KR102386631B1 - Microbead for embolization and composition for treatment of proliferative diseases - Google Patents

Abstract

An embodiment includes a biocompatible polymer, and the polymer is intended to provide microbeads for embolization including an iron adsorption block capable of adsorbing an iron component. The microbead for embolization according to the present embodiment adsorbs iron and effectively blocks the iron component delivered to the cancer cells, so that through the embolization procedure, it has a very improved effect in the treatment of cancers such as liver cancer.

Description

Microbeads for embolization and compositions for treating proliferative diseases

The present application relates to microbeads for embolization and a composition for treating proliferative diseases.

Embolization or embolization is a substance that treats tumors by inserting specific substances into blood vessels to block blood that delivers oxygen and nutrients to tumor tissues.

As a general embolic insert must have biocompatible, hydrophilic, non-toxic and biodegrability conditions, micro-particles such as chitosan, starch, gelatin, albumin, sodium alginic acid, etc. are mainly used as embolic materials. are researching

In particular, gelatin is used by applying what was developed as a hemostatic product using mammalian (cow, pig) gelatin in the 1960s, and has an irregular shape by cutting or mixing the porous sponge sheet type. In addition, it is difficult to expect the embolization effect that clinicians want because the gelatin granules are agglomerated during the micro-conduit embolization procedure.

On the other hand, local treatments such as carotid artery chemoembolization (TACE), percutaneous ethanol injection (PEIT), and radiofrequency ablation (RFA) are being used in cases where resection is not applicable among liver cancer patients. In particular, carotid chemoembolization is a procedure that blocks blood vessels by injecting an anticancer agent and Lipiodol through an artery that supplies nutrients and oxygen to the tumor (embolization). However, when complications caused by embolization procedures or drugs occur, the treatment adversely affects the treatment. are reported in various ways. Post-embolization syndrome is the most common complication after carotid artery chemoembolization, and may include vomiting, anorexia, high fever, and abdominal pain. These complications reduce the quality of life of patients, and sometimes even cause treatment to be stopped despite the effective treatment.

Recently, 'microsphere embolization', which developed carotid chemoembolization, has been implemented and it is possible to effectively remove cancer cells using a large amount of anticancer drugs. The microsphere embolization is a method of selectively administering to cancer cells, 'embolic drug-releasing microspheres', which are very small microspheres that contain an anticancer agent and can be slowly released over a long period of time, and continuously inject a high concentration of an anticancer agent into the tumor blood vessels. It has the advantage of having a high treatment response rate and a great effect on inhibition. However, as the drug-releasing microspheres are composed of semi-permanent embolic materials rather than temporary embolic materials, and occlusion of the embolized hepatic artery occurs, repeated procedures are difficult and there is a high risk of exposure to persistent inflammatory reactions.

Korean Publication No. 10-2001-0068458

The present application relates to microbeads for embolization and a composition for treating proliferative diseases, which have improved iron adsorption rate and can effectively inhibit cancer cell proliferation.

The microbead for embolization according to an embodiment includes a biocompatible polymer, and the biocompatible polymer includes a cross-linked gelatin and iron adsorption block.

In one embodiment, the iron adsorption block may include fucoidan and/or polyphenol.

In one embodiment, the polyphenol is a biodegradable anionic polyphenol, from tannin, gallic acid, tannic acid, catechin, epicatechin, epigallocatechin gallate, quercetin, resveratrol, isoflavones, flavonoids, and seaweed-derived polyphenols. It may include one or more selected.

In one embodiment, the gelatin is amination gelatin, and may include cross-linking of cationic amination gelatin and anionic fucoidan.

In one embodiment, the weight ratio of the gelatin to the iron adsorption block may be about 4:1 to about 10:1.

In one embodiment, the gelatin comprises a first gelatin having a first average molecular weight; and a second gelatin having a second average molecular weight smaller than the first average molecular weight.

In one embodiment, the microbead for embolization procedure may have an iron adsorption rate (IAd24; Iron Adsorption 24) of about 5%/100 mg or more after 24 hours based on 100 mg of the microbead for embolization procedure represented by Equation 1 below. there is:

; [Equation 1]

;

Here, IC0 is the initial molar concentration of the FeCl ₃ aqueous solution, and the IC24 is the molar concentration of iron ions in the FeCl ₃ aqueous solution after adding the microbeads for embolization to the FeCl ₃ aqueous solution and leaving it for 24 hours.

In one embodiment, the microbead for embolization procedure may have an iron adsorption rate (IAd48) of about 5%/100 mg or more after 48 hours based on 100 mg of the microbead for embolization procedure represented by the following Equation 2:

; [Equation 2]

;

Here, the IC0 is the initial molar concentration of the FeCl ₃ aqueous solution, and the IC48 is the molar concentration of iron ions in the FeCl ₃ aqueous solution after adding the microbeads for embolization to the FeCl ₃ aqueous solution and leaving it for 48 hours.

The microbead for embolization according to an embodiment includes a biocompatible polymer, and the biocompatible polymer includes cross-linked gelatin and iron adsorption block, and may be combined with an anticancer agent.

In one embodiment, the combined anticancer agent may be one selected from doxorubicin, irinotecan, gemcitabine, oxaliplatin, and docetaxel.

In one embodiment, the microbead for embolization procedure may have an anticancer drug adsorption (AAd) of about 10%/100 mg or more after 1 hour based on 100 mg of the microbead for embolization procedure represented by Equation 6 below. there is:

; [Equation 6]

;

Here, AC0 is the initial mg/ml concentration of the anticancer drug solution, and AC1 is the mg/ml concentration of the anticancer agent in the anticancer drug solution after adding the microbeads for embolization to the anticancer drug solution and leaving it for 1 hour.

The composition for treating a proliferative disease according to an embodiment may include cross-linked gelatin and an iron adsorption block, and may include microbeads for embolization that are combined with an iron component and/or an anticancer agent.

In one embodiment, the proliferative disease may include one or more selected from neovascularization, tumor, cancer, bone disease, fibroproliferative disorder, enlarged prostate, renal cyst, and atherosclerosis.

In one embodiment, the cancer is a solid tumor, blood cancer, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, colorectal cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer It may include one or more selected from cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

The microbead for embolization according to the embodiment includes a polymer including an iron adsorption block capable of adsorbing iron. Accordingly, the microbead for embolization according to the embodiment can effectively adsorb iron.

In addition, the microbeads for embolization according to the embodiment have a high iron adsorption rate after 24 hours and an iron adsorption rate after 48 hours. Accordingly, the microbead for embolization according to the embodiment has a fast iron adsorption property.

Therefore, the microbead for embolization according to the embodiment is injected into the human body, particularly, the hepatic carotid artery, etc. to block the blood supplied to the cancer cells, etc., and is supplied to the cancer cells to block iron ions necessary for the survival and proliferation of cancer cells. .

Accordingly, the microbead for embolization according to the embodiment can effectively necrosis of cancer cells by blocking blood vessels.

In addition, the microbead for embolization according to the embodiment can effectively absorb iron ions that are ejected when cancer cells or the like are necrotic.

