WO2016178448A1 - Hydrogel particles and composite embolic material - Google Patents

Abstract

Provided are: hydrogel particles comprising at least one biodegradable polymer of gelatin and chitosan and at least one C₁₈-C₂₆ aliphatic hydrocarbon derivative of alkyl amines and alkyl amides, wherein the C-H stretching vibration peak of methylene (CH₂) of C₁₈-C₂₆ aliphatic hydrocarbon has an FT-IR spectrum shown in the wave number range of 2850-3000 cm^-1; and a composite embolic material comprising the same.

Description

Hydrogel particles and complex embolic material

The invention relates to hydrogel particles and complex embolic materials used in embolization.

Liver tissue is oxygenated and nourished by two blood vessels. One is a vessel called the portal vein that exits the small and large intestines, and the other is the hepatic artery that comes directly from the aorta. Normal liver tissue is supplied primarily from the portal vein, while tumor tissue is supplied mainly from the hepatic artery. Therefore, by selecting only the hepatic arteries that supply the tumor and administering the anticancer agent and blocking the blood vessel after the anticancer agent, only the tumor can be selectively necrotic without significantly damaging normal liver tissue.

Liver cancer chemoembolization (transarterial chemoembolization) is a treatment that finds a hepatic artery that nourishes liver tumors, administers anticancer drugs, and then blocks the blood vessels.

Through the femoral artery located in the inguinal (groin), a thin tube of about 2-3 mm, called a catheter, is inserted into the hepatic artery. When the catheter enters the hepatic artery, the hepatic arterial angiogram is taken by injecting angiography to obtain information about the location, size, and blood supply of the tumor. Once the treatment policy is determined, a thin tube about 1 mm thick is used to find a hepatic artery that goes to the liver tumor.

Average Typical examples of embolic materials used in embolization liver chemistry, may be mentioned lipiodol ^® (lipiodol ^®) and gelpom ^® (gelfoam ^®).

Lipiodol ^® is an iodide ethyl ester of fatty acids extracted from poppy seed oil, which is optionally deposited on liver tumors when mixed with anticancer agents. Lipiodol ^® is a fat-soluble iodine based contrast media, it may serve as the embolic material having embolic effect of microvessels.

Overuse of iodine-based contrast agents can cause side effects such as nausea, vomiting, hives, itching, hypotensive shock, respiratory arrest, cardiac arrest, and convulsions. Lipiodol ^® can function as an embolic substance, but because it is a fat-soluble iodine-based contrast agent, excessive use of Lipiodol ^® can cause side effects such as nausea, vomiting, hives, itching, hypotensive shock, respiratory arrest, cardiac arrest, and convulsions.

Gelfoam ^® promotes blood clot formation in the hepatic artery or blocks blood flow to block the nutrients supplied to the liver tumor.

Gelpom ^® is composed of protein, so does the safety is not excellent, but the selective deposition in the liver tumors did not function as a contrast agent, in the case of using only gelpom ^® alone, or artery or vein connected to other organs such as the brain, not the hepatic artery in Side effects can occur in blood clots or block blood flow.

Also, for example, even when subjected to liver chemical embolization of chemotherapy and lipiodol ^® primary injection after gelpom ^® as a secondary injection which, as in the case of using only gelpom ^® alone, or the brain and non-hepatic Side effects can occur that form blood clots or block blood flow in arteries or veins that are connected to other organs, such as.

The present invention aims to provide a complex embolic material and an embolizing hydrogel particle for use in minimizing the side effects of an iodine-based contrast agent and at the same time improving the function of selective thrombus formation or blood flow blocking.

The problem to be solved by the invention is not limited to the above-mentioned technical problem, and other technical problems not mentioned will be clearly understood by those skilled in the art from the following description.

Hydrogel particles according to one embodiment of the invention, biodegradable polymer of at least one of gelatin (chilatin) and chitosan (chitosan) and at least one C ₁₈ ~ C ₂₆ aliphatic hydrocarbon derivative of alkyl amine and alkyl amide.

