675 g/mL), stirring at room temperature, reacting for 30 minutes, and washing with ethanol and deionized water to obtain the small-particle-size polyvinyl alcohol embolism microspheres.
Comparative example 1
As compared with preparation example 1, a polyvinyl alcohol having a weight average molecular weight of 100000g/mol was used, and the other conditions were not changed.
Comparative example 2
In comparison with preparation example 1, mechanical stirring was used instead of an ultrasonic homogenizer, and the other conditions were not changed.
Comparative example 3
In comparison with preparation example 1, n-octanal was used instead of n-butyraldehyde, and the other conditions were not changed.
Comparative example 4
In comparison with preparation 1, no linear aldehyde was added in step 3, and the other conditions were not changed.
Comparative example 5
In comparison with preparation example 1, isobutyraldehyde was used instead of n-butyraldehyde, and the other conditions were not changed.
Test example 1
Small particle size microsphere yield test: and screening the microspheres obtained by the experiment, and calculating the proportion of the weight of the microspheres in the particle size range of 5-40 microns to the total weight. The results are shown in Table 1.
Table 1 comparison of yields of small particle size microspheres from different methods
As can be seen from the data in Table 1, the embolic microspheres prepared in examples 1-6 have a particle size range of 90% or more between 5-40 microns, and the small particle size microspheres yield is significantly higher than that of the small particle size microspheres prepared in comparative examples 1, 2, 4, 5. Comparative example 3 was similar to examples 1-6, and also used a linear aldehyde, and the yield of small particle size microspheres was 97%.
The shear force provided by mechanical agitation is relatively smaller, resulting in larger produced microsphere sizes and a broader particle size distribution, relative to an ultrasonic homogenizer, such that the target particle size (5-40 microns) microsphere yields are low.
Test example 2
Elastic modulus test: placing the polyvinyl alcohol embolism microsphere into a nanoindentation instrument, compressing the microsphere at a rate of 1% of strain amount per second in a compression mode, calculating the elastic modulus of the microsphere according to the data, and repeating 5 spheres to obtain an average value. The test results are shown in Table 2.
Table 2 comparison of elastic modulus for different methods
As can be seen from the data in Table 2, the polyvinyl alcohol embolic microspheres prepared in examples 1-6 have extremely low elastic modulus and good compression set properties; in particular, example 1, the microspheres had an elastic modulus of only 2.5 MPa and had very excellent compression set properties. In comparative example 1, the elastic modulus of the microspheres is too high and the compression set performance is poor due to the use of polyvinyl alcohol with too high molecular weight and the use of n-octanal with too long carbon chain in comparative example 3.
The weight average molecular weight of the polyvinyl alcohol affects the degree of crosslinking of the microspheres, thereby affecting the particle size and elasticity of the microspheres. The larger the molecular weight of the polyvinyl alcohol, the longer the molecular chain, the higher the crosslinking degree of the microsphere, the lower the water content, the smaller the particle size and the larger the elastic modulus.
Test example 3
Drug loading rate test: taking embolic microspheres, removing water on the surfaces of the microspheres, weighing 1g of microspheres into a penicillin bottle, adding 4mL of 20 mg/mL doxorubicin hydrochloride aqueous solution, sealing the penicillin bottle, placing the penicillin bottle on a flat-plate oscillator for oscillation at 180 rpm, and respectively sucking 10 μl of sample after 3 minutes and diluting to 2 mL. The concentration of doxorubicin hydrochloride solution was measured at 480nm using an ultraviolet spectrophotometer, and the drug adsorption amount and drug loading rate of the embolic microspheres were calculated for 3 minutes, and the test results are shown in table 3.
Table 3 comparison of 3 min drug loading rates for different microspheres
As can be seen from the data in Table 3, the polyvinyl alcohol embolic microspheres prepared in examples 1-6 have extremely high amounts of chemotherapeutic drugs that can be loaded in the same time, and provide great convenience in clinical use.
Test example 4
Drug release rate test: taking 1g of microspheres loaded with doxorubicin, adding 1000mLPBS into a dissolution instrument cup, placing the microspheres into a dissolution instrument rotating basket, mounting the rotating basket on a dissolution rod, setting the rotating speed of the dissolution instrument to be 100 rpm, starting the instrument and starting timing. At three prescribed time points, 1 day, 7 days and 28 days, about 2mL release medium was pipetted into a clean 10 mL penicillin bottle and poured back into the dissolution cup where the sample was located after the test was completed. At the time point of medium replacement, the dissolution instrument is paused to rotate and the dissolution cup is taken out, the old medium in the cup is discarded, the dissolution cup is rinsed with purified water and reinstalled, then 1000mL of PBS is measured by a measuring cylinder to the dissolution cup as a new release medium, and the dissolution instrument is restarted. The concentration of doxorubicin in the dissolved samples was measured at 480nm using an ultraviolet spectrophotometer, and the sampling time points and results were clearly recorded. The test results are shown in Table 4.
TABLE 4 comparison of drug release rates for different microspheres
As can be seen from the data in Table 4, the polyvinyl alcohol embolic microspheres prepared in examples 1-6 released chemotherapeutic agents for a longer duration, and may have a longer-acting local chemotherapeutic effect.
Claims (14)
1. The preparation method of the small-particle-size embolic microsphere is characterized by comprising the following steps of:
s1: adding water-soluble molecules containing unsaturated bonds and aldehyde or acetal structures and a first catalyst into a polyvinyl alcohol aqueous solution for reaction, adjusting the pH of a reaction system to 7-9 after the reaction is finished, and concentrating the solution to obtain a polyvinyl alcohol embolism microsphere intermediate; the weight average molecular weight of the polyvinyl alcohol is 55000-70000g/mol;
s2: adding the intermediate of the polyvinyl alcohol embolism microsphere prepared in the step S1, a cross-linking agent and an initiator into water for dissolution, adding a solvent and a surfactant, and then stirring/uniformly mixing the mixture under inert gas atmosphere by using a homogenizing device for reaction; washing after the reaction is finished to obtain polyvinyl alcohol embolism microspheres;
s3: C3-C6 linear aldehyde is dissolved in a solvent, the polyvinyl alcohol embolism microsphere prepared in the step S2 and a second catalyst are added, stirring reaction is carried out, and cleaning is carried out after the reaction is finished, so that the small-particle-size polyvinyl alcohol embolism microsphere is obtained.
2. The method for producing small particle diameter embolic microspheres according to claim 1, wherein the water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure is N- (2, 2-dimethoxyethyl) -2-acrylamide or 4-acrylamidobutyraldehyde dimethyl acetal; the first catalyst is inorganic acid; the cross-linking agent is 2-acrylamide-2-methylpropanesulfonic acid sodium salt or 3-sulfopropyl acrylic acid potassium salt; the initiator is at least one of V-50, potassium persulfate and sodium persulfate; the solvent in the step S2 is at least one of liquid paraffin, ethyl acetate or butyl acetate; the surfactant is at least one of Tween 80 or cellulose acetate butyrate; the second catalyst is an organic acid.
3. The method for preparing small particle size embolic microspheres according to claim 1, wherein the concentration of the aqueous polyvinyl alcohol solution in step S1 is 0.15-0.25g/mL; the concentration of the water-soluble molecules containing unsaturated bonds and aldehyde or acetal structures in the polyvinyl alcohol aqueous solution is 4-6mg/mL; the first catalyst is at least one of concentrated hydrochloric acid, concentrated nitric acid or perchloric acid, and the concentration of the first catalyst in the polyvinyl alcohol aqueous solution is 52-72mg/mL.
4. The method for producing small particle diameter embolic microspheres according to claim 1, wherein the concentration of the water-soluble molecules containing unsaturated bonds and aldehyde or acetal structures in the aqueous polyvinyl alcohol solution in step S1 is 5mg/mL; the concentration of the first catalyst in the polyvinyl alcohol aqueous solution is 62mg/mL; the concentration of the polyvinyl alcohol aqueous solution is 0.2g/mL; the weight average molecular weight of the polyvinyl alcohol is 65000g/mol; the concentrated solution was concentrated to a viscosity of 1500cps.
5. The method for preparing small particle diameter embolic microspheres according to claim 1, wherein the concentration of the polyvinyl alcohol embolic microsphere intermediate, the cross-linking agent, the initiator, the water and the surfactant in the solvent in step S2 is 0.15-0.18g/mL,0.03-0.05g/mL,0.7-1.75mg/mL,0.09-0.17g/mL,0.07-0.09g/mL, respectively.
6. The method for preparing small particle size embolic microspheres according to claim 1, wherein the concentration of the polyvinyl alcohol embolic microsphere intermediate, the cross-linking agent, the initiator, the water, and the surfactant in the solvent in step S2 is 0.17g/mL,0.04g/mL,1.2mg/mL,0.12g/mL,0.08g/mL, respectively.
7. The method for preparing small-particle-size embolic microspheres according to claim 1, wherein the reaction temperature in step S1 is 10-35 ℃ and the reaction time is 3-8 hours; the reaction temperature in the step S2 is 40-55 ℃ and the reaction time is 1-2h.
8. The method for preparing small particle size embolic microspheres according to claim 1, wherein the linear aldehyde in step S3 is n-butyraldehyde, propionaldehyde or n-valeraldehyde.
9. The method for producing small particle diameter embolic microspheres according to claim 1, wherein the linear aldehyde in step S3 is n-butyraldehyde.
10. The method for preparing small particle size embolic microspheres according to claim 1, wherein the concentration of the solution of the linear aldehyde in step S3 after dissolution in the solvent is 0.05-0.1g/mL.
11. The method for preparing small particle size embolic microspheres according to claim 1, wherein the solvent in step S3 is at least one of dimethyl sulfoxide, butyl acetate, ethyl acetate, n-heptane, or cyclohexane.
12. The method for preparing small particle size embolic microspheres according to claim 1, wherein the second catalyst in step S3 is at least one of methane sulfonic acid or trichloroacetic acid, at a concentration of 0.06-0.14g/mL solvent.
13. The preparation method of small-particle-size embolic microspheres according to claim 1, wherein the mass ratio of the linear aldehyde to the polyvinyl alcohol embolic microspheres in the step S3 is (1-2): 1, a step of; the stirring reaction was carried out at room temperature.
14. Small particle size polyvinyl alcohol embolic microspheres prepared by the method of preparing small particle size embolic microspheres according to any one of claims 1-13.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310409122.5A CN116159178B (en) | 2023-04-18 | 2023-04-18 | Small-particle-size embolism microsphere and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310409122.5A CN116159178B (en) | 2023-04-18 | 2023-04-18 | Small-particle-size embolism microsphere and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116159178A CN116159178A (en) | 2023-05-26 |
| CN116159178B true CN116159178B (en) | 2023-07-04 |
Family
ID=86414891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310409122.5A Active CN116159178B (en) | 2023-04-18 | 2023-04-18 | Small-particle-size embolism microsphere and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116159178B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003137931A (en) * | 2001-10-31 | 2003-05-14 | Sekisui Chem Co Ltd | Method for producing polyvinyl acetal resin |
| US6680046B1 (en) * | 1998-10-16 | 2004-01-20 | Biosphere Medical, S.A. | Method of embolization using polyvinyl alcohol microspheres |
| CN106916333A (en) * | 2015-12-28 | 2017-07-04 | 武汉德骼拜尔外科植入物有限公司 | A kind of polyvinyl alcohol medical sponge and preparation method thereof |
| DE102018222807A1 (en) * | 2017-12-22 | 2019-06-27 | Shandong Rientech Medical Technology Co., Ltd. | Degradable embolic microspheres with high drug loading capacity and process for their preparation |
| CN112957517A (en) * | 2021-02-23 | 2021-06-15 | 苏州微尺度科技有限公司 | Embolism microsphere, preparation method thereof and drug-loaded embolism microsphere |
| CN114099765A (en) * | 2021-11-30 | 2022-03-01 | 上海汇禾医疗科技有限公司 | Photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere and preparation method thereof |
| CN115671370A (en) * | 2021-12-30 | 2023-02-03 | 上海汇禾医疗科技有限公司 | Embolism microsphere capable of slowly releasing medicine and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6911219B2 (en) * | 2001-09-27 | 2005-06-28 | Surgica Corporation | Partially acetalized polyvinyl alcohol embolization particles, compositions containing those particles and methods of making and using them |
| US20120032369A1 (en) * | 2010-08-09 | 2012-02-09 | Diamond Charles M | Method for making hydrophobic organic fiber and particulate for sorbing liquid hydrocarbons |
-
2023
- 2023-04-18 CN CN202310409122.5A patent/CN116159178B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6680046B1 (en) * | 1998-10-16 | 2004-01-20 | Biosphere Medical, S.A. | Method of embolization using polyvinyl alcohol microspheres |
| JP2003137931A (en) * | 2001-10-31 | 2003-05-14 | Sekisui Chem Co Ltd | Method for producing polyvinyl acetal resin |
| CN106916333A (en) * | 2015-12-28 | 2017-07-04 | 武汉德骼拜尔外科植入物有限公司 | A kind of polyvinyl alcohol medical sponge and preparation method thereof |
| DE102018222807A1 (en) * | 2017-12-22 | 2019-06-27 | Shandong Rientech Medical Technology Co., Ltd. | Degradable embolic microspheres with high drug loading capacity and process for their preparation |
| CN112957517A (en) * | 2021-02-23 | 2021-06-15 | 苏州微尺度科技有限公司 | Embolism microsphere, preparation method thereof and drug-loaded embolism microsphere |
| CN114099765A (en) * | 2021-11-30 | 2022-03-01 | 上海汇禾医疗科技有限公司 | Photo-initiated cross-linked polyvinyl alcohol drug-loaded embolism microsphere and preparation method thereof |
| CN115671370A (en) * | 2021-12-30 | 2023-02-03 | 上海汇禾医疗科技有限公司 | Embolism microsphere capable of slowly releasing medicine and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Effects of temperature and solvent composition on the intrinsic viscosity of polyvinyl butyral in ethanol/water solutions;Wenwen luan, et al;journal of molecular liquids;336;全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116159178A (en) | 2023-05-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10624854B2 (en) | Method for preparing degradable drug-loaded microsphere for embolization, and product obtained therefrom | |
| AU689086B2 (en) | Improvements in or relating to contrast agents | |
| US9023321B2 (en) | Methods for producing microbubbles | |
| JPH059132A (en) | Fine particle consisting of biodegradable polymer, drug containing said fine particle and preparation of said fine particle and said drug | |
| EP0633030A1 (en) | Protein encapsulated insoluble gas microspheres and their preparation and use as ultrasonic imaging agents | |
| KR101703821B1 (en) | Self-assembled nano-structured particle and method for preparing | |
| CN102198117B (en) | Thermosensitive polymeric microcapsules and preparation method and use thereof | |
| CN109070054B (en) | Method for producing porous cellulose medium | |
| CN113694248A (en) | Embolism microsphere based on soluble starch and preparation and application thereof | |
| Wheatley et al. | Structural studies on stabilized microbubbles: development of a novel contrast agent for diagnostic ultrasound | |
| CN116159178B (en) | Small-particle-size embolism microsphere and preparation method thereof | |
| US6919068B2 (en) | Method of preparing gas-filled polymer matrix microparticles useful for echographic imaging | |
| CN114478927A (en) | Embolic microsphere and gradient cross-linking preparation method | |
| US9220709B2 (en) | Drug loaded contrast agents: combining diagnosis and therapy | |
| CN111632154A (en) | Phase-transition nanobubble, preparation method and application thereof | |
| CN113041363B (en) | Magnetic hollow protein microsphere and preparation method and application thereof | |
| CN106267164B (en) | Monodisperse insulin/chitosan gel rubber microballoon of size tunable and preparation method thereof | |
| CN114259599B (en) | Iodine complexing polyvinyl alcohol embolism microsphere capable of X-ray developing and preparation method thereof | |
| CN105943506B (en) | One kind is absorbable from pore microsphere for injection and preparation method thereof | |
| KR100681369B1 (en) | Multi-Stage Method for Producing Gas-Filled Microcapsules | |
| CN112972754A (en) | Visual fucoidin embolism microsphere and preparation method thereof | |
| Xu et al. | Monodisperse Polyaspartic Acid Derivative Microspheres for Potential Tumor Embolization Therapy | |
| CN114588115B (en) | Preparation method of PLGA drug sustained-release microspheres | |
| CN115232477B (en) | Temperature-sensitive dendronized gelatin fluorescent microsphere, and preparation method and application thereof | |
| CN116036295A (en) | Matrine sustained and controlled release material and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |