HYDRATION GEL PARTICLE FOR CHEMOEMBOLIZATION COMPRISING BIODEGRADABLE POLYMER

Abstract

The present invention relates to microparticles that can be used as drug-loaded hydrogel particles for embolization and a method for manufacturing same. The microparticles of the present invention have a very excellent anticancer agent adsorption ability, a short anticancer agent adsorption time, and a controllable decomposition time when administered in vivo. Therefore, when the microparticles of the present invention are used in chemoembolization, not only the anticancer effect is excellent, but also side effects can be minimized.

Claims

1. Microparticles comprising: (a) gelatin, collagen, or a mixture thereof; and (b) a biodegradable anionic polymer.

2. The microparticles of claim 1, wherein the biodegradable anionic polymer is an oxidized anionic polymer.

3. The microparticles of claim 1, wherein the biodegradable anionic polymer is selected from the group consisting of chondroitin sulfate, dextran sulfate, dermatan sulfate, sodium alginate sulfate, heparin, keratan sulfate, hyaluronic acid, or a mixture thereof.

4. The microparticles of claim 1, wherein the biodegradable anionic polymer is selected from the group consisting of oxidized chondroitin sulfate, oxidized dextran sulfate, oxidized dermatan sulfate, oxidized sodium alginate sulfate, oxidized heparin, oxidized keratan sulfate, oxidized hyaluronic acid, or a mixture thereof.

5.-7. (canceled)

8. The microparticles of claim 7, wherein the drug is an anticancer drug.

9. The microparticles of claim 8, wherein the anticancer drug is an anthracycline-based anticancer drug.

10. The microparticles of claim 9, wherein the anthracycline-based anticancer drug is selected from the group consisting of daunorubicin, doxorubicin, epirubicin, idarubicin, gemcitabine, mitoxantrone, pirarubicin, and valrubicin.

11. The microparticles of claim 8, wherein the anticancer drug is irinotechan.

12. The microparticles of claim 1, wherein the microparticles are microspheres.

13. A method for manufacturing microparticles, the method comprising: (a) dissolving gelatin, collagen, or a mixture thereof in an aqueous solvent; (b) dissolving a biodegradable anionic polymer in an aqueous solvent; and (c) mixing the solution of gelatin, collagen, or the mixture thereof and the biodegradable anionic polymer solution.

14. The method of claim 13, wherein the biodegradable anionic polymer is an oxidized anionic polymer.

15. The method of claim 13, wherein the biodegradable anionic polymer is selected from the group consisting of chondroitin sulfate, dextran sulfate, dermatan sulfate, sodium alginate sulfate, heparin, keratan sulfate, hyaluronic acid, or a mixture thereof.

16. The method of claim 13, wherein the biodegradable anionic polymer is selected from the group consisting of oxidized chondroitin sulfate, oxidized dextran sulfate, oxidized dermatan sulfate, oxidized sodium alginate sulfate, oxidized heparin, oxidized keratan sulfate, oxidized hyaluronic acid, or a mixture thereof.

17. The method of claim 13, further comprising (d) adding the mixture solution as the resultant product in step (c) to an organic solvent, followed by emulsification through stirring.

18. The method of claim 17, wherein the organic solvent is n-butyl acetate, cellulose acetate butyrate, medium chain triglyceride (MCT) oil, or a mixture solvent thereof.

19. The method of claim 17, further comprising (e) washing and drying the microparticles generated by the emulsification.

20. The method of claim 19, wherein the washing is conducted with an organic solvent selected from n-butyl acetate, cellulose acetate butyrate, medium chain triglyceride (MCT) oil, or a mixture solvent thereof.

21. The method of claim 17, further comprising (f) subjecting the microparticles generated by the emulsification to thermal treatment at a temperature of 90 to 200° C. for 0.5 to 5 hours.

22. The method of claim 21, further comprising (g) washing the thermally treated microparticles.

23. The method of claim 22, further comprising (h) dehydrating and drying the microparticles.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1 shows images of powdered microspheres and hydrogel particles manufactured through thermal treatment of the present disclosure.

[0056] FIG. 2A shows an enlarged image of observation of doxorubicin-adsorbed hydrogel particles of the present disclosure; and FIG. 2B illustrates the doxorubicin adsorption ability of hydrogel particles of the present disclosure over time.

[0057] FIG. 3 is a graph showing the degradability of the hydrogel particles of the present disclosure according to the degree of substitution of an anionic polymer.

[0058] FIG. 4 shows the drug loading ability of the hydrogel particles of the present disclosure according to the presence or absence of thermal curing.

[0059] FIG. 5 shows the drug adsorption ability of hydrogel particles manufactured using a non-oxidized anionic polymer, in order to investigate the drug adsorption ability according to the oxidation or non-oxidation of an anionic polymer contained in the hydrogel particles of the present disclosure.

[0060] FIG. 6 shows the drug release ability of DC Bead and HepaSphere, existing commercially available products, in order to investigate the drug release ability of the hydrogel particles of the present disclosure.

[0061] FIG. 7 shows an image of hydrogel particles manufactured of collagen and oxidized chondroitin sulfate of the present disclosure and an image of hydrogel particles after loading doxorubicin.

[0062] FIG. 8 shows an image of hydrogel particles manufactured of gelatin and oxidized dextran sulfate of the present disclosure and an image of hydrogel particles after loading doxorubicin.

DETAILED DESCRIPTION

[0063] Hereinafter, the present disclosure will be described in more detail with reference to examples. These examples are provided only for the purpose of illustrating the present disclosure in more detail, and therefore, according to the purpose of the present disclosure, it would be apparent to a person skill in the art that these examples are not construed to limit the scope of the present disclosure.

EXAMPLES

[0064] Throughout the present specification, the “%” used to express the concentration of a specific material, unless otherwise particularly stated, refers to (wt/wt) % for solid/solid, (wt/vol) % for solid/liquid, and (vol/vol) % for liquid/liquid.

Example 1

Oxidation Reaction of Chondroitin Sulfate

[0065] First, 50 g of chondroitin sulfate was completely dissolved in 450 ml of distilled water. Then, 5 g of sodium periodate was completely dissolved in 50 ml of distilled water, and this solution was added to 450 ml of the chondroitin sulfate solution, followed by stirring at room temperature for 18 hours. After the reaction was completed, the residual sodium periodate was removed by ultra-filtration, and oxidized chondroitin sulfate having a degree of substitution (DS) of about 25% was obtained by vacuum drying. The results of the degree of substitution according to the ratio of chondroitin sulfate and sodium periodate added are shown in Table 1 below.

TABLE-US-00001 TABLE 1 Degree of Chondroitin Sodium Distilled Reaction substitution Sulfate Periodate water time (DS) 50 g 15 g 500 ml 18 hours 75-80% 12 g 55-60% 6 g 30-35% 5.5 g 25-30% 5 g 20-25% 4.5 g 16-20%

Example 2

Composition Ratio of Drug-Loaded Hydrogel Particles for Embolization

[0066] To manufacture drug-loaded hydrogel particles for embolization of the present disclosure, the composition proportions of gelatin and the anionic polymer oxidized chondroitin sulfate and the degree of substitution of the oxidized chondroitin sulfate are shown in Table 2 below. A hydrogel stock solution was prepared by mixing a gelatin aqueous solution and an oxidized chondroitin sulfate aqueous solution, and the contents of gelatin and oxidized chondroitin sulfate in Table 2 represent the contents of the two substances in the hydrogel stock solution prepared by mixing the two aqueous solutions.