Hydrogel gel particles according to an embodiment of the present invention, the FT stretching CH peak of the methylene (CH ₂ ) of C ₁₈ ~ C ₂₆ aliphatic hydrocarbons (FT 2) appears in the frequency range of 2850 cm ^-1 to 3000 cm ^{- 1} FT Have an IR spectrum.

Hydrogel particles in accordance with one embodiment of the invention is an iodide C ₁₈ ~ C ₂₆ average absorption of the fatty acid ester exceeds 50% by weight, based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid esters.

Hydrogel particles in accordance with one embodiment of the invention, followed by the addition of a phosphate buffered saline (PBS) centrifuged was then measured after removing the supernatant the iodide C ₁₈ ~ C ₂₆ average residual content of the iodide C ₁₈ fatty acid ester More than 25% by weight based on the amount of C ₂₆ fatty acid ester added.

The complex embolic material according to an embodiment of the present invention includes the hydrogel particles and the iodide C ₁₈ to C ₂₆ fatty acid ester.

The C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative may be a C ₁₈ to C ₂₆ n-alkyl derivative.

The alkyl amine may be C ₁₈ to C ₂₆ n-alkyl amine. The C ₁₈ to C ₂₆ n-alkyl amine may be octadecylamine.

The alkyl amide may be C ₁₈ to C ₂₆ n-alkyl amide. The C ₁₈ to C ₂₆ n-alkyl amide may be an octadecane amide.

The iodide C ₁₈ ~ C ₂₆ fatty acid ester may be ethyl monoiodostearate.

The iodide C ₁₈ ~ C ₂₆ may be an average water absorption of the fatty acid ester it exceeds 70% by weight, based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid esters.

An average value of the average absorption of the iodide C ₁₈ to C ₂₆ fatty acid ester may be greater than 85 wt% to less than 88 wt% based on the amount of the iodide C ₁₈ to C ₂₆ fatty acid ester added.

The average residual content of the phosphoric acid was added to buffered saline (PBS) centrifugation was separated with the iodide, measured after removal of the supernatants C ₁₈ ~ C ₂₆ fatty acid esters are based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid ester And greater than 35% by weight.

The added amount of was added to the phosphate-buffered saline (PBS) centrifugation was separated measured after removing the supernatant the iodide C ₁₈ ~ C ₂₆ average residual content of the average value of the iodide C ₁₈ ~ C ₂₆ fatty acid ester of a fatty acid ester And from greater than 72 weight percent to less than 77 weight percent based on the total weight.

Specific details of other embodiments are included in the detailed description and the drawings.

1 is a micrograph of a test sample 1 according to an embodiment of the present invention.

2 is a micrograph of a test sample 2 according to an embodiment of the present invention.

3 is a micrograph of a test sample 3 according to an embodiment of the present invention.

4 is a photomicrograph of Experimental Sample 4 according to an embodiment of the invention.

5 is a micrograph of an experimental sample 5 according to an embodiment of the present invention.

6 is a micrograph of a test sample 6 according to an embodiment of the present invention.

7 and 8 are comparative plots of the experimental samples lipiodol ^® absorbent hydrogel particles of the comparative sample with the hydrogel particles in accordance with one embodiment of the invention.

9 and 10 are experimental compound embolism lipiodol ^® residual content comparison graph of the material sample and the comparative composite material sample embolization according to one embodiment of the invention.

Figure 11 is a graph comparing the amount of test compound lipiodol ^® embolic material sample for lipiodol ^® content of the comparison compound embolic material sample based on the analysis gas chromatography (GC).

12 to 14 are graphs of gas chromatography (GC) analysis of Lipiodol ^® content of experimental complex embolic samples according to an embodiment of the present invention.

15 and 16 are graphs of gas chromatography (GC) analysis of Lipiodol ^® content of comparative complex embolic samples.

17 is a graph of gas chromatography (GC) analysis results of a standard product.

18 to 20 are FT-IR spectra of hydrogel particles of a test sample according to an embodiment of the present invention.

21 and 22 are FT-IR spectra of hydrogel particles of a comparative sample.

Advantages and features of the invention, and methods of achieving them will be apparent with reