CN113444193A - Preparation method of narrow-particle-size polyvinyl acetate embolism microsphere with controllable drug-loading performance - Google Patents
Preparation method of narrow-particle-size polyvinyl acetate embolism microsphere with controllable drug-loading performance Download PDFInfo
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Abstract
The invention belongs to the technical field of preparation of embolization microspheres, and particularly relates to a preparation method of polyvinyl acetate embolization microspheres with narrow particle sizes and controllable drug-loading performance. The invention has simple preparation process, low cost of raw materials and high yield; the phase ratio and the crystallinity of the partially hydrolyzed polyvinyl acetate are controllable; the drug loading process is simple, the applicable drug range is wide, and the drug loading capacity is large; the drug release process is easy to control, and the burst release phenomenon can be effectively inhibited.
Description
Technical Field
The invention belongs to the technical field of preparation of embolism microspheres, and particularly relates to a preparation method of narrow-particle-size polyvinyl acetate embolism microspheres with controllable drug-loading performance.
Background
Transarterial chemoembolization (TACE) is currently the standard treatment for patients with mid-stage Hepatocellular carcinoma (HCC). Depending on the type of embolization material used, there are major groups of traditional embolization (cTACE) and Drug-loaded microsphere embolization (DEB-TACE). cTACE can inhibit tumor growth by mixing different embolic agents (such as iodized oil, degradable starch microspheres, gelatin, etc.) with antitumor drugs (such as mitomycin, cisplatin, adriamycin, etc.) and injecting into tumor blood vessels. The DEB-TACE loads the antitumor drug into the embolism microsphere through the electrostatic interaction between the drug molecules and the embolism microsphere skeleton, and then injects the antitumor drug into tumor blood vessels to inhibit the tumor growth. Compared with DEB-TACE, cTACE has the problem of poor controllability in the process of loading and releasing the drug, and is easy to generate burst effect to cause higher biological toxicity and serious side effect; thus, there is still a lack of standard cTACE treatment regimens today. The drug loaded by DEB-TACE is combined with the microspheres through ion exchange effect, and can form slow and long-term release effect in tumor blood vessels, so that the drug has lower toxicity and side effect, and the universality of treatment process, and is the mainstream of TACE development at present.
The current microsphere products suitable for DEB-TACE on the market mainly comprise DC Bead, Heapsphere, Callisphere and the like, wherein the chemical structure of the DC Bead is a copolymer of vinyl alcohol, N-acryloyl-aminoacetaldehyde-dimethyl acetal, 2-acrylamide-2-methylpropanesulfonic acid sodium and the like; HepaSphere is a copolymer of vinyl alcohol and acrylic acid; callisphere is mainly the copolymer of polyvinyl alcohol, acrylate, 2-acrylamide-2-methyl sodium propane sulfonate and the like. However, the DC bead has the defects of complex structure and high preparation cost; HepaSphere and Callisphere have the disadvantage of wide particle size distribution range of microspheres; callisphere also has the disadvantage of a low drug load. Therefore, the preparation of the embolism microsphere with good drug loading performance and narrow particle size distribution has important significance for improving the treatment effect of DEB-TACE.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a preparation method of polyvinyl acetate embolism microsphere, the prepared embolism microsphere has the characteristic of narrow particle size distribution and controllable drug-loading performance, and the defects of low drug-loading rate and wide particle size distribution range of the current DEB-TACE microsphere product are overcome.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of polyvinyl acetate embolism microsphere is characterized by comprising the following steps:
s1, under the protection of nitrogen, dissolving the dispersant in water to obtain a dispersant aqueous solution;
s2, dissolving an initiator in vinyl acetate to obtain a vinyl acetate monomer in which the initiator is dissolved;
s3, heating the dispersant aqueous solution to 64-66 ℃, then pouring vinyl acetate monomer dissolved with initiator, heating to 70-72 ℃ for reaction for 1-3 hours, heating to 75-77 ℃ for reaction for 1-3 hours, and keeping nitrogen bubbling constant in the reaction process;
the nitrogen gas is introduced in the reaction process to play two main roles: (i) carrying out atmosphere protection on the reaction to prevent implosion; (ii) the bubbling nitrogen bubbles play a role in stirring, and the dispersing capacity of the polymer droplets is improved.
And S4, after the reaction is finished, cooling, standing, filtering, washing and drying to obtain the polyvinyl acetate embolism microsphere.
The traditional free radical polymerization polyvinyl acetate is an atactic, high-branching degree and amorphous polymer, the glass transition temperature of the traditional free radical polymerization polyvinyl acetate is about 32 ℃, and the traditional free radical polymerization polyvinyl acetate is often used for preparing water-based adhesives. At present, the suspension emulsion polymerization method is generally used for preparing microspheres containing polyvinyl acetate, but the method has the defects of wide microsphere particle size distribution (50-700 μm), low glass transition temperature, low yield (about 40 percent) and the like.
In order to solve the problem of wide particle size range of the embolism microsphere, the invention takes vinyl acetate monomer as raw material, and the free radical polymerization method and the suspension emulsion polymerization method are effectively combined, so as to accurately regulate and control the material molar ratio, atmosphere, reaction temperature, stirring speed, dispersant dosage and the like in the polymerization reaction process, thereby realizing high yield and narrow particle size distribution of the polyvinyl acetate microsphere. Meanwhile, in order to improve the drug-loading capacity of the embolization microsphere, the drug-loading microsphere matrix with controllable hydrophilic and hydrophobic properties is designed and prepared by considering that most antitumor drugs have stronger hydrophobic property and utilizing the characteristic of hydrophobic-hydrophobic interaction between the antitumor drugs and the matrix with certain hydrophobic property, so that the related problems of the microsphere can be possibly improved. Therefore, the hydrolysis degree and the crystallinity of the polyvinyl acetate microspheres are accurately controlled, and the microspheres are endowed with proper hydrophilic and hydrophobic properties, so that the microspheres are endowed with good water dispersibility and controllable drug loading performance. The invention has the advantages of simple preparation process, high yield, low cost and the like.
Preferably, in steps S1 and S2, the feeding molar ratio of the vinyl acetate, the initiator, the dispersant and the water is 1.0: [0.0015-0.0020 ]]:[(2.7-4.5)×10-5]：[10-12.8]. Further, the feeding molar ratio of the vinyl acetate, the initiator, the dispersant and the water is 1.0:0.0015: 3.2X 10-5:10.2；1.0:0.00152:3.32×10-5:10.2；1.0:0.0015:4.43×10-5:10.2；1.0:0.0015:2.68×10-5:10.2。
Preferably, the dispersing agent includes, but is not limited to, vinyl pyrrolidone, polyvinyl alcohol 1788, polyvinyl alcohol 2888.
Preferably, the initiator includes, but is not limited to, azobisisobutyronitrile, dibenzoyl peroxide.
Preferably, step S3 is specifically: heating the aqueous solution of the dispersing agent to 65 ℃, then pouring a vinyl acetate monomer dissolved with an initiator, heating to 70 ℃ for reaction for two hours, heating to 75 ℃ for reaction for two hours, and keeping nitrogen bubbling constant in the reaction process.
Preferably, in step S4, the cooling is slow cooling to room temperature.
Preferably, in step S4, the resting is a greenhouse resting overnight.
Preferably, in step S4, the washing is performed by washing the solid product obtained by filtration with a 0.01 wt% sodium lauryl sulfate solution at 40 ℃ and deionized water.
Preferably, in step S1, the dispersant is dissolved in water by magnetic stirring at a speed of 300-350 rpm.
Preferably, in step S2, the initiator is dissolved in vinyl acetate with stirring.
The invention also provides the polyvinyl acetate embolism microsphere prepared by the preparation method.
The polyvinyl acetate embolism microsphere prepared by the method is applied to the treatment of DEB-TACE, and can effectively overcome the defects of low drug loading and wide particle size distribution range of the conventional DEB-TACE microsphere product.
Compared with the prior art, the invention has the beneficial effects that:
the invention takes vinyl acetate monomer as raw material, and effectively combines a free radical polymerization method and a suspension emulsion polymerization method to prepare the polyvinyl acetate embolism microsphere with good drug-loading performance and narrow particle size distribution, thereby solving the defects of low drug-loading rate and wide particle size distribution range of the current DEB-TACE microsphere product. The invention has simple preparation process, low cost of raw materials and high yield; the phase ratio and the crystallinity of the partially hydrolyzed polyvinyl acetate are controllable; the drug loading process is simple, the applicable drug range is wide, and the drug loading capacity is large; the drug release process is easy to control, and the burst release phenomenon can be effectively inhibited.
Drawings
FIG. 1 is a scanning electron microscope image of a polyvinyl acetate embolic microsphere;
FIG. 2 is a graph of the particle size distribution of a polyvinyl acetate embolization microsphere;
FIG. 3 is an X-ray diffraction pattern of a polyvinyl acetate embolic microsphere after 16 hours of partial hydrolysis;
FIG. 4 is a differential scanning calorimetry curve of a polyvinyl acetate embolization microsphere after 16 hours of partial hydrolysis;
FIG. 5 is a differential scanning calorimetry curve of a polyvinyl acetate embolization microsphere after 48 hours of partial hydrolysis;
FIG. 6 is a differential scanning calorimetry curve of a polyvinyl acetate embolization microsphere after 72 hours of partial hydrolysis;
FIG. 7 is a differential scanning calorimetry curve of a polyvinyl acetate embolization microsphere after 96 hours of partial hydrolysis;
FIG. 8 is a thermogravimetric analysis plot of partially hydrolyzed polyvinylacetate embolization microspheres for 96 hours (a), 72 hours (b), and 48 hours (c);
FIG. 9 is a standard curve of absorbance of doxorubicin hydrochloride solution as a function of concentration.
Detailed Description
The following further describes the embodiments of the present invention. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The experimental procedures in the following examples were carried out by conventional methods unless otherwise specified, and the test materials used in the following examples were commercially available by conventional methods unless otherwise specified.
EXAMPLE 1 Synthesis of Polyvinylacetate embolic microspheres
(1) 100mL of deionized water was charged to a 250mL three-necked flask with a condensing reflux unit attached. Under nitrogen protection, 0.5g of polyvinylpyrrolidone (molecular weight 29000) was dissolved in 100mL of deionized water in a three-neck flask under magnetic stirring (stirring speed 300-.
(2) 0.134g of Azobisisobutyronitrile (AIBN) was dissolved with stirring in 50mL of vinyl acetate (VAc), and the temperature of the solution in the three-necked flask was heated to 65 ℃. Then slowly pouring the VAc monomer dissolved with AIBN into a three-neck flask, raising the temperature of the solution to 70 ℃ for reaction for two hours, and then raising the temperature of the solution to 75 ℃ for reaction for two hours; the nitrogen bubbling should be maintained during the reaction (the nitrogen outlet extends from the conduit to the bottom of the reaction solution).
(3) After the reaction is finished, the three-neck flask is placed in a room temperature environment to be slowly cooled. After cooling was complete, the contents of the flask were transferred to a 500mL beaker and allowed to stand overnight. The reaction mixture after standing was filtered with suction, and the resulting solid product was washed with 0.01 wt% sodium dodecyl sulfate solution (SDS) at 40 ℃ and 100mL of deionized water. And after washing, putting the solid product in an oven at 40 ℃ for drying overnight to obtain the polyvinyl acetate embolism microsphere.
EXAMPLE 2 Synthesis of Polyvinylacetate embolic microspheres
(1) 100mL of deionized water was charged to a 250mL three-necked flask with a condensing reflux unit attached. Under nitrogen protection, 1.5g of polyvinyl alcohol 1788 was dissolved in 100mL of deionized water in a three-necked flask under magnetic stirring (stirring speed 300-350 rpm).
(2) 0.2g of dibenzoyl peroxide (BPO) was dissolved with stirring in 50mL of vinyl acetate (VAc) and the temperature of the solution in the three-necked flask was heated to 65 ℃. The VAc monomer with BPO dissolved therein was then slowly poured into a three-necked flask and the solution temperature was raised to 70 ℃ for two hours. The solution was then allowed to warm to 75 ℃ for two more hours.
(3) After the reaction is finished, the three-neck flask is placed in a room temperature environment to be slowly cooled. After cooling was complete, the contents of the flask were transferred to a 500mL beaker and allowed to stand overnight. The reaction mixture after standing was filtered with suction, and the resulting solid product was washed with 0.01 wt% sodium dodecyl sulfate solution (SDS) at 40 ℃ and 100mL of deionized water. And after washing, putting the solid product in an oven at 40 ℃ for drying overnight to obtain the polyvinyl acetate embolism microsphere.
EXAMPLE 3 Synthesis of Polyvinylacetate embolic microspheres
(1) 100mL of deionized water was charged to a 250mL three-necked flask with a condensing reflux unit attached. Under nitrogen protection, 2.0g of polyvinyl alcohol 1788 was dissolved in 100mL of deionized water in a three-necked flask under magnetic stirring (stirring speed 300-350 rpm).
(2) 0.134g of Azobisisobutyronitrile (AIBN) was dissolved with stirring in 50mL of vinyl acetate (VAc), and the temperature of the solution in the three-necked flask was heated to 65 ℃. The VAc monomer with dissolved AIBN was then slowly poured into a three-necked flask and the solution temperature was raised to 70 ℃ for two hours of reaction. The solution was then allowed to warm to 75 ℃ for two more hours.
(3) After the reaction is finished, the three-neck flask is placed in a room temperature environment to be slowly cooled. After cooling was complete, the contents of the flask were transferred to a 500mL beaker and allowed to stand overnight. The reaction mixture after standing was filtered with suction, and the resulting solid product was washed with 0.01 wt% sodium dodecyl sulfate solution (SDS) at 40 ℃ and 100mL of deionized water. And after washing, putting the solid product in an oven at 40 ℃ for drying overnight to obtain the polyvinyl acetate embolism microsphere.
EXAMPLE 4 Synthesis of Polyvinylacetate embolic microspheres
(1) 100mL of deionized water was charged to a 250mL three-necked flask with a condensing reflux unit attached. Under nitrogen protection, 2.0g of polyvinyl alcohol 2888 was dissolved in 100mL of deionized water in a three-necked flask under magnetic stirring (stirring speed of 300-350 rpm).
(2) 0.134g of Azobisisobutyronitrile (AIBN) was dissolved with stirring in 50mL of vinyl acetate (VAc), and the temperature of the solution in the three-necked flask was heated to 65 ℃. The VAc monomer with dissolved AIBN was then slowly poured into a three-necked flask and the solution temperature was raised to 70 ℃ for two hours of reaction. The solution was then allowed to warm to 75 ℃ for two more hours.
(3) After the reaction is finished, the three-neck flask is placed in a room temperature environment to be slowly cooled. After cooling was complete, the contents of the flask were transferred to a 500mL beaker and allowed to stand overnight. The reaction mixture after standing was filtered with suction, and the resulting solid product was washed with 0.01 wt% sodium dodecyl sulfate solution (SDS) at 40 ℃ and 100mL of deionized water. And after washing, putting the solid product in an oven at 40 ℃ for drying overnight to obtain the polyvinyl acetate embolism microsphere.
Experimental example 1 test of yield and particle size Dispersion of Polyvinylacetate embolic microspheres
(1) And (3) calculating the yield:
the polyvinyl acetate embolic microspheres dried in examples 1-4 were weighed and the yield was calculated to be in the range of about 60-70%. Wherein the yield of example 1 is 71%, the yield of example 2 is 69%, the yield of example 3 is 73%, and the yield of example 4 is 70%.
Yield% (% of microspheres mass after drying (g) × 100%/vinyl acetate monomer mass (g).
(2) Testing the particle size dispersity:
placing the agglomerated polyvinyl acetate embolism microsphere in a powder beater, adding 2 wt% of anhydrous sodium sulphate as an antistatic agent, and tightly covering a machine cover. The powdering machine was started and powdering was first performed for 60 seconds to prevent overheating. And after the powdering machine is cooled, performing second round of powdering for 60 seconds. This procedure was repeated 3-5 times until a powder of polyvinylacetate embolic microspheres with uniformly dispersed particle size was obtained, the morphology of the obtained microspheres being shown in fig. 1 (test results of examples 1-4 were consistent). Scanning electron microscope images of the polyvinylacetate embolization microsphere powder were analyzed by using professional image analysis software ImageJ to measure the particle size distribution of the microspheres, and the results are shown in fig. 2 (the counted number of the microspheres is not less than 300), and the particle size distribution is mainly 110-140 μm (the test results of examples 1-4 are consistent). The number average diameter D of the polyvinylacetate embolizing microspheres of example 3 was calculated according to equations (1) and (2), respectivelyn118.7 μm and weight-average diameter Dw128.2 μm; the polydispersity index (PDI) of the polyvinylacetate embolized microspheres was calculated to be 1.08 according to equation (3), and D in examples 1, 2, and 4 was calculatedn、DwAnd the PDI value is close to that of the example 3, and the deviation is not more than 10 percent, which shows that the polyvinyl acetate embolism microsphere prepared by the invention has smaller particle size dispersion degree and narrow particle size distribution.
PDI＝Dw/DnFormula (3);
in formulae (1) to (3), DnRepresents a number average diameter, DwRepresents a weight average diameter, DiN represents the diameter of a microsphereiRepresenting the number of microspheres in the sample that have both Di diameters.
Experimental example 2 testing of thermal stability and drug-loading Performance of polyvinyl acetate embolic microspheres
(1) Partial hydrolysis of polyvinyl acetate embolic microspheres
The polyvinyl acetate embolic microspheres can be partially hydrolyzed using three methods:
the method comprises the following steps: a three-necked flask with a condensing reflux unit was charged with 25mL of methanol, 175mL of deionized water was then added, and the solution in the flask was magnetically stirred at 350 rpm. 20g of sodium hydroxide were weighed and added to the flask to mix with the solution while the solution was warmed to 40 ℃. Then 20g of anhydrous sodium sulphate was weighed and added to the solution, waiting for 30 minutes until it was fully dissolved. 1.0g of the polyvinyl acetate embolic microspheres were weighed and added to the solution and hydrolyzed under magnetic stirring at 350rpm at 40 ℃ for 16, 48, 72 or 96 hours. After the hydrolysis reaction was complete, the product was poured into a beaker containing 300mL of deionized water and allowed to stand overnight. After the hydrolysate had precipitated completely, it was separated from the liquid by suction filtration and the product was washed with a large amount of deionized water. After washing, the product was dried in an oven at 40 ℃ overnight.
The second method comprises the following steps: a three-necked flask with a condensing reflux unit was charged with 20mL of ethanol, followed by 131mL of deionized water, and the solution in the flask was magnetically stirred at 350 rpm. 15g of sodium hydroxide was weighed and added to the flask to mix with the solution while the solution was warmed to 40 degrees Celsius. 15g of anhydrous sodium sulphate was then weighed and added to the solution, waiting 30 minutes until it was fully dissolved. 0.75g of the polyvinyl acetate embolic microspheres are weighed and added to the solution and hydrolyzed under magnetic stirring at 350rpm at 40 ℃ for 16, 48, 72 or 96 hours. After the hydrolysis reaction was complete, the product was poured into a beaker containing 300mL of deionized water and allowed to stand overnight. After the hydrolysate had precipitated completely, it was separated from the liquid by suction filtration and the product was washed with a large amount of deionized water. After washing, the product was dried in an oven at 40 ℃ overnight.
The third method comprises the following steps: a three-necked flask with attached condensing reflux was charged with a mixture of 8mL of methanol and 16mL of methyl acetate, then 176mL of deionized water was added and the solution in the flask was magnetically stirred at 350 rpm. 20g of sodium hydroxide was weighed and added to the flask to mix with the solution while the solution was warmed to 40 degrees Celsius. Then 20g of anhydrous sodium sulphate was weighed and added to the solution, waiting for 30 minutes until it was fully dissolved. 1.0g of the polyvinyl acetate embolic microspheres were weighed and added to the solution and hydrolyzed under magnetic stirring at 350rpm at 40 ℃ for 16, 48, 72 or 96 hours. After the hydrolysis reaction was complete, the product was poured into a beaker containing 300mL of deionized water and allowed to stand overnight. After the hydrolysate had precipitated completely, it was separated from the liquid by suction filtration and the product was washed with a large amount of deionized water. After washing, the product was dried in an oven at 40 ℃ overnight.
(2) Thermal stability testing of polyvinyl acetate embolization microspheres
Taking the partially hydrolyzed polyvinyl acetate embolism microsphere as an example, the X-ray diffraction pattern analysis is carried out on the embolism microsphere (the X-ray diffractometer is tested by a MiniFlex 600 model of Rigaku, Japan, the ray source is Cu/Ka, the angle is 5-90 degrees, and the stepping angle is 0.02 degree). The X-ray diffraction pattern of the polyvinyl acetate after 16 hours of partial hydrolysis is shown in fig. 3 (the test results of 48, 72 or 96 hours of hydrolysis are consistent with those of 16 hours), and diffraction peaks of the polyvinyl alcohol monoclinic unit cells (101) and (200) can be observed at 19.9 ° and 22.7 °, respectively. The above test results show that by partially hydrolyzing polyvinyl acetate, a mixed phase of polyvinyl acetate and polyvinyl alcohol can be obtained, since polyvinyl acetate has hydrophobicity and polyvinyl alcohol has hydrophilicity. By controlling the hydrolysis degree, the mass ratio of the mixed phase can be effectively adjusted, so that a microsphere product with hydrophilic and hydrophobic properties between polyvinyl acetate and polyvinyl alcohol is obtained.