TABLE-US-00002 TABLE 2 Gelatin Oxidized chondroitin Composition (%) sulfate (%) 1 3 7.5% DS of about 59% 2 4 3 5 4 5 .sup. 5% DS of about 41% 5 7.5% 6 5 .sup. 5% DS of about 32% 7 7.5% 8  10% 9 5 7.5% DS of about 20% 0 10 * The percent (%) indicating the content of each ingredient in the hydrogel stock solution

Example 3

Manufacture of Drug-Loaded Hydrogel Particles for Embolization 1 (Thermal Treatment)

[0067] First, 60 ml of a gelatin solution and 60 ml of an oxidized chondroitin sulfate solution were mixed in a tube according to each composition shown in Table 2 above, and the tube was immersed in a water bath at 50° C., followed by stirring for 10 minutes. Then, 120 ml of the mixture solution of the gelatin solution and the oxidized chondroitin sulfate solution was sprayed into 600 ml of a collection solution (medium chain triglyceride oil (MCT oil)); or n-butyl acetate (containing 10% cellulose acetate butyrate)), maintained at 4° C., by using an encapsulator, while the collection solution was stirred, thereby preparing an emulsion (microparticles). After the spraying of the mixture solution was completed, the stirring was stopped, the particles formed in the collection solution were settled by a long period of stabilization, and the collection solution in the upper layer was discarded. Washing was sequentially conducted using n-butyl acetate and acetone, and vacuum drying was performed, thereby obtaining microspheres (microparticles). The obtained microspheres were thermally treated at 150° C. for 2 hours, and immersed in distilled water until completely swollen or hydrated, and then hydrogel particles with a diameter of 100-300 μm were collected through sieving. The collected hydrogel particles were dehydrated with acetone, followed by vacuum drying, thereby obtaining final powdered microspheres. Images of the manufactured final powdered microspheres and the hydrogel particles upon swelling are shown in FIG. 1.

Example 4

Drug Adsorption Test of Drug-Loaded Hydrogel Particles for Embolization

[0068] A doxorubicin adsorption test was conducted on the microspheres manufactured according to each of the compositions in Example 2 by the method in Example 3. First, a 5 mg/ml solution of doxorubicin was prepared by dissolving 50 mg of doxorubicin in 10 ml of distilled water. Then, about 270-300 mg of the manufactured microspheres were collected in a 10 ml-glass vial, and 10 ml of the prepared 5 mg/ml doxorubicin solution was slowly added thereto. Shaking was conducted three to five times once every two minutes so that the microspheres were well mixed with doxorubicin. After 5, 10, and 20 minutes, the content of doxorubicin contained in the supernatant was measured to check the amount of the drug adsorbed to the microspheres. The total volume of the drug-adsorbed hydrogel particles was about 2 ml. The image of the drug-adsorbed hydrogel particles is shown in FIG. 2A, and the test results are shown in Table 3 and FIG. 2b. As can be seen from the microsphere weights in Table 3, the degree of swelling of microspheres after drug adsorption varied depending on the degree of substitution of chondroitin sulfate. Specifically, the volume after hydrogenation became larger as the degree of substitution of chondroitin sulfate was lower.

TABLE-US-00003 TABLE 3 Oxidized Time of 99% Gelatin chondroitin Microsphere doxorubicin Composition (%) sulfate weight adsorption 1 3 7.5% DS of 300 mg 20 minutes 2 4 about 59% 20 minutes 3 5 5 minutes 4 5 .sup. 5% DS of 280 mg 10 minutes 5 7.5% about 41% 5 minutes 6 5 .sup. 5% DS of 280 mg 20 minutes 7 7.5% about 32% 10 minutes 8  10% 270 mg 10 minutes 9 5 7.5% DS of 270 mg 10 minutes 10 10 about 20% 20 minutes

Example 5

Degradation Test of Drug-Loaded Hydrogel for Embolization 1 (Degradability Depending on Degree of Substitution)

[0069] To investigate the effect of the degree of substitution (DS) of oxidized chondroitin sulfate on the hydrogel degradability, microspheres were manufactured using composition 3 (DS of about 59%), composition 5 (DS of about 41%), and composition 9 (DS of about 20%) in Table 2 by the method in Example 3, respectively, and thermally treated at 150° C. for 2 hours. The manufactured microspheres were weighed to 100 mg each and swollen in 15 ml of 1× PBS, and then the time taken for the microspheres to completely degrade was checked with shaking at 100 rpm in a shaking water bath. The results are shown in Table 4. As shown in Table 4, the time of degradation of microspheres became longer as the degree of substitution of chondroitin sulfate increased.

TABLE-US-00004 TABLE 4 Degree of Time of substitution thermal Time of Hydrogel Composition (DS) treatment degradation Microsphere 1 3 About 59% 5 hours About 30 days Microsphere 2 5 About 41% 5 hours About 14 days Microsphere 3 9 About 20% 5 hours About 7 days

Example 6

Degradation Test of Drug-Loaded Hydrogel for Embolization 2 (Degradability Depending on Time of Thermal Treatment)

[0070] To investigate the effect of the time of thermal treatment on the hydrogel degradability, microspheres were manufactured using composition 7 in Table 2 by the method in Example 3, and thermally treated at 150° C. for 1, 2, and 5 hours, separately. The manufactured microspheres were weighed to 100 mg each and swollen in 15 ml of 1× PBS, and then the time taken for the microspheres to completely degrade was checked with shaking at 100 rpm in a shaking water bath. The results are shown in FIGS. 3 and 4. As shown in FIGS. 3 and 4, the time of degradation became relatively longer as the time of thermal curing increased.

Example 7

Degradation Test of Drug-Loaded Hydrogel for Embolization 3 (Degradability Depending on Content of Gelatin)

[0071] To investigate the effect of the content of gelatin on the hydrogel degradability, microspheres were manufactured using ratios of compositions 1, 2, and 3 (gelatin: 3%, 4%, and 5%, respectively, and oxidized chondroitin sulfate: 7.5%) in Table 2 by the method in Example 3, and thermally treated at 150° C. for 5 hours. The manufactured microspheres were weighed to 100 mg each and swollen in 15 ml of 1× PBS, followed by shaking at 100 rpm in a shaking water bath. The remaining microspheres after one month were weighed to calculate the degree of degradation. The results are shown in Table 5. As shown in Table 5, the rate of degradation became faster as the content of gelatin was lower.

TABLE-US-00005 TABLE 5 Gelatin Time of content thermal Time of Hydrogel Composition (%) treatment degradation Microsphere 4 1 3 5 hours About 7 days Microsphere 5 2 4 5 hours About 21 days Microsphere 6 3 5 5 hours About 30 days

Example 8

Degradation Test of Drug-Loaded Hydrogel for Embolization 4 (Degradability Depending on Content of Oxidized Chondroitin Sulfate)

[0072] To investigate the effect of the content of oxidized chondroitin sulfate on the hydrogel degradability, microspheres were manufactured using ratios of compositions 6, 7, and 8 (gelatin: 5%, and oxidized chondroitin sulfate: 5%, 7.5%, and 10%, respectively) in Table 2 by the method in Example 3, and thermally treated at 150° C. for 5 hours. The manufactured microspheres were weighed to 100 mg each and swollen in 15 ml of 1× PBS, followed by shaking at 100 rpm in a shaking water bath. The remaining microspheres after one month were weighed to calculate the degree of degradation. The results are shown in Table 6. As shown in Table 6, the rate of degradation became faster as the content of oxidized chondroitin sulfate was lower.

TABLE-US-00006 TABLE 6 Oxidized Time of chondroitin thermal Time of Hydrogel Composition sulfate (%) treatment degradation Microsphere 7 6 5 5 hours About 4 days Microsphere 8 7 7.5 5 hours About 7 days Microsphere 9 8 10 5 hours About 12 days

Example 9

Difference in Drug Loading Ability of Drug-Loaded Hydrogel for Embolization According to Presence or Absence of Thermal Treatment

[0073] Microspheres were manufactured using the ratio of composition 3 in Table 2 by the method in Example 3. The microspheres having undergone thermal treatment for 2 hours and the microspheres not having undergone thermal treatment were taken at an amount of 280 mg each, and, by the method in Example 4, 10 ml of a 5 mg/ml doxorubicin solution was slowly added to check the degree of doxorubicin adsorption. The naked-eye results after a 30-minute observation are shown in FIG. 5 (Left panel: without thermal treatment, and right panel: with thermal treatment). As shown in the left panel of FIG. 5, in the absence of thermal treatment, little drug adsorption occurred, and the shape of the microparticles was not maintained due to low hardness thereof.

Example 10

Manufacture of Drug-Loaded Hydrogel Particles for Embolization 2 (Sodium Cyanoborohydride Treatment)

[0074] After 20 ml of a 5% gelatin solution and 20 ml of a 7.5% oxidized chondroitin sulfate solution were mixed in a tube according to the ratio of composition 3 in Table 2, the tube was immersed in a water bath at 50° C., followed by stirring for 10 minutes. Then, 40 ml of the mixture solution was sprayed into 200 ml of the collection solution n-butyl acetate (10% cellulose acetate butyrate), prepared at 4° C., by using an encapsulator, while the collection solution was stirred, thereby preparing an emulsion (microparticles). Then, 1 g of sodium cyanoborohydride (SCBH) was dissolved in 10 ml of distilled water, and this solution was slowly added to the collection solution containing the microparticles, followed by reaction for 24 hours. After the reaction was completed, the stirring was stopped, the particles formed in the collection solution were settled by a long period of stabilization, and the collection solution in the upper layer was discarded. Washing was sequentially conducted using n-butyl acetate and acetone. The microparticles were completely swollen in distilled water, and sodium cyanoborohydride remaining in the microparticles was removed by carrying out stirring for 30 minutes and exchanging of distilled water three times, and then hydrogel particles with a diameter of 100-300 μm were collected through sieving. The collected hydrogel particles were dehydrated with acetone, followed by vacuum drying, thereby obtaining final microspheres.

Example 11

Manufacture of Drug-Loaded Hydrogel Particles for Embolization 3 (Glutaraldehyde Treatment)

[0075] After 20 ml of a 5% gelatin solution and 20 ml of a 7.5% oxidized chondroitin sulfate solution were mixed in a tube according to the ratio of composition 3 in Table 2, the tube was immersed in a water bath at 50° C., followed by stirring for 10 minutes. Then, 40 ml of the mixture solution was sprayed into 200 ml of the collection solution n-butyl acetate (10% cellulose acetate butyrate), prepared at 4° C., by using an encapsulator, while the collection solution was stirred, thereby preparing an emulsion (microparticles). Then, 10 ml of 25% glutaraldehyde (GA) was slowly added to the collection solution containing the microparticles, followed by reaction for 24 hours. After the reaction was completed, the stirring was stopped, and the particles were settled by a long period of stabilization, the collection solution in the upper layer was discarded. Washing was sequentially conducted using n-butyl acetate and acetone. The microparticles were completely swollen in distilled water, and glutaraldehyde remaining in the microparticles was removed by carrying out stirring for 30 minutes and exchanging of distilled water three times, and then hydrogel particles with a diameter of 100-300 μm were collected through sieving. The collected hydrogel particles were dehydrated with acetone, followed by vacuum drying, thereby obtaining final microspheres.

Example 12

Manufacture of Drug-Loaded Hydrogel Particles for Embolization 4 (EDC/NHS Treatment)

[0076] After 20 ml of a 5% gelatin solution and 20 ml of a 7.5% chondroitin sulfate solution were mixed in a tube according to the ratio of composition 3 in Table 2, the tube was immersed in a water bath at 50° C., followed by stirring for 10 minutes. Then, 40 ml of the mixture solution was sprayed into 400 ml of the collection solution n-butyl acetate (10% cellulose acetate butyrate), prepared at 4° C., by using an encapsulator, while the collection solution was stirred, thereby preparing an emulsion (microparticles). Then, 1 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and 1 g of N-hydroxysuccinimide (NHS) were dissolved in 10 ml of distilled water, and this solution was slowly added to the collection solution containing the microparticles, followed by reaction for 24 hours. After the reaction was completed over, the stirring was stopped, the particles were settled by a long period of stabilization, and the collection solution in the upper layer was discarded. Washing was sequentially conducted using n-butyl acetate and acetone. The microparticles were completely swollen in distilled water, and EDC/NHS remaining in the microparticles was removed by carrying out stirring for 30 minutes each and exchanging of distilled water three times, and then hydrogel particles with a diameter of 100-300 μm were collected through sieving. The collected hydrogel particles were dehydrated with acetone, followed by vacuum drying, thereby obtaining final microspheres.

Example 13

Difference in Ability of Drug-Loaded Hydrogel Particles for Embolization According to Manufacturing Method (Drug Adsorption Time and Degradability)

[0077] In order to investigate the difference in drug loading ability according to the manufacturing method, a doxorubicin adsorption test was performed, by the method in Example 4, on a total of four types of microspheres, that is, hydrogel particles manufactured through thermal treatment in Example 3, hydrogel particles manufactured by addition of sodium cyanoborohydride in Example 10, hydrogel particles manufactured by addition of glutaraldehyde in Example 11, and hydrogel particles manufactured by addition of EDC/NHS in Example 12. In addition, hydrogel particles without doxorubicin adsorption were weighed to 100 mg each and placed in 15 ml of 1× PBS, and the degradability was checked for three months with shaking at 100 rpm in a shaking water bath. The results are shown in Table 7. As shown in Table 7, the drug adsorption ability of the hydrogel particles manufactured using SCBH, GA, or EDC/NHS was significantly lower than that of the hydrogel particles manufactured by thermal curing. The hydrogel particles manufactured by thermal curing can control the time of degradation thereof by the degree of substitution (DS) of chondroitin sulfate (CS) but showed no great difference in drug adsorption ability. However, the microspheres manufactured using SCBH, GA, or EDC/NHS can control the time of degradation thereof according to the amount of SCBH, GA, or EDC/NHS used and also showed a significant difference in drug adsorption ability.

TABLE-US-00007 TABLE 7 Time of 99% Degree of Micro- Crosslinking doxorubicin 100% Hydrogel spheres method adsorbed degradation Microsphere 10 300 mg Thermal curing CS (DS59%) about 5 minutes about 12 weeks Microsphere 11 CS (DS41%) about 5 minutes about 10 weeks Microsphere 12 300 mg Sodium cyanoboro 1 g about 30 minutes 13 weeks or more Microsphere 13 hydride (SCBH) 0.5 g about 60 minutes about 8 weeks Microsphere 14 300 mg Glutaraldehyde (GA) 10 ml 40 minutes or more 13 weeks or more Microsphere 15 5 ml 60 minutes or more about 10 weeks Microsphere 16 300 mg EDC/NHS 1 g/1 g about 40 minutes 13 weeks or more Microsphere 17 0.5 g/0.5 g 60 minutes or more about 8 weeks * Observed once a week

Example 14

Manufacture of Drug-Loaded Hydrogel Particles for Embolization 5 (Non-Oxidized Chondroitin Sulfate vs. Oxidized Chondroitin Sulfate)

[0078] In order to investigate the effect of the oxidation of chondroitin sulfate on drug-adsorption of hydrogel, hydrogel particles were manufactured by the same method as in Example 3 except that non-oxidized chondroitin sulfate was used instead of oxidized chondroitin sulfate. Then, the drug adsorption ability of the manufactured hydrogel particles was checked by the method in Example 4. The results are shown in FIG. 6. As shown in FIG. 6, favorable doxorubicin adsorption did not occur in the hydrogel particles manufactured of non-oxidized chondroitin sulfate. The reason seems to be that chondroitin sulfate, when not oxidized, cannot conjugate to gelatin, and thus non-oxidized chondroitin sulfate was all washed off and removed during the manufacture of microspheres. Therefore, it could be seen that hydrogel particles manufactured of non-oxidized chondroitin sulfate showed a very poor drug adsorption ability.

