CN113694248A - Embolism microsphere based on soluble starch and preparation and application thereof - Google Patents
Embolism microsphere based on soluble starch and preparation and application thereof Download PDFInfo
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- C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/602—Type of release, e.g. controlled, sustained, slow
Abstract
The invention provides an embolism microsphere based on soluble starch and preparation and application thereof. The embolism microsphere is prepared by soluble starch, an olefin polar monomer, an initiator and a cross-linking agent through an inverse suspension polymerization technology, wherein a continuous phase comprises an oil phase and a surfactant, and a dispersed phase comprises the soluble starch, the olefin polar monomer, the initiator and the cross-linking agent. According to the invention, the olefin polar monomer and the soluble starch are subjected to free radical grafting and then cross-linking to obtain the embolism microsphere, the embolism microsphere is rich in porous structure, pores extend towards the interior of the microsphere, so that the specific surface area of the embolism microsphere is larger, and the surface of the embolism microsphere has a large amount of hydrophilic polar groups, so that the embolism microsphere can generate electrostatic adsorption with a medicament, and a good medicament slow release effect of the embolism microsphere is realized. The embolism microsphere prepared by the invention has the drug loading of 191mg/g for doxorubicin hydrochloride and the entrapment rate of 96%, and effectively improves the drug loading and the entrapment rate of the starch embolism microsphere.
Description
Technical Field
The invention belongs to the technical field of microsphere preparation. More particularly, relates to an embolism microsphere based on soluble starch and preparation and application thereof.
Background
The hepatic artery chemoembolization (TACE) plays an important role in the treatment of hepatocellular carcinoma, is the first choice treatment method for hepatocellular carcinoma in middle and late stages at present, and the key point of success of TACE is the design of an embolic agent, which blocks tumor blood vessels and blocks the nutrient source and oxygen supply of the tumor. The embolism microsphere is used as a novel drug delivery and embolism system, and is embolized to a lesion part through an artery by adsorbing chemotherapeutic drugs, so that the drugs are slowly released, and the anticancer effect is achieved. Theoretically, the drug-loaded embolization microsphere can not only realize higher local drug concentration and improve the treatment effect of TACE, but also reduce systemic toxicity, and is gradually the research focus and key point in the field.
According to the degradability of raw materials, the embolism microsphere can be divided into biodegradable microsphere and non-biodegradable microsphere, the starch microsphere is a typical biodegradable microsphere, can be gradually degraded under the action of serum amylase in blood flow, and is considered as an ideal targeted drug carrier due to the advantages of large specific surface area, high efficiency, low toxicity, no immunogenicity, directional slow-release delivery system and the like. The reverse emulsion method is the most common method for preparing starch microspheres, the synthesis process is simple, the reaction conditions are mild and easy to control, and the reaction reproducibility is good, for example, the heparin starch microsphere vascular embolization agent with the anti-tumor effect is prepared by the reverse emulsion method in patent CN201810440203.0, but the embolization agent has no porous structure on the surface, the corresponding specific surface area is smaller, and the drug loading rate and the encapsulation rate are limited directly.
Therefore, the search for a starch microsphere with a porous structure to increase the drug loading and encapsulation efficiency has considerable necessity in the technical field of embolic microsphere preparation.
Disclosure of Invention
Aiming at the defects of the existing starch microspheres, the invention provides an embolization microsphere based on soluble starch and preparation and application thereof, so that the porous structure of the embolization microsphere is realized, and the drug loading rate and the encapsulation efficiency of the embolization microsphere are improved.
The invention aims to provide an embolization microsphere based on soluble starch.
Another object of the present invention is to provide a method for preparing the above embolizing microspheres.
It is still another object of the present invention to provide the use of the above embolic microspheres as/in the preparation of a drug delivery vehicle.
The above purpose of the invention is realized by the following technical scheme:
the invention provides an embolism microsphere based on soluble starch, which is prepared by using soluble starch, an olefin polar monomer, an initiator and a cross-linking agent through an inverse suspension polymerization technology, wherein a continuous phase comprises an oil phase and a surfactant, and a dispersed phase comprises the soluble starch, the olefin polar monomer, the initiator and the cross-linking agent.
According to the invention, the infrared spectrum is utilized to analyze and identify the embolism microsphere of the soluble starch, and the characteristic peaks of carboxyl and starch are found to appear at the same time, which indicates that the preparation method of the invention can successfully introduce carboxyl into the starch microsphere; the embolization microsphere is characterized by adopting an optical microscope and a scanning electron microscope, the optical microscope shows that the embolization microsphere has uniform particle size distribution and good dispersibility, and the scanning electron microscope shows that the embolization microsphere has a smooth surface and is porous after freeze-drying, so that the embolization microsphere has a large specific surface area and can effectively realize high drug loading and high encapsulation rate; in addition, the invention also utilizes a hemolysis experimental data graph to carry out quantitative calculation, finds that the hemolysis rate of the embolism microsphere is lower than 5 percent, accords with the national standard, shows that the embolism microsphere can not cause obvious hemolysis and has biological safety.
According to the invention, the olefin polar monomer and the soluble starch are subjected to free radical grafting and then cross-linking to obtain the embolism microsphere, the embolism microsphere is rich in porous structure, pores extend towards the interior of the microsphere, so that the specific surface area of the embolism microsphere is larger, and the surface of the embolism microsphere has a large amount of hydrophilic polar groups, so that the embolism microsphere can generate electrostatic adsorption with a medicament, and a good medicament slow release effect of the embolism microsphere is realized. The embolism microsphere prepared by the invention has the drug loading of 191mg/g for doxorubicin hydrochloride and the entrapment rate of 96%, and effectively improves the drug loading and the entrapment rate of the starch embolism microsphere.
Preferably, the mass ratio of the soluble starch, the olefin polar monomer, the initiator and the cross-linking agent is 10: 5-10: 0.1-0.3: 0.1 to 0.2.
Most preferably, the mass ratio of the soluble starch, the olefin polar monomer, the initiator and the cross-linking agent is 10: 10: 0.2: 0.1, see example 1.
Preferably, the olefin polar monomer comprises one or more of acrylic acid, methacrylic acid or 2-acrylamide-2-methylpropanesulfonic acid.
Most preferably, the olefinic polar monomer is acrylic acid, see example 1.
Preferably, the soluble starch comprises one or more of soluble corn starch, soluble tapioca starch, soluble potato starch or soluble sweet potato starch.
Preferably, the initiator comprises one or more of sodium persulfate, ammonium persulfate or potassium persulfate.
Preferably, the crosslinking agent comprises one or more of epichlorohydrin, N' -methylene-bisacrylamide, sodium trimetaphosphate or glutaraldehyde.
Preferably, the oil phase comprises one or more of n-hexane, liquid paraffin, vegetable oil, kerosene or cyclohexane.
Preferably, the surfactant comprises one or more of Span 80, tween 80, Span 60 or tween 60.
Preferably, the mass ratio of the soluble starch, the oil phase and the surfactant is 1: 10-20: 0.02 to 0.5.
Most preferably, the mass ratio of the soluble starch, the oil phase and the surfactant is 1: 15: 0.4, see example 1.
The invention also provides a preparation method of the embolism microsphere, which comprises the following steps:
s1, mixing an olefin polar monomer, an initiator, a cross-linking agent and a soluble starch solution to obtain a dispersed phase;
s2, mixing and heating the oil phase and the surfactant to obtain a continuous phase;
s3, adding the dispersed phase obtained in the step S1 into the continuous phase obtained in the step S2, heating, standing, cleaning and drying to obtain the embolism microsphere based on the soluble starch.
Preferably, the preparation method of the soluble starch solution is specifically to dissolve soluble starch in water, and then add sodium hydroxide aqueous solution to mix, so as to obtain the soluble starch solution.
Preferably, the heating in step S3 is heating at 70-90 ℃.
Further preferably, in the step S3, stirring is further performed during heating, and the rotation speed of stirring is 200 to 700 r/min.
Preferably, the heating in the step S4 is performed at 70-90 ℃ for 1-3 h.