Meanwhile, differential scanning calorimetry (using Perkinelmer STA-6000 type differential scanning calorimeter for testing, the temperature range is 30-815 deg.C, and the heating rate is 10 deg.C for min)-1Nitrogen atmosphere in the test environment), as shown in the differential scanning calorimetry curve of fig. 4, polyvinyl alcohol and polyethylene can be observed at 231 ℃ and 325 ℃ simultaneouslyThe single phase dissolution peak of vinyl acetate and a new dissolution peak was observed at 281 ℃. The peak dissolution temperature is between that of single-phase polyvinyl alcohol and polyvinyl acetate, and it can be concluded that it is a mixed phase of polyvinyl alcohol and polyvinyl acetate produced through hydrolysis reaction. That is, after hydrolysis reaction, partial polyvinyl acetate molecular chain segment is converted into polyvinyl alcohol molecular chain segment, and the product is gradually converted into mixed phase of polyvinyl alcohol and polyvinyl acetate from single phase of polyvinyl acetate. When the hydrolysis time is increased to 48 hours, 72 hours and 96 hours, the dissolution peak of the polyvinyl acetate in the differential scanning calorimetry curve disappears, and the dissolution peak of the mixed phase shifts to about 270 ℃; on the other hand, as the hydrolysis time increased, the dissolution peak area of the single-phase polyvinyl alcohol at 231 ℃ gradually decreased, and the area of the mixed-phase dissolution peak gradually increased, as shown in fig. 5, 6, and 7. It is shown that as the degree of hydrolysis increases, the first polyvinyl alcohol molecular segment formed can blend with the mixed phase through intermolecular hydrogen bonding to form a thicker crystalline region.
Further, the mass fractions of the mixed phases after 16, 48, 72 and 96 hours of partial hydrolysis were calculated by differential scanning calorimetry to be 33.2%, 65.8, 79.7% and 90.1%, respectively. Due to the stronger intermolecular hydrogen bonding and higher crystallinity, the polyvinylacetate embolization microspheres that were partially hydrolyzed for 96 hours had higher thermal stability and decomposition temperature than the microspheres that were partially hydrolyzed for 48 and 72 hours, as shown in fig. 8.
(3) Drug loading performance test of polyvinyl acetate embolism microsphere
Taking the partially hydrolyzed polyvinyl acetate embolism microsphere as an example, the method for effectively evaluating the drug loading performance of the partially hydrolyzed polyvinyl acetate embolism microsphere by constructing an in-vitro adsorption model of the adriamycin comprises the following steps:
1) establishing a standard curve:
doxorubicin hydrochloride was prepared as a standard solution at a concentration of 25mg/mL and diluted to sample solutions of 12.5mg/mL, 6.25mg/mL, 3.125mg/mL, and 1.5625mg/mL, respectively. The absorbances of the standard solution and the sample solution were measured at the maximum absorption wavelength of doxorubicin (480nm) by uv-vis spectroscopy, and the measured absorbances were plotted as ordinate and the corresponding sample concentration as abscissa as a standard curve, as shown in fig. 9.
2) Drug loading:
dispersing 120mg of partially hydrolyzed polyvinyl acetate embolism microsphere into 1mL of deionized water, then adding 1mL of 25mg/mL doxorubicin hydrochloride aqueous solution, shaking and mixing at room temperature, eluting the incompletely adsorbed doxorubicin hydrochloride with deionized water, collecting the eluate and testing the absorbance of the eluate. And comparing the measured absorbance with a standard concentration curve of the doxorubicin hydrochloride solution, and calculating to obtain the concentration of the incompletely adsorbed drug.
Adsorbed concentration (mg/mL) ═ original concentration (mg/mL) — unadsorbed concentration (mg/mL);
drug loading (%) (adsorption concentration/original concentration) × 100%;
drug loading capacity (mg/g microsphere) — adsorption concentration/microsphere mass.
3) Test results
The results of the in vitro adsorption test of partially hydrolyzed polyvinyl acetate embolic microspheres on doxorubicin are shown in table 1, and the drug loading rate of the original polyvinyl acetate embolic microspheres is 9.2% and the drug loading capacity is 19.2 mg/g microspheres by calculation; the drug loading rate of the polyvinyl acetate embolism microsphere which is partially hydrolyzed for 48 hours is 46.4 percent, and the drug loading capacity is 97 mg/g microsphere; the drug loading rate of partial hydrolysis for 72 hours is 60.0 percent, and the drug loading capacity is 125 mg/g microsphere; the drug loading rate of the partial hydrolysis for 96 hours is 25.6 percent, and the drug loading capacity is 53 mg/g microsphere. Compared with the DEB-TACE microsphere products on the market at present, such as Callisphere (19.2 mg/g microsphere), DC Bead (75 mg/g microsphere) and the like, the partially hydrolyzed polyvinyl acetate embolism microsphere has the advantage of higher drug loading capacity.
Meanwhile, as can be seen from table 1, there is a dynamic adsorption equilibrium between the partially hydrolyzed microspheres and doxorubicin hydrochloride. Unhydrolyzed microspheres (almost completely hydrophobic) have only a small adsorption capacity for doxorubicin, while microspheres that have been hydrolyzed for too long a period of time (almost completely hydrophilic) also have not as high an adsorption capacity for doxorubicin. The surface energy state of the microspheres between hydrophilic and hydrophobic states shows that the microspheres can generate synergistic effect with the hydrophilic and hydrophobic properties of the adriamycin, so that the optimal adsorption effect is achieved. At the moment, the microspheres and the adriamycin are combined by means of physical hydrophilic and hydrophobic power and are not influenced by pH change of a body fluid environment, so that burst release can be effectively avoided.
TABLE 1 in vitro adsorption test results of polyvinyl acetate embolic microspheres to doxorubicin
The embodiments of the present invention have been described in detail, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, and the scope of protection is still within the scope of the invention.
Claims (9)
1. A preparation method of polyvinyl acetate embolism microsphere is characterized by comprising the following steps:
s1, under the protection of nitrogen, dissolving the dispersant in water to obtain a dispersant aqueous solution;
s2, dissolving an initiator in vinyl acetate to obtain a vinyl acetate monomer in which the initiator is dissolved;
s3, heating the dispersant aqueous solution to 64-66 ℃, then pouring vinyl acetate monomer dissolved with initiator, heating to 70-72 ℃ for reaction for 1-3 hours, heating to 75-77 ℃ for reaction for 1-3 hours, and keeping nitrogen bubbling constant in the reaction process;
and S4, after the reaction is finished, cooling, standing, filtering, washing and drying to obtain the polyvinyl acetate embolism microsphere.
2. The method of claim 1, wherein in steps S1 and S2, the method further comprisesThe feeding molar ratio of the vinyl acetate, the initiator, the dispersant and the water is 1.0: (0.0015-0.0020)]:[(2.7-4.3)×10-5]：[10-12.8]。
3. The method for preparing embolism microsphere of polyvinyl acetate according to claim 1, wherein the dispersing agent includes but is not limited to vinyl pyrrolidone, polyvinyl alcohol 1788, polyvinyl alcohol 2888.
4. The method of claim 1, wherein the initiator includes but is not limited to azobisisobutyronitrile and dibenzoyl peroxide.
5. The method for preparing the polyvinyl acetate embolism microsphere according to the claim 1, wherein the step S3 is specifically as follows: heating the aqueous solution of the dispersing agent to 65 ℃, then pouring a vinyl acetate monomer dissolved with an initiator, heating to 70 ℃ for reaction for two hours, heating to 75 ℃ for reaction for two hours, and keeping nitrogen bubbling constant in the reaction process.
6. The method of claim 1, wherein the cooling step S4 is slow cooling to room temperature.
7. The method of claim 1, wherein the step S4 is carried out by standing in a greenhouse overnight.
8. The method of claim 1, wherein the washing step S4 is to wash the filtered solid product with 0.01 wt% sodium dodecyl sulfate solution at 40 ℃ and deionized water.
9. Polyvinyl acetate embolization microspheres made by the method of any one of claims 1-8.
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| KR20000019409A (en) * | 1998-09-11 | 2000-04-06 | 박호군 | Preparing method of uniformly micro spherical polyvinyl acetate |
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| KR20000019409A (en) * | 1998-09-11 | 2000-04-06 | 박호군 | Preparing method of uniformly micro spherical polyvinyl acetate |
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