Accordingly, the microbead for embolization according to the embodiment can effectively prevent cancer cells from growing again.

The microbead for embolization according to the embodiment can be very effectively used for the treatment of cancer such as liver cancer and the treatment of proliferative diseases.

The low molecular weight microbeads for embolic treatment and the composition for treating proliferative diseases including the same according to the embodiment have low viscosity and can pass through the microtubule, and in the blood vessel for about 1 day to about 10 days, or about 2 days to It is safely absorbed within about 3 days, so recanalization and re-treatment are easy, and normal blood vessels can be maintained and protected during re-treatment. In addition, the low molecular weight microbead for embolization procedure and the composition for treating proliferative disease comprising the same according to the embodiment selectively embolize the lesion blood vessels of the tumor while protecting the normal blood vessels, and side effects such as post-embolism syndrome as well as the inflammatory reaction side effects can be reduced.

The microbead for embolic treatment and the composition for treating proliferative disease comprising the same according to the embodiment are gradually released into the blood as the gelatin beads combined with the iron adsorption block are gradually absorbed into the body, thus selectively exhibiting a safe anticancer effect on cancer cells Side effects are minor. Therefore, it can be used for the treatment of various solid cancers that proliferate by making new blood vessels.

1 is a diagram illustrating a process of manufacturing microbeads for embolization according to an embodiment.
FIG. 2 is a calibration curve showing the absorbance for each concentration of the microbeads for embolization of the present application for light in a wavelength band of 550 nm, which is the basis for calculating the doxorubicin binding rate according to an embodiment.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for explaining the present invention in more detail, and it is for those of ordinary skill in the art to which the present invention pertains that the scope of the present invention is not limited by these examples according to the gist of the present invention. it will be self-evident

The microbead for embolization according to the embodiment includes a biocompatible polymer. The microbead for embolization according to the embodiment may be composed of the biocompatible polymer.

The microbead for embolization according to the embodiment may contain the biocompatible polymer in an amount of about 80 parts by weight or more based on 100 parts by weight of the bead. The microbead for embolization according to the embodiment may contain the biocompatible polymer in an amount of about 90 parts by weight or more based on 100 parts by weight of the bead. The microbead for embolization according to the embodiment may contain the biocompatible polymer in an amount of about 95 parts by weight or more based on 100 parts by weight of the bead. The microbead for embolization according to the embodiment may contain the biocompatible polymer in an amount of about 97 parts by weight or more based on 100 parts by weight of the bead. The microbead for embolization according to the embodiment may contain the biocompatible polymer in an amount of about 99 parts by weight or more based on 100 parts by weight of the bead.

The biocompatible polymer means a polymer that does not cause a problem in the human body when injected into the human body. The biocompatible polymer may be a cross-linked biodegradable polymer that can be decomposed in the body after a certain period of time while having excellent mechanical properties. The biocompatible polymer may be a cross-linked biodegradable polymer. The biocompatible polymer may be an enzyme-degradable biodegradable polymer or a chemically hydrolyzed biodegradable polymer. The biocompatible polymer may be an enzyme-decomposable biodegradable polymer that is easily decomposed by enzymes present in the body's metabolic system.

In addition, due to the biodegradability of the biocompatible polymer, there is no problem of causing inflammation in the body or spreading to other organs through blood vessels to cause cerebral thrombosis.

The biocompatible polymer may include cross-linked gelatin and an iron adsorption block (iron adsorption polymer). The iron adsorption block (iron adsorption polymer) may perform an iron adsorption function in the biocompatible polymer.

The iron adsorption block may include fucoidan and/or polyphenol. Alternatively, the iron adsorption block may include fucoidan or fucoidan and polyphenol.

The iron component (Fe) adsorption block may include a high content of hydroxyl groups (-OH). Accordingly, the iron adsorption block can adsorb a large amount of iron ions.

The polyphenol (polyphenol) is an aromatic alcohol compound extracted from plants. The polyphenol may have a plurality of hydroxyl groups as a functional group having two or more phenol groups in one molecule. The polyphenol is a biodegradable anionic polyphenol, and includes at least one selected from tannin, gallic acid, tannic acid, catechin, epicatechin, epigallocatechin gallate, quercetin, resveratrol, isoflavones, flavonoids, and seaweed-derived polyphenols. may be doing

In addition, the polyphenol may include catechin extracted from green tea, resveratrol extracted from wine, or quercetin extracted from apple or onion. In addition, the polyphenol may include flavonoids extracted from fruits or isoflavones extracted from soybeans.

The polyphenol may include epigallocatechin gallate (EGCG).

Since the microbead for embolization according to the embodiment includes the iron adsorption block, it is possible to effectively adsorb iron ions.

The gelatin may be amination gelatin, and the microbead for embolization may include a cross-linking of cationic amination gelatin and anionic fucoidan. The gelatin may include an amine group and a carboxylic acid group. In this case, the amination gelatin may have a relatively high content of the amine group. More specifically, the amination gelatin may include an improved content of amine groups by reacting commercially available gelatin with amines. Examples of the amine include ethylenediamine (1,2-diaminoethane), 1,1-dimethylethylenediamine, 1,2-dimethylethylenediamine, ethambutol, tetra kiss dimethylaminoethylene (tetrakis(dimethylamino)ethylene) or tetramethylethylenediamine (TMEDA), and the like.

The weight ratio of the gelatin to the iron adsorption block may be about 4:1 to about 10:1, but is not limited thereto. The weight ratio of the gelatin to the iron adsorption block is from about 4:1 to about 10:1, from about 4:1 to about 9:1, from about 4:1 to about 8:1, from about 4:1 to about 7:1, about 4:1 to about 6: 1, about 4:1 to about 5: 1, about 5: 1 to about 10:1, about 5: 1 to about 9: 1, about 5: 1 to about 8:1, about 5: 1 to about 7: 1, about 5: 1 to about 6: 1, about 6: 1 to about 10: 1, about 6: 1 to about 9: 1, about 6: 1 to about 8: 1, about 6:1 to about 7:1, about 7:1 to about 10:1, about 7:1 to about 9:1, about 7:1 to about 8:1, about 8:1 to about 10:1, from about 8:1 to about 9:1, or from about 9:1 to about 10:1. The weight ratio of the gelatin to the iron adsorption block may be about 5:1 to about 7:1.

In addition, the biocompatible polymer may include gelatin. The biocompatible polymer may include gelatin having different molecular weights. The biocompatibility may include a first gelatin having a first average molecular weight and a second gelatin having a second average molecular weight smaller than the first average molecular weight. In addition, the biocompatible polymer further comprises a third gelatin having a third average molecular weight smaller than the second average molecular weight, and the first gelatin, the second gelatin and the third gelatin may be cross-linked with each other. . In addition, the biocompatible polymer further comprises a fourth gelatin having a fourth average molecular weight that is smaller than the third average molecular weight, and the first gelatin, the second gelatin, the third gelatin and the fourth gelatin are each other. can be cross-linked.

The first average molecular weight may be 40,000 to 100,000, 15,000 to 39,000, or 5,000 to 14,000, and the second average molecular weight may be 15,000 to 39,000, 5,000 to 14,000, or 500 to 4,000.

The first average molecular weight may be 40,000 to 100,000 or 15,000 to 39,000, the second average molecular weight may be 15,000 to 39,000 or 5,000 to 14,000, and the third average molecular weight may be 5,000 to 14,000 or 500 to 4,000.

In addition, the first average molecular weight may be 40,000 to 100,000, the second average molecular weight may be 15,000 to 39,000, the third average molecular weight may be 5,000 to 14,000, and the fourth average molecular weight may be 500 to 4,000. The first average molecular weight is the first average molecular weight is 40,000 to 60,000, the second average molecular weight is 15,000 to 30,000, the third average molecular weight is 7,000 to 12,000, and the fourth average molecular weight is 2,000 to about 5,000 days. can

The gelatin may include more gelatin having a relatively high average molecular weight than gelatin having a relatively low average molecular weight. In this case, the microbeads for embolization, which are formed by crosslinking the gelatin, are decomposed relatively slowly in the body.

The gelatin may include more gelatin having a relatively low average molecular weight than gelatin having a relatively high average molecular weight. In this case, the microbeads for embolization, which are formed by crosslinking the gelatin, are decomposed relatively quickly in the body.

When the gelatin included in the biocompatible polymer includes a first gelatin having a first average molecular weight and a second gelatin having a second average molecular weight smaller than the first average molecular weight, based on 100 parts by weight of the gelatin, the The first gelatin may be included as about 80 parts by weight or less, about 75 parts by weight or less, about 70 parts by weight or less, about 65 parts by weight or less, or about 60 parts by weight or less.

The average molecular weight to be described above or to be described later means a weight average molecular weight. In addition, the unit of the average molecular weight may be a dalton.

The average molecular weight of the first gelatin, the second gelatin, the third gelatin, and the fourth gelatin may be adjusted by a hydrolysis process. That is, gelatin having a high average molecular weight is hydrolyzed, and gelatin having a low average molecular weight can be produced.

The gelatin may include mammalian-derived gelatin or fish-derived gelatin. In particular, when the gelatin includes the fish-derived gelatin, concerns about the occurrence of mad cow disease or foot-and-mouth disease caused by gelatin using conventional cattle or pigs can be solved.

In addition, when the gelatin is formed of the fish-derived gelatin, the microbeads for embolization according to the embodiment may be formed at a relatively low temperature and may have a uniform porous spherical shape.

The gelatin may include glycine (GLYSINE), proline (PROLINE), and hydroxyproline (HYDROXYPROLINE). Accordingly, the microbead for embolization according to the embodiment may have elasticity, flexibility, and expandability according to the reaction conditions. Accordingly, the microbead for embolization according to the embodiment may be applied to the blood vessel to predict the blood closure time.

The gelatin may be fish-derived gelatin. The fish-derived gelatin is prepared from the fish skin of turbulent fish species, and may have a property of gelling at a lower temperature than gelatin using cattle or pigs. For example, the fish-derived gelatin is easily crosslinked in a sol state at about 20 to about 40, and microbeads for embolization according to the embodiment may be formed.

In addition, the gelatin may be prepared from animal-derived collagen or fish-derived collagen. The gelatin may be extracted from the collagen by applying heat to the collagen. In addition, the gelatin is generally available in the market, such as marine collagen peptides or collagen peptides.

The fucoidan may be extracted from brown algae such as seaweed, mozuku (seaweed), kelp, and seaweed. In addition, the fucoidan may include a sulfate group and polysaccharides such as fucose. That is, the fucoidan may have a chemical structure in which the sulfate group and the polysaccharide are bonded.

The fucoidan may include glucuronic acid represented by Formula 1 below.

[Formula 1]

The fucoidan may include a unit represented by the following formula (2).

[Formula 2]

The average molecular weight of the fucoidan may be about 3,000 to about 40,000. The average molecular weight of the fucoidan may be about 5,000 to about 30,000. The average molecular weight of the fucoidan may be about 6,000 to about 25,000. The average molecular weight of the fucoidan may be about 7,000 to about 20,000.

Since the fucoidan contains the hydroxyl group and the sulfate group at the same time, it can not only adsorb iron ions, but also can be efficiently combined with an anticancer agent such as doxorubicin. Accordingly, the microbead for embolization according to the embodiment can effectively deliver the anticancer agent, such as doxorubicin, while adsorbing iron ions.

In addition, the fucoidan may help improve liver function. That is, the fucoidan may be an adjuvant drug for improving liver function. In addition, the fucoidan may be an auxiliary drug having an anticancer effect. Accordingly, the microbead for embolization according to the embodiment can effectively act on liver cancer and the like.

The microbead for embolization according to the embodiment may have a high iron adsorption rate. In the microbead for embolic treatment according to the embodiment, the iron adsorption rate expressed by Equations 1 to 5 below may be high.

In the microbeads for embolization according to the embodiment, the iron adsorption rate (IAd24) after 24 hours based on 100 mg of the microbeads for embolization represented by the following formula 1 may be about 5%/100 mg or more:

; [Equation 1]

;

Here, IC0 is the initial molar concentration of the FeCl ₃ aqueous solution, and the IC24 is the molar concentration of iron ions in the FeCl ₃ aqueous solution after adding the microbeads for embolization to the FeCl ₃ aqueous solution and leaving it for 24 hours.

After 24 hours, the iron adsorption rate may be about 6%/100 mg or more. After 24 hours, the iron adsorption rate may be about 7%/100 mg or more. After 24 hours, the iron adsorption rate may be about 8%/100 mg or more. After 24 hours, the iron adsorption rate may be about 9%/100 mg or more. After 24 hours, the iron adsorption rate may be about 10%/100 mg or more. After 24 hours, the iron adsorption rate may be about 50%/100 mg or less.

In the microbeads for embolization according to the embodiment, the iron adsorption rate (IAd48) after 48 hours based on 100 mg of the microbeads for embolization represented by the following Equation 2 may be about 5%/100 mg or more:

; [Equation 2]

;

Here, the IC0 is the initial molar concentration of the FeCl ₃ aqueous solution, and the IC48 is the molar concentration of iron ions in the FeCl ₃ aqueous solution after adding the microbeads for embolization to the FeCl ₃ aqueous solution and leaving it for 48 hours.

After the 48 hours, the iron adsorption rate may be about 6%/100 mg or more. After 48 hours, the iron adsorption rate may be about 7%/100 mg or more. After 48 hours, the iron adsorption rate may be about 8%/100 mg or more. After the 48 hours, the iron adsorption rate may be about 9%/100 mg or more. After the 48 hours, the iron adsorption rate may be about 10%/100 mg or more. After 48 hours, the iron adsorption rate may be about 50%/100 mg or less.

In the microbeads for embolization according to the embodiment, the iron adsorption rate (IAd1) after 1 hour based on 100 mg of the microbeads for embolization represented by the following Equation 3 may be about 5%/100 mg or more:

; [Equation 3]

;

Here, IC0 is the initial molar concentration of the FeCl ₃ aqueous solution, and IC1 is the molar concentration of iron ions in the FeCl ₃ aqueous solution after adding the microbeads for embolization to the FeCl ₃ aqueous solution and leaving it for 1 hour.

After 1 hour, the iron adsorption rate may be about 6%/100 mg or more. After 1 hour, the iron adsorption rate may be about 7%/100 mg or more. After 1 hour, the iron adsorption rate may be about 8%/100 mg or more. After 1 hour, the iron adsorption rate may be about 9%/100 mg or more. After 1 hour, the iron adsorption rate may be about 10%/100 mg or more. After 1 hour, the iron adsorption rate may be about 50%/100 mg or less.

In the microbeads for embolization according to the embodiment, the iron adsorption rate (IAd12) after 12 hours based on 100 mg of the microbeads for embolization represented by Equation 4 may be about 5%/100 mg or more:

; [Equation 4]

;

Here, the IC0 is the initial molar concentration of the FeCl ₃ aqueous solution, and the IC12 is the molar concentration of iron ions in the FeCl ₃ aqueous solution after adding the microbeads for embolization to the FeCl ₃ aqueous solution and leaving it for 12 hours.

After 12 hours, the iron adsorption rate may be about 6%/100 mg or more. After 12 hours, the iron adsorption rate may be about 7%/100 mg or more. After 12 hours, the iron adsorption rate may be about 8%/100 mg or more. After 12 hours, the iron adsorption rate may be about 9%/100 mg or more. After 12 hours, the iron adsorption rate may be about 10%/100 mg or more. After 12 hours, the iron adsorption rate may be about 50%/100 mg or less.

In the microbeads for embolization according to the embodiment, the iron adsorption rate (IAd72) after 72 hours based on 100 mg of the microbeads for embolization represented by the following formula 5 may be about 5%/100mg or more:

; [Equation 5]

;

Here, the IC0 is the initial molar concentration of the FeCl ₃ aqueous solution, and the IC72 is the molar concentration of iron ions in the FeCl ₃ aqueous solution after adding the microbeads for embolization to the FeCl ₃ aqueous solution and leaving it for 72 hours.

After 72 hours, the iron adsorption rate may be about 6%/100 mg or more. After 72 hours, the iron adsorption rate may be about 7%/100 mg or more. After 72 hours, the iron adsorption rate may be about 8%/100 mg or more. After 72 hours, the iron adsorption rate may be about 9%/100 mg or more. After 72 hours, the iron adsorption rate may be about 10%/100 mg or more. After 72 hours, the iron adsorption rate may be about 50%/100 mg or less.

In Equations 1 to 5, the IC0 may be about 0.018 M concentration.

The microbead for embolization according to the embodiment includes a biocompatible polymer, and the biocompatible polymer includes cross-linked gelatin and iron adsorption block, and may be combined with an anticancer agent. Here, the microbead for embolization may be to chelate an anticancer agent.

The anticancer agent to be bound is not specifically limited, and the anticancer agent capable of binding to the microbead for embolization according to the present embodiment may be used without limitation. Specifically, the combined anticancer agent may be one selected from doxorubicin, irinotecan, gemcitabine, oxaliplatin, and docetaxel.

The microbead for embolization according to the embodiment may have a high anticancer agent binding rate, particularly a high doxorubicin binding rate. In particular, since the biocompatible polymer includes the fucoidan and the like, the microbead for embolization according to the embodiment may have a high iron adsorption rate as well as a high anticancer drug binding rate, particularly a high doxorubicin binding rate.

The microbeads for embolization according to the embodiment may have an anticancer agent binding rate (AAd) of about 10%/100mg or more after 1 hour based on 100 mg of the microbeads for embolization represented by the following formula 6:

; [Equation 6]

;

Here, AC0 is the initial mg/ml concentration of the anticancer drug solution, and AC1 is the mg/ml concentration of the anticancer agent in the anticancer drug solution after adding the microbeads for embolization to the anticancer drug solution and leaving it for 1 hour. Here, the anticancer agent may be doxorubicin.

The anticancer agent binding rate (AAd) may be about 10%/100mg or more. The anticancer agent binding rate (AAd) may be about 20%/100mg or more. The anticancer agent binding rate (AAd) may be about 30%/100mg or more. The anticancer agent binding rate (AAd) may be about 50%/100mg or more. The anticancer drug binding rate (AAd) may be about 60%/mg or more. The anticancer agent binding rate (AAd) may be about 90%/100mg or less.

Here, the AC0 may be at a concentration of about 1 mg/ml.

The microbead for embolization according to the embodiment is formed by crosslinking the gelatin and the iron adsorption block. The microbead for embolization according to the embodiment includes a crosslinking agent. The crosslinking agent crosslinks the gelatin and the iron adsorption block.

In this case, the crosslinking agent is formaldehyde, glutaraldehyde, dialdehyde starch, epoxy compound, glutaraldehyde glyoxal, glyoxal, 2,2-dimethoxy-2 - Phenylacetophenone, tripolyphosphate sodium salt, diacetaldehyde PEG, scleraldehyde (scleraldehyde), diethyl squarate, epichlorohydrin and at least one selected from the group consisting of genipin (genipin) characterized in that do it with

The microbead for embolization according to the embodiment may contain the crosslinking agent in an amount of about 0.20 parts by weight to about 50 parts by weight based on 100 parts by weight of the gelatin. In more detail, the microbead for embolization according to the embodiment may include about 3 parts by weight to about 20 parts by weight of the crosslinking agent based on 100 parts by weight of the gelatin.

The microbeads for embolization according to the embodiment may have an average particle diameter of about 10 μm to about 2000 μm. In more detail, the microbeads for embolization according to the embodiment may have an average particle diameter of about 50 μm to about 2000 μm. In more detail, the microbeads for embolization according to the embodiment may have an average particle diameter of about 50 μm to about 1000 μm.

The microbead for embolization according to the embodiment has a porous structure. The microbead for embolization according to the embodiment may have a sponge structure. That is, the microbead for embolization according to the embodiment may include micropores. The microbead for embolization according to the embodiment may have a porosity of about 20 vol% to about 70 vol%. Accordingly, the microbead for embolization according to the embodiment may have high elasticity and swelling rate.

The microbead for embolization according to the embodiment is formed by crosslinking gelatin having a relatively large average molecular weight and gelatin having a relatively small average molecular weight. Accordingly, the microbead for embolization according to the embodiment may have a desired decomposition rate while having a desired particle size. For example, the average diameter of the microbeads for embolization according to the embodiment may be determined by the content and average molecular weight of gelatin having a relatively large average molecular weight. In addition, the decomposition rate of the microbead for embolization according to the embodiment may be determined by the content and average molecular weight of gelatin having a relatively small average molecular weight.

Accordingly, the microbead for embolization according to the embodiment may have a desired particle size and a desired decomposition rate depending on the content and average molecular weight of the first gelatin and the second gelatin. As a result, the microbead for embolization according to the embodiment may have an appropriate size and an appropriate decomposition rate, be embolized in a target blood vessel, maintain the embolization effect until a desired time, and then be decomposed.