Further preferably, in the step S4, stirring is further performed during heating, and the rotation speed of stirring is 200 to 700 r/min.
Preferably, the cleaning is performed by using an organic solvent and deionized water, specifically, the embolism microsphere is repeatedly washed by using the organic solvent, repeatedly washed by using the deionized water after centrifugation, and finally centrifuged.
Further preferably, the organic solvent is one or more of absolute ethyl alcohol, ethyl acetate, petroleum ether or acetone.
The invention effectively improves the drug loading rate and the encapsulation efficiency of the starch embolism microsphere, so the application of the embolism microsphere in the preparation of drug delivery carrier is also within the protection scope of the invention.
Preferably, the drug comprises doxorubicin hydrochloride.
The invention has the following beneficial effects:
1) according to the invention, the olefin polar monomer and the soluble starch are subjected to free radical grafting and then cross-linking to obtain the embolism microsphere, the embolism microsphere is rich in porous structure, pores extend towards the interior of the microsphere, so that the specific surface area of the embolism microsphere is larger, and the surface of the embolism microsphere has a large amount of hydrophilic polar groups, so that the embolism microsphere can generate electrostatic adsorption with a medicament, and a good medicament slow release effect of the embolism microsphere is realized. The embolism microsphere prepared by the invention has the drug loading of 191mg/g for doxorubicin hydrochloride and the entrapment rate of 96%, and effectively improves the drug loading and the entrapment rate of the starch embolism microsphere.
2) The particle size of the embolism microsphere is 50-500 microns, the embolism microsphere is mainly distributed between 100-300 microns, the size of the embolism microsphere is in accordance with the ideal size, the embolism microsphere is round and smooth, the surface is smooth, and the structure is stable.
3) The embolism microsphere has the advantages of biodegradability, biocompatibility, nontoxicity, no immunogenicity and the like, the hemolysis rate is lower than 5%, and the embolism microsphere conforms to the national standard, shows that the embolism microsphere can not cause obvious hemolysis and has biosafety.
4) The preparation method is simple, can be used for preparing a large amount of the compound in a short time, has high production efficiency and high industrial feasibility, and has good and wide application prospect.
Drawings
FIG. 1 is a graph comparing infrared absorption spectra.
Fig. 2 is a graph of the results of optical microscope scanning.
FIG. 3 is a scanning electron microscope result chart.
FIG. 4 is a graph of data from a hemolysis experiment.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
EXAMPLE 1 preparation of embolic microspheres based on soluble starch
Preparation of embolism microsphere
S1, dissolving 2g of soluble cassava starch in 20mL of water, adding 500 mu L of 0.2mol/L sodium hydroxide aqueous solution, mixing and dissolving to obtain a soluble cassava starch solution;
s2, stirring and mixing acrylic acid, ammonium persulfate and N, N' -methylene bisacrylamide with the soluble cassava starch solution obtained in the step S1 to obtain a dispersion phase; (the mass ratio of the soluble cassava starch to the acrylic acid to the ammonium persulfate to the N, N' -methylene bisacrylamide is 10: 10: 0.2: 0.1);
s3, mixing n-hexane and Span 80, heating to 85 ℃, and stirring at the rotating speed of 300r/min to obtain a continuous phase; (the mass ratio of the soluble cassava starch to the normal hexane to the Span 80 meets 1: 15: 0.4);
s4, adding the dispersed phase obtained in the step S2 into the continuous phase obtained in the step S3, continuously heating at 85 ℃, stirring at a rotating speed of 300r/min, standing for layering after 1h, washing an oil phase remained on the surface of the microsphere with ethyl acetate, washing and separating with deionized water, and drying to obtain the embolism microsphere based on the soluble starch.
Second, embolism microsphere structure and performance test
(1) The embolization microspheres obtained in this example and the soluble tapioca starch used as the raw material were analyzed and identified by infrared spectroscopy to obtain a comparison graph of the infrared absorption spectrum curve of fig. 1. As can be seen from FIG. 1, the infrared absorption spectrum curve of the embolization microsphere has characteristic peaks of carboxyl and starch at the same time, which indicates that the preparation method of the invention successfully introduces carboxyl into the starch microsphere.
(2) The embolization microspheres obtained in this example were characterized by an optical microscope and a scanning electron microscope to obtain fig. 2 and 3. As can be seen from FIG. 2, the particle size distribution of the embolism microsphere is uniform, and the dispersity is good; as can be seen from FIG. 3, the embolic microspheres have smooth surfaces and are porous after lyophilization; the specific surface area of the embolism microsphere is larger by combining with the figure 2 and the figure 3, which shows that the preparation method of the invention effectively realizes high drug loading and high encapsulation efficiency of the embolism microsphere.
(3) The embolized microspheres obtained in this example were subjected to a hemolysis test by first centrifuging fresh rat blood, collecting erythrocytes, and diluting with physiological saline to obtain a 10% erythrocyte suspension. Mixing normal saline and erythrocyte suspension according to the volume ratio of 1: 1 as a negative control group; taking deionized water and erythrocyte suspension according to the volume ratio of 1: 1 as a positive control group; the embolized microspheres were dispersed in the erythrocyte suspension at 1mg/mL, 3mg/mL, 5mg/mL, 10mg/mL, and 15mg/mL to prepare an experimental group. After the control group and the experimental group are incubated at 37 ℃ for 1h, the absorbance is detected at the wavelength of 540nm to obtain a hemolysis experiment data graph shown in figure 4, the hemolysis rate of the embolism microsphere is calculated to be lower than 5% according to the following formula, the national standard is met, and the embolism microsphere does not cause obvious hemolysis and has biological safety.
Percent of hemolysis (A)sample-A0.9％NaCl)×100/(ADI water-A0.9％NaCl)
EXAMPLE 2 preparation of embolic microspheres based on soluble starch
S1, dissolving 2g of soluble potato starch in 20mL of water, adding 500 mu L of 0.2mol/L sodium hydroxide aqueous solution, and mixing and dissolving to obtain a soluble potato starch solution;
s2, mixing methacrylic acid, sodium persulfate and sodium trimetaphosphate with the soluble potato starch solution obtained in the step S1 to obtain a dispersion phase; (the mass ratio of the soluble potato starch to the methacrylic acid to the sodium persulfate to the sodium trimetaphosphate is 10: 5: 0.3: 0.2);
s3, mixing the liquid paraffin and Span 60, heating to 85 ℃, and stirring at the rotating speed of 300r/min to obtain a continuous phase; (the mass ratio of the soluble potato starch, the liquid paraffin and the Span 60 meets 1: 20: 0.5);
s4, adding the dispersed phase obtained in the step S2 into the continuous phase obtained in the step S3, continuously heating at 85 ℃, stirring at a rotating speed of 300r/min, standing for layering after 1h, washing an oil phase remained on the surface of the microsphere with ethyl acetate, washing and separating with deionized water, and drying to obtain the embolism microsphere based on the soluble starch.
Example 3 preparation of embolic microspheres based on soluble starch
S1, dissolving 2g of soluble corn starch in 20mL of water, adding 500 mu L of 0.2mol/L sodium hydroxide aqueous solution, mixing and dissolving to obtain a soluble corn starch solution;
s2, stirring and mixing acrylic acid, potassium persulfate and sodium trimetaphosphate with the soluble corn starch solution obtained in the step S1 to obtain a dispersion phase; (the mass ratio of the soluble corn starch to the acrylic acid to the potassium persulfate to the sodium trimetaphosphate is 10: 10: 0.1: 0.1);
s3, mixing kerosene and Span 80, heating to 90 ℃, and stirring at the rotating speed of 200r/min to obtain a continuous phase; (the mass ratio of the soluble corn starch, the kerosene and the Span 80 meets 1: 10: 0.02);
s4, adding the dispersed phase obtained in the step S2 into the continuous phase obtained in the step S3, continuously heating at 85 ℃, stirring at a rotating speed of 300r/min, standing for layering after 1h, washing an oil phase remained on the surface of the microsphere with ethyl acetate, washing and separating with deionized water, and drying to obtain the embolism microsphere based on the soluble starch.
Example 4 preparation of embolic microspheres based on soluble starch
S1, dissolving 2g of soluble sweet potato starch in 20mL of water, adding 500 mu L of 0.2mol/L sodium hydroxide aqueous solution, and mixing and dissolving to obtain a soluble sweet potato starch solution;
s2, stirring and mixing acrylic acid, ammonium persulfate and N, N' -methylene bisacrylamide with the soluble sweet potato starch solution obtained in the step S1 to obtain a dispersion phase; (the mass ratio of the soluble sweet potato starch to the acrylic acid to the ammonium persulfate to the N, N' -methylene-bisacrylamide is 10: 6: 0.18: 0.14);
s3, mixing the vegetable oil and the Tween 80, heating to 70 ℃, and stirring at the rotating speed of 700r/min to obtain a continuous phase; (the mass ratio of the soluble sweet potato starch, the vegetable oil and the Tween 80 meets 1: 15: 0.4);
s4, adding the dispersed phase obtained in the step S2 into the continuous phase obtained in the step S3, continuously heating at 70 ℃, stirring at a rotating speed of 700r/min, standing for layering after 1h, washing an oil phase remained on the surface of the microsphere with ethyl acetate, washing and separating with deionized water, and drying to obtain the embolism microsphere based on the soluble starch.
Example 5A method for preparing embolic microspheres based on soluble starch
S1, dissolving 2g of soluble sweet potato starch in 20mL of water, adding 500 mu L of 0.2mol/L sodium hydroxide aqueous solution, and mixing and dissolving to obtain a soluble sweet potato starch solution;
s2, stirring and mixing acrylic acid, 2-acrylamide-2-methylpropanesulfonic acid, ammonium persulfate and epoxy chloropropane with the soluble sweet potato starch solution obtained in the step S1 to obtain a dispersion phase; (the mass ratio of the soluble sweet potato starch to acrylic acid: 2-acrylamide-2-methylpropanesulfonic acid, ammonium persulfate and epichlorohydrin satisfies 10: 7.5: 2.5: 0.25: 0.1);
s3, mixing cyclohexane and Tween 60, heating to 85 ℃, and stirring at the rotating speed of 300r/min to obtain a continuous phase; (the mass ratio of the soluble sweet potato starch, the cyclohexane and the Tween 60 meets 1: 15: 0.3);
s4, adding the dispersed phase obtained in the step S2 into the continuous phase obtained in the step S3, continuously heating at 90 ℃, stirring at a rotating speed of 200r/min, standing for layering after 1h, washing an oil phase remained on the surface of the microsphere with ethyl acetate, washing and separating with deionized water, and drying to obtain the embolism microsphere based on the soluble starch.
Comparative example 1
The preparation method is the same as that of example 1, except that the mass ratio of the soluble tapioca starch to acrylic acid in step S2 is 10: 2.5.
comparative example 2
The preparation method is the same as that of example 1, except that the mass ratio of the soluble tapioca starch to acrylic acid in step S2 is 10: 20.
comparative example 3
The preparation method of example 2 is the same, except that the mass ratio of the soluble potato starch to the methacrylic acid in step S2 is 10: 2.5.
comparative example 4
The preparation method of example 2 is the same, except that the mass ratio of the soluble potato starch to the methacrylic acid in step S2 is 10: 20.
comparative example 5
The preparation method is the same as that of example 5, except that the mass ratio of the soluble sweet potato starch to the acrylic acid and the 2-acrylamide-2-methylpropanesulfonic acid in step S2 is 10: 2.5: 1.
comparative example 6
The preparation method is the same as that of example 5, except that the mass ratio of the soluble sweet potato starch to the acrylic acid and the 2-acrylamide-2-methylpropanesulfonic acid in step S2 is 10: 10: 10.
comparative example 7
The same preparation method as in example 1 except that the heating temperature in steps S3 and S4 was 40 ℃.
Comparative example 8
The same preparation method as in example 1 except that the heating temperature in steps S3 and S4 was 120 ℃.
Comparative example 9
The same preparation method as that of example 1 except that the stirring speed in steps S3 and S4 was 100 r/min.
Comparative example 10
The same preparation method as that of example 1 except that the stirring speed in steps S3 and S4 was 900 r/min.
Examples of the experiments
Respectively dispersing 50mg of the embolization microspheres prepared in examples 1 to 5 and comparative examples 1 to 10 into 5mL of 2mg/mL doxorubicin hydrochloride solution, shaking at a rotation speed of 100rpm/min for 24h, and respectively calculating the drug loading rate and the encapsulation rate of the embolization microspheres according to the residual doxorubicin hydrochloride concentration in the solution, wherein the drug loading rate is the drug mass in the embolization microspheres/the quality of the embolization microspheres, and the encapsulation rate is the drug mass in the embolization microspheres/the drug input rate × 100%, and the results are shown in table 1:
TABLE 1
As can be seen from Table 1, the drug loading and encapsulation efficiency of examples 1-5 are both high, especially the best of example 1; the comparative examples 1 to 10 in which the types and the amounts of the raw materials or the experimental parameters were changed could not be used to prepare microspheres effectively, or could not be used as embolization microspheres in practical applications. The invention shows that the medicine carrying amount of the prepared embolism microsphere to the doxorubicin hydrochloride is up to 191mg/g, the entrapment rate is up to 96 percent, and the medicine carrying amount and the entrapment rate of the starch embolism microsphere are effectively improved by specifically controlling the type and the dosage of the raw materials and the parameters of each step.
In conclusion, the embolism microsphere prepared by the invention is rich in porous structure, the pores extend to the interior of the microsphere, so that the specific surface area of the embolism microsphere is larger, and the surface of the embolism microsphere is provided with a large number of hydrophilic polar groups, so that the embolism microsphere can generate electrostatic adsorption with a medicament, and a good medicament slow-release effect of the embolism microsphere is realized. The embolism microsphere prepared by the invention has the drug loading of 191mg/g for doxorubicin hydrochloride and the entrapment rate of 96%, and effectively improves the drug loading and the entrapment rate of the starch embolism microsphere.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. The embolism microsphere is characterized in that the embolism microsphere is prepared by soluble starch, an olefin polar monomer, an initiator and a cross-linking agent through an inverse suspension polymerization technology, wherein a continuous phase comprises an oil phase and a surfactant, and a disperse phase comprises the soluble starch, the olefin polar monomer, the initiator and the cross-linking agent.
2. The embolic microsphere of claim 1, wherein the mass ratio of the soluble starch, the olefinic polar monomer, the initiator and the cross-linking agent is 10: 5-10: 0.1-0.3: 0.1 to 0.2.
3. The embolic microsphere of claim 1, wherein the olefinic polar monomer comprises one or more of acrylic acid, methacrylic acid, or 2-acrylamido-2-methylpropanesulfonic acid.
4. The embolic microsphere of claim 1, wherein the soluble starch comprises one or more of soluble corn starch, soluble tapioca starch, soluble potato starch, or soluble sweet potato starch.
5. The embolic microsphere of claim 1, wherein the initiator comprises one or more of sodium persulfate, ammonium persulfate, or potassium persulfate.
6. The embolic microsphere of claim 1, wherein the cross-linking agent comprises one or more of epichlorohydrin, N' methylenebisacrylamide, sodium trimetaphosphate, or glutaraldehyde.
7. The embolization microsphere of claim 1, wherein the mass ratio of the soluble starch, the oil phase and the surfactant is 1: 10-20: 0.02 to 0.5.
8. A method for preparing the embolism microsphere of any one of claims 1 to 7, which is characterized by comprising the following steps:
s1, mixing an olefin polar monomer, an initiator, a cross-linking agent and a soluble starch solution to obtain a dispersed phase;
s2, mixing and heating the oil phase and the surfactant to obtain a continuous phase;
s3, adding the dispersed phase obtained in the step S1 into the continuous phase obtained in the step S2, heating, standing, cleaning and drying to obtain the embolism microsphere based on the soluble starch.
9. Use of an embolization microsphere according to any one of claims 1 to 7 as a drug delivery vehicle.
10. The use of claim 9, wherein the medicament comprises doxorubicin hydrochloride.
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