Example 15

Drug Release Comparison Test of Drug-Loaded Hydrogel for Embolization of Present Disclosure and Commercially Available Drug-Loaded Embolic Agents

[0079] After 50 mg of doxorubicin was adsorbed onto the microspheres 2 (100-300 μm) in Example 5 and the commercially available embolic agents HepaSphere™ (200-400 μm) and DC Bead™ (100-300 μm), a release test was conducted in 1× PBS solution at 50 rpm. As shown in the results of FIG. 7, HepaSphere™ and DC Bead™ hardly release the drug after 2 hours, but the hydrogel (microsphere 2, Bead) presented in the present disclosure continuously released the drug. In addition, microsphere 2 (Bead) completely degraded over one month to release the overall drug, showing a final drug release rate of 100%, but the non-degradable HepaSphere™ and DC Bead™ showed a final drug release rate of less than 30%, indicating a very great difference in drug release rate.

Example 16

Manufacture of Drug-Loaded Hydrogel Particles for Embolization 6 (Collagen and Oxidized Chondroitin Sulfate Particles)

[0080] After 20 ml of a 10% gelatin solution and 20 ml of a 7.5% oxidized chondroitin sulfate solution were mixed, the mixture was stirred for 10 minutes. Then, the mixture solution was sprayed into 200 ml of the collection solution n-butyl acetate (10% cellulose acetate butyrate), prepared at 4° C., by using an encapsulator, while the collection solution was stirred, thereby preparing an emulsion (microparticles). After the spraying was completed, the stirring was stopped, the particles were settled by a long period of stabilization, and the collection solution in the upper layer was discarded. Washing was sequentially conducted using n-butyl acetate and acetone, and followed by vacuum drying, thereby obtaining microparticles. The obtained microparticles were subjected to thermal treatment at 150° C. for 2 hours, and then completely swollen in distilled water, and hydrogel particles with a diameter of 100-300 μm were collected through sieving. The collected hydrogel particles were dehydrated with acetone, followed by vacuum drying, thereby obtaining final powdered microspheres. The images of the hydrogel particles when the manufactured powdered microspheres were swollen in distilled water and when doxorubicin was loaded are shown in FIG. 8.

Example 17

Manufacture of Drug-Loaded Hydrogel Particles for Embolization 8 (Gelatin and Oxidized Dextran Sulfate Particles)

[0081] After 20 ml of a 5% gelatin solution and 20 ml of a 7.5% oxidized dextran sulfate (DS 20%) were mixed using the ratio of composition 3 in Table 2, the mixture was stirred for 10 minutes. Then, the mixture solution was sprayed into 200 ml of the collection solution n-butyl acetate (10% cellulose acetate butyrate) at 4° C. by using an encapsulator while the collection solution was stirred, thereby preparing an emulsion (microparticles). After the spraying was completed, the stirring was stopped, the particles were settled by a long period of stabilization, and the collection solution in the upper layer was discarded. Washing was conducted using n-butyl acetate and acetone, and followed by vacuum drying, thereby obtaining microparticles. The obtained microparticles were subjected to thermal treatment at 150° C. for 2 hours, and completely swollen in distilled water, and hydrogel particles with a diameter of 100-300 μm were collected through sieving. The collected hydrogel particles were dehydrated with acetone, followed by vacuum drying, thereby obtaining final powdered microspheres. The images of the hydrogel particles when the manufactured powdered microspheres were swollen in distilled water and when doxorubicin was loaded are shown in FIG. 9.