In particular, the microbead for embolization according to the embodiment may have a fast decomposition rate, and after being first treated on a patient, it may be replaced and operated several times in other blood vessels of the patient depending on the patient's condition. Therefore, the microbead for embolization according to the embodiment can effectively treat a patient.

The micro-particles for embolization according to the embodiment are manufactured using gelatin. Accordingly, the microbead for embolization according to the embodiment is excellent in biocompatible (biocompatible), expandability, elasticity and flexibility. In addition, the particle diameter of the microbeads for embolization according to the embodiment may vary from about 50 μm to about 2000 μm, and the embolization particles according to the embodiment exhibit a porous spherical shape with a uniform sponge structure. Accordingly, the microbead for embolization according to the embodiment can minimize the stimulation of blood vessels.

In addition, by crosslinking with various contents of gelatin of various average molecular weights, microbeads for embolization according to the embodiment can be prepared. Accordingly, the microbeads for embolization according to the embodiment are used alone or in combination, so that the duration of vascular occlusion can be predictably controlled.

In addition, the microbead for embolization according to the embodiment has a high iron adsorption rate after 24 hours and an iron adsorption rate after 48 hours. Accordingly, the microbead for embolization according to the embodiment has a fast iron adsorption property.

Therefore, the microbead for embolization according to the embodiment is injected into the human body, particularly, the liver carotid artery, etc., and can block the blood supplied to the cancer cells and the like, as well as block the iron ions supplied to the cancer cells.

Accordingly, the microbead for embolization according to the embodiment can effectively necrosis of cancer cells by blocking blood vessels.

In addition, the microbead for embolization according to the embodiment can effectively absorb iron ions that are ejected when cancer cells or the like are necrotic.

Accordingly, the microbead for embolization according to the embodiment can effectively prevent cancer cells from growing again.

The microbead for embolization according to the embodiment can be used very effectively for cancer treatment such as liver cancer.

Referring to FIG. 1 , it may be manufactured by the following process according to the embodiment.

First, gelatin is prepared (S10). The gelatin may be mammal-derived gelatin or fish-derived gelatin. The weight average molecular weight of the gelatin may be about 50,000 to about 100,000.

The gelatin may be obtained from mammalian collagen or fish collagen. Alternatively, the gelatin is commercially available. As for the gelatin, the contents described above may be referred to.

Thereafter, the gelatin may be hydrolyzed to adjust to an appropriate molecular weight. The gelatin may be hydrolyzed in subcritical water.

More specifically, the gelatin is dissolved or dispersed in water to form an aqueous solution or aqueous dispersion. In this case, the content of gelatin in the aqueous solution or the aqueous dispersion may be 3wt% to 20wt%.

Thereafter, the aqueous solution or the aqueous dispersion is maintained in a subcritical state for a predetermined time. For example, the aqueous solution or aqueous dispersion may be maintained at a temperature of about 100° C. to about 250° C., in a state of about 30 atmospheres to about 80 atmospheres, for about 10 minutes to about 5 hours. Accordingly, the gelatin is hydrolyzed and a polypeptide is formed. In addition, carbon dioxide (CO2) and nitrogen (N2) may be included in the hydrolysis process in the subcritical water state.

In addition, the gelatin may be hydrolyzed by an enzyme. In addition, the gelatin may be hydrolyzed by acid. The gelatin may be hydrolyzed simultaneously by the subcritical water and the enzyme.

Thereafter, the hydrolyzed gelatin may be fractionated. The hydrolyzed gelatin may be fractionated by molecular weight by using gel filtration chromatography (Gel Filtration Chromatography), water as a solvent. The hydrolyzed gelatin is fractionated by HPLC (1260 HPLC system, Agilent, USA) connected to a fraction collector (G1364C 1260 FC-AS, Agilent, USA), and can be divided according to molecular weight. Polypeptides divided according to molecular weight can be obtained by various methods capable of fractionating oligomers or polymers by molecular weight. The hydrolyzed gelatin may be separated by molecular weight through a column.

Accordingly, gelatin according to the molecular weight can be obtained. For example, the gelatin, the second gelatin and the third gelatin may be obtained.

As described above, gelatin according to molecular weight can be obtained, respectively.

For example, the hydrolyzed gelatin may be fractionated to obtain gelatin having an average molecular weight of about 40,000 to 60,000, gelatin having an average molecular weight of about 20,000 to about 30,000, gelatin having an average molecular weight of about 8,000 to about 12,000, and about 1,000 Gelatin having an average molecular weight of from to about 2,000 can each be obtained.

Thereafter, the gelatin may be aminated. The amination gelatin may be effectively reacted with the iron adsorbing polymer, in particular, the fucoidan and/or polyphenol, and the like.

The amination process may be performed by the following method.

At slightly acidic, eg, pH 4.5 to pH 6, the gelatin and a sufficient amount of the diamine are mixed. Thereafter, a catalyst is added to the gelatin and the diamine mixture, and reacted at a temperature of about 30° C. to about 45° C., so that the amination gelatin can be prepared.

Then, the iron adsorption polymer is prepared (S20). The fucoidan may be extracted from seaweed and the like. In addition, the polyphenol may be prepared by extracting from plants such as green tea.

Thereafter, the gelatin and the iron adsorbing polymer are cross-linked by a cross-linking agent (S30).

The crosslinking agent may be as described above.

The crosslinking reaction is carried out in an aqueous solution containing the gelatin and the iron adsorbing polymer in an amount of about 3 wt% to about 10 wt%. After the crosslinking agent is added to the aqueous solution in the above content, the gelatin and the iron adsorbing polymer are crosslinked by the crosslinking agent at a temperature of about 20° C. to about 40° C. for about 6 hours to about 12 hours.

For example, the gelatin and the iron adsorbing polymer aqueous solution and the crosslinking agent solution are mixed in a weight ratio of 100:0.5 to 100:10. Thereafter, the mixed solution is first stirred at a temperature of about 20° C. to about 40° C., at about 1000 rpm to about 1500 rpm, for about 5 minutes to about 120 minutes. Thereafter, the first stirred mixed solution is secondarily stirred for about 10 minutes to about 48 hours at about 1 rpm to about 500 rpm at a temperature of about 20° C. to about 40° C. Accordingly, an aqueous polymer solution in which the gelatin and the iron adsorbing polymer are cross-linked can be prepared.

More specifically, in the first stirring step, when the stirring speed is out of the stirring speed range of about 1000 rpm to about 1500 rpm, bubbles are formed, and a problem in which the density is lowered may occur. Also, in the first stirring step, when stirring at a temperature of 20° C. or less, the mixed solution may be gelled. In addition, in the first stirring step, when the mixed solution is stirred at a temperature of 40° C. or higher, a problem in that the density is lowered as bubbles are generated may occur.

In addition, in the second stirring step, when the stirring speed exceeds 500 rpm, as the mixed solution gels, there may be a problem that it cannot be easily crosslinked in a sol state, and the water absorbency is significantly lowered. can occur. Accordingly, when the stirring speed exceeds 500 rpm, the functionality as a microbead for embolization may be reduced.

In addition, in the second stirring step, when out of the above temperature range, as the mixed solution gels and hardens, an aqueous gelatin crosslinking solution may not be easily prepared. In addition, the stirring time of 10 minutes to 48 hours in the second stirring is to improve absorption and maintain a uniform shape.

Accordingly, by the cross-linking step, a cross-linked aqueous gelatin solution is prepared. Thereafter, the cross-linked gelatin aqueous solution is dropped and sprayed on the oil to prevent the cross-linked gelatin in the gel state from aggregating, and the porous spherical cross-linked gelatin particles having a uniform sponge structure having a particle diameter of about 50 μm to 2,000 μm are produced. can be manufactured. In addition, since the degree of exposure of the cross-linked gelatin to oils and fats is low, oils and fats can be easily separated from the cross-linked gelatin.

Cross-linked gelatin particles having a spherical sponge structure are formed. The crosslinked gelatin particles may have various average particle diameters depending on the content of gelatin according to the average molecular weight, the content of the fucoidan or polyphenol, the content of the crosslinking agent, the crosslinking temperature and the crosslinking time, and the like. For example, the cross-linked gelatin particles may have an average particle diameter of about 50 μm to about 2000 μm depending on the above conditions.

More specifically, the gelatin may be fish gelatin. That is, the gelatin used for the hydrolysis may be derived from fish. In particular, the fish gelatin is prepared from the fish skin of turbulent fish species, and may have a property of gelling at a lower temperature than gelatin using cattle or pigs. Accordingly, the fish gelatin is easily crosslinked in a sol state at a temperature of about 20 to about 40° C., and a porous sphere having a uniform sponge structure having a particle size of about 50 to about 2000 μm can be formed. In addition, when the gelatin is derived from the fish gelatin, the viscosity in the non-gelatinized state is low and the molecular weight is small, so that it can be dripped or sprayed at a higher concentration. Accordingly, in the present embodiment, gelatin microparticles having a high visible density can be prepared.

In addition, the concentration of the aqueous gelatin solution derived from the fish gelatin may be 3wt% to about 20wt%. In addition, in the second stirring step, the concentration of the crosslinking agent in the prepared gelatin crosslinking aqueous solution may be about 0.05 wt% to about 10 wt%.

More specifically, the gelatin fine particle emulsion is sprayed or dropped into oil and fat through a nozzle by compressed air in an encapsulator. At this time, the temperature of the particle solution may be about 20 °C to about 40 °C, and the temperature passing through the nozzle may be about 65 °C to about 75 °C. In addition, as the frequency is set to 40 to 6000 Hz, the size of the spherical gelatin droplet to be dropped or sprayed can be controlled.

In addition, the fat may be an ester-based fat, hydrocarbon-based fat, animal fat or vegetable fat. Specifically, the oil is olive oil, soybean oil, canola oil, grape seed oil, soybean oil, palm oil, paraffin oil, alpha-bisabolol (α-bisabolol), stearyl glycyrrhetinate (stearyl glycyrrhetinate), salicylic acid (salicylic) acid), tocopheryl acetate, panthenol, glyceryl stearate, cetyl octanolate, isopropyl myristate, 2-ethylene isofelagonate (2-ethylene isopelagonate), di-c12-13 alkyl malate, ceteatyl octanoate, butylene glycol dicaptylate/dicaptylate dicaprate), isononyl isostearate, isostearyl isostearate, cetyl octanoate, octyldodecyl myristate, cetyl esters ), c10-30 cholesterol/lanosterol ester, hydrogenated castor oil, mono-glycerides, diglycerides, triglycerides ), beeswax, carnauba wax, suctosedistearate, PEG-8 beeswax, candelilla (euphorbia cerifera) wax), minerals oil, squalene, squalene squalane, monoglyceride, diglyceride, triglyceride, medium chain glyceride, myglyol, or cremophor.

Preferably, the fat and oil may be paraffin oil, but it is not limited thereto, and more preferably, the fat and oil is characterized in that 0 to 5 wt% of a crosslinking agent is mixed with respect to 100 wt% of the fat and oil. makes it easier to maintain the spherical shape.

In addition, at this time, the fat is cooled to a temperature of 0 ~ 10 ℃ so that the gelatin can easily form a spherical shape as it exists.

Accordingly, cross-linked spherical gelatin particles can be prepared.

Thereafter, the cross-linked gelatin particles are washed and dried (S40). After the oil containing the spherical gelatin particles is stirred, washing and drying processes are performed to form porous gelatin microparticles having a sponge structure.

The cross-linked spherical gelatin particles may be washed with an organic solvent.

The oil and fat containing the spherical gelatin fine particles prepared in step S40 is stirred at a temperature of about 0° C. to about 10° C. at about 400 rpm to about 1400 rpm, left still, and washed with an organic solvent. Accordingly, the fats and oils and the crosslinking agent contained in the crosslinked spherical gelatin particles are removed, and the crosslinked spherical gelatin particles are solidified.

Thereafter, the solidified gelatin particles are freeze-dried for about 3 hours to about 48 hours, and thus, cross-linked porous gelatin microparticles having a sponge structure are formed. In this case, the porous gelatin microparticles of the sponge structure formed have a particle size of about 150 μm to about 2000 μm.

More specifically, in the washing and drying step, by stirring the oil containing the gelatin particles at 400 to 1400 rpm, the gelatin particles can be easily formed into a spherical shape, and the spherical gelatin has suitable physical properties to have In addition, at this time, as the fat and oil maintain a temperature range of 0 to 10° C., the spherical gelatin particles of the fat and oil phase are prevented from aggregating with each other so that the spherical shape can be maintained.

In addition, wherein the organic solvent is petroleum ether, ethyl ether, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, isobutyl isobutyrate, 2-ethylhexyl acetate, ethylene glycol diacetate C9 acetate, C10 Acetate, methyl ethyl ketone, methyl isobutyl ketone, methyl isoamyl ketone, methyl n-amyl ketone, dibutyl ketone, cyclohexanone, isophorone, acetaldehyde, n-butylaldehyde, crotonaldehyde, 2-ethylhexaaldehyde, Isobutylaldehyde, propionaldehyde, ethyl 3-ethoxypropionate, toluene, xylene, trichloroethane, propylene glycol monomethyl ethyl acetate, ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether, diethylene glycol monobutyl Ether acetate, dibutyl phthalate, idetyl phthalate, dimethyl phthalate, dioctyl phthalate, dioctyl terephthalate, butyl octyl phthalate, butyl benzene phthalate, dioctyl adipate, triethylene glycol di-2-ethylhexanoate, trioctyl trimethylitate, glyceryl triacetate, glyceryl/tripropionine, 2,2,4-trimethyl-1,3-pentanediol diisobutylate, or mixtures thereof.

Preferably, the organic solvent is ethyl ether or isopropyl acetate.

Thereafter, the beads for embolization according to the embodiment are added to deionized water to prepare a formulation (S50).

As described above, the microparticles for embolic treatment of the present invention are excellent in biocompatible, expandability, elasticity and flexibility as they are manufactured using fish gelatin, and exhibit a porous spherical shape with a uniform sponge structure with a particle size of 150 to 2000 μm. Accordingly, it is possible to facilitate vascular occlusion while minimizing vascular stimulation, and is characterized in that it is manufactured by the following manufacturing method.

In addition, since gelatin having different molecular weights is cross-linked to form microbeads for embolization according to the embodiment, the microbeads for embolization according to the embodiment may be decomposed in the body at a desired time.

In addition, since the iron adsorption polymer contains the fucoidan and/or the polyphenol, the microbead for embolization according to the embodiment has improved iron adsorption power.

Accordingly, the microbead for embolization according to the embodiment can effectively remove cancer cells.

The composition for treating a proliferative disease according to an embodiment may include cross-linked gelatin and iron adsorption block, and may include microbeads for embolic treatment, which are combined with an iron component and/or an anticancer agent. The microbead for embolization may be adsorbed, bound, or chelated with an iron component and/or an anticancer agent.

The proliferative disease may include one or more selected from neovascularization, tumor, cancer, bone disease, fibroproliferative disorder, enlarged prostate, renal cyst, and atherosclerosis.

The cancer is a solid tumor, blood cancer, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, colorectal cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, It may include one or more selected from kidney cancer, bladder cancer, pancreatic cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. The cancer may in particular be liver cancer.

Hereinafter, the present invention will be described in more detail by way of Examples, but the scope of the present invention is not limited by the Examples.

production example

Amination of gelatin preparation

10 g of the first gelatin (average molecular weight of about 42,000) was mixed with 250 mL of a 0.1 M phosphate buffer solution (pH 5.3) to prepare a first gelatin solution. After adding 5.6 g of a 1,2-ethylenediamine solution to the first gelatin solution, the pH was adjusted to 5 using HCl. Then, 5.35 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride as a catalyst was added to the first gelatin solution. Thereafter, the 1,2-ethylenediamine and the catalyst-added first gelatin solution was reacted at a temperature of 37° C. for about 8 hours. Thereafter, the reacted first gelatin solution was washed with deionized water through a dialysis process for 48 hours, and through a freeze-drying process, the first amination gelatin was prepared.

A second gelatin solution was prepared by mixing 10 g of the second gelatin (average molecular weight of about 31,000) in 250 mL of a 0.1 M phosphate buffer solution (pH 5.3). After adding 5.6 g of a 1,2-ethylenediamine solution to the second gelatin solution, the pH was adjusted to 5 using HCl. Thereafter, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride as a catalyst was added to the second gelatin solution. Thereafter, the 1,2-ethylenediamine and the catalyst-added second gelatin solution was reacted at a temperature of 37° C. for about 8 hours. Thereafter, the reacted second gelatin solution was washed with deionized water through a dialysis process for 48 hours, and a second amination gelatin was prepared through a freeze-drying process.

Example 1

Preparation of cross-linked gelatin particles

35 parts by weight of the first amination gelatin, 15 parts by weight of the second amination gelatin, and 7.5 parts by weight of fucoidan (MSC, kelp fukuidan raw material) were dissolved in deionized water to prepare an aqueous gelatin solution of about 5 wt%. Then, 37 mL of formaldehyde was added to 100 mL of an aqueous solution containing 15 wt% methanol to prepare an aqueous crosslinking agent solution.

Then, 0.2 mL of the aqueous crosslinking agent solution was added to 20 mL of the gelatin aqueous solution, and the mixed aqueous solution was first stirred at about 30° C. at a speed of 1000 rpm for 30 minutes, and then a second time at 30° C. at a speed of 200 rpm for 24 hours. Aqueous solution of cross-linked gelatin cross-linked in a sol state was prepared by stirring.

Then, the prepared gelatin crosslinking solution was injected into Encapsulator B-390 (BUCHI, Switzerland) adjusted to a frequency of 400 Hz, electronegativity of 1200 V, and nozzle temperature of 75° C. Spherical gelatin microparticles were formed in the paraffin oil by dropping into 100 mL of paraffin oil containing . At this time, as the paraffin oil, 100 mL of paraffin oil containing 1 mL of 37% formaldehyde was used.

Thereafter, the paraffin oil containing the spherical gelatin particles was stirred at 0° C. at 1000 rpm, and then left still for 30 minutes.

Next, by adding isopropyl ethyl alcohol to the spherical gelatin droplets and washing, the spherical gelatin was solidified and paraffin oil and formaldehyde were removed.

By freeze-drying the solidified gelatin spheres for 24 hours, gelatin microbeads containing fucoidan were prepared.

The gelatin microbeads were mixed alone or in deionized water in a ratio of 5:5.

Examples 2-8 and Comparative Examples 1-2

The first amination gelatin, the second amination gelatin, the fucoidan and epigallocatechin gallate (EGCG, R&O food product) each content was as shown in Table 1 below, except that the remaining examples were The gelatin microbeads were prepared in the same manner as in Example 1.

However, in the case of Examples 5 to 8, the gelatin microbeads were prepared by additionally adding EGCG according to the parts by weight shown in Table 1 below to the aqueous gelatin solution. In addition, in the case of Comparative Examples 1 and 2, the gelatin aqueous solution was prepared according to the components and weight parts shown in Table 1 below, and the other manufacturing processes were the same as in Example 1 to prepare the gelatin microbeads. did

division Primary Amination Gelatin
(parts by weight) Second Amination Gelatin
(parts by weight) fucoidan
(parts by weight) EGCG
(parts by weight) Example 1 35 15 7.5 - Example 2 35 15 5 - Example 3 35 15 2.5 - Example 4 35 15 One - Example 5 10 40 7.5 0.5 Example 6 10 40 7.5 0.25 Example 7 15 35 7.5 0.5 Example 8 15 35 7.5 0.25 Comparative Example 1 50 0 0 0 Comparative Example 2 15 35 0 0

Experimental example

Iron adsorption rate measurement

About 100 mg of the gelatin microbeads prepared in Examples 1 to 8 were added to 10 ml of an aqueous solution of FeCl ₃ having a concentration of 0.018 M, and the mixture was uniformly mixed. Thereafter, the gelatin microbeads were immersed in the FeCl ₃ aqueous solution, and the filtrate of the upper layer of the FeCl ₃ aqueous solution was collected by time.

Then, the content of iron contained in the upper filtrate was measured by ICP (Inductively Coupled Plasma), and based on the volume of the collected aqueous solution and the content of iron, the Fe concentration in the FeCl ₃ aqueous solution was calculated. Accordingly, the iron adsorption rate was calculated according to Equation 1 above.

Table 2 below shows the iron adsorption rate over time confirmed for each Example:

division 1 hour later
adsorption rate
(%/100mg) after 12 hours
adsorption rate
(%/100mg) after 24 hours
adsorption rate
(%/100mg) after 48 hours
adsorption rate
(%/100mg) after 72 hours
adsorption rate
(%/100mg) Example 1 10.88 11.86 11.57 10.62 10.59 Example 2 9.00 11.60 10.51 8.46 9.28 Example 3 8.67 9.49 7.05 7.26 7.62 Example 4 6.41 8.62 7.06 6.72 6.83 Example 5 11.73 10.47 8.07 7.90 7.98 Example 6 10.63 10.47 8.07 7.90 7.98 Example 7 10.79 12.21 10.68 10.55 12.87 Example 8 13.07 12.70 9.57 10.61 11.88 Comparative Example 1 No iron adsorption Comparative Example 2 No iron adsorption

As shown in Table 2, the gelatin microbeads prepared in Examples 1 to 8 had a high iron adsorption rate.

Doxorubicin binding rate

About 100 mg of the gelatin microbeads prepared in Examples 1 to 8, Comparative Examples 1 and 2, respectively, were added to a 10ml doxorubicin solution at a concentration of about 1 mg/ml, and the mixture was uniformly mixed. Then, the gelatin microbeads were immersed for 1 hour. Then, the filtrate of the upper layer of the doxorubicin solution was collected and absorbance was measured using light in a wavelength band of about 550 nm.

Each absorbance for Examples 1 to 8, Comparative Example 1 and Comparative Example 2 was measured in the 550 nm wavelength band, and each concentration was calculated based on the calibration curve according to FIG. 2, and each prepared by comparison with the initial concentration The binding rate (%/100 mg) of doxorubicin adsorbed to the gelatin microbeads was calculated.

division absorbance After adsorption, concentration (mg/ml) Doxorubicin adsorption rate (%/100mg) Example 1 0.6233 0.1956 84.44 Example 2 0.7947 0.2509 74.91 Example 3 1.1483 0.3651 63.49 Example 4 2.8003 0.8986 10.14 Example 5 1.0647 0.3381 66.19 Example 6 0.1860 0.0544 94.56 Example 7 0.4137 0.1279 87.21 Example 8 0.6960 0.2191 78.09 Comparative Example 1 3.107 0.9977 0.23 Comparative Example 2 3.083 0.9899 1.01

As described in Table 3, the gelatin microbeads prepared in Examples 1 to 8 had a high doxorubicin binding rate.

particle size analysis

The gelatin micro-particles prepared in the above example were analyzed through a scanning electron microscope, and the gelatin micro-particles of porous spheres having a uniform sponge structure with a particle diameter of about 150 μm to about 355 μm were prepared. could check

Claims (14)

a first gelatin having a first average molecular weight;
a second gelatin having a second average molecular weight less than the first average molecular weight; and
A microbead for embolization, comprising a biocompatible polymer cross-linked with an iron adsorption block,
The first gelatin and the second gelatin are aminated,
The first gelatin and the second gelatin are obtained by hydrolyzing gelatin,
The first average molecular weight is 40,000 to 60,000, 15,000 to 39,000, or 5,000 to 14,000,
The second average molecular weight is 15,000 to 39,000, 5,000 to 14,000, or 500 to 4,000,
Microbeads for embolization.
The method of claim 1,
The iron adsorption block will include fucoidan and / or polyphenol, embolic microbeads.
3. The method of claim 2,
The polyphenol is a biodegradable anionic polyphenol, and includes at least one selected from tannin, gallic acid, tannic acid, catechin, epicatechin, epigallocatechin gallate, quercetin, resveratrol, isoflavones, flavonoids, and polyphenols derived from seaweed That is, microbeads for embolization procedures.
The method of claim 1,
A microbead for embolization, comprising crosslinking of cationic amination, the first gelatin, the second gelatin, and anionic fucoidan.
The method of claim 1,
The weight ratio of the first gelatin and the second gelatin to the iron adsorption block is 4:1 to 10:1, microbeads for embolization.
delete The method of claim 1,
Microbeads for embolization, wherein the iron adsorption rate (IAd24) after 24 hours based on 100 mg of the microbeads for embolization, represented by the following formula 1, is 5%/100mg or more:
[Equation 1]

;
Here, the IC0 is the initial molar concentration of the FeCl ₃ aqueous solution,
The IC24 is the molar concentration of iron ions in the FeCl ₃ aqueous solution after adding the microbeads for embolization to the aqueous solution and leaving _it for 24 hours.
The method of claim 1,
Microbeads for embolization, having an iron adsorption rate (IAd48) of 5%/100 mg or more after 48 hours based on 100 mg of the microbeads for embolization, represented by the following formula 2:
[Equation 2]

;
Here, the IC0 is the initial molar concentration of the FeCl ₃ aqueous solution,
The IC48 is the molar concentration of iron ions in the FeCl ₃ aqueous solution after adding the microbeads for embolization to the aqueous solution and leaving _it for 48 hours. a first gelatin having a first average molecular weight;
a second gelatin having a second average molecular weight less than the first average molecular weight; and
A microbead for embolization, comprising a biocompatible polymer cross-linked with an iron adsorption block,
The first gelatin and the second gelatin are aminated,
The first gelatin and the second gelatin are obtained by hydrolyzing gelatin,
The first average molecular weight is 40,000 to 60,000, 15,000 to 39,000, or 5,000 to 14,000,
the second average molecular weight is 15,000 to 39,000, 5,000 to 14,000, or 500 to 4,000;
The microbead for the embolization procedure is to combine with an anticancer agent,
Microbeads for embolization.
10. The method of claim 9,
The combined anticancer agent is selected from doxorubicin, irinotecan, gemcitabine, oxaliplatin, and docetaxel, microbeads for embolization.
10. The method of claim 9,
Microbeads for embolization, having an anticancer agent binding rate (AAd) of 10%/100 mg or more after 1 hour based on 100 mg of the microbeads for embolization, represented by the following formula:
[Equation 6]

Here, the AC0 is the initial mg/ml concentration of the anticancer drug solution,
The AC1 is the mg/ml concentration of the anticancer agent in the anticancer agent solution after the microbead for embolization is added to the anticancer agent solution and left for 1 hour.
a first gelatin having a first average molecular weight;
a second gelatin having a second average molecular weight less than the first average molecular weight; and
A composition for the treatment of proliferative diseases, comprising microbeads for embolization, wherein the iron adsorption block contains a cross-linked biocompatible polymer,
wherein the first gelatin and the second gelatin are aminated;
It is combined with an iron component and/or an anticancer agent,
The first gelatin and the second gelatin are obtained by hydrolyzing gelatin,
The first average molecular weight is 40,000 to 60,000, 15,000 to 39,000, or 5,000 to 14,000,
The second average molecular weight is 15,000 to 39,000, 5,000 to 14,000, or 500 to 4,000,
A composition for treating a proliferative disease.
13. The method of claim 12,
The proliferative disease is neovascularization, tumor, cancer, bone disease, fibroproliferative disorder, prostatic hyperplasia, renal cyst, and a composition for treating proliferative diseases comprising one or more selected from atherosclerosis.
14. The method of claim 13,
The cancer is a solid tumor, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, colorectal cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, Bladder cancer, pancreatic cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and a composition for treating a proliferative disease comprising at least one selected from melanoma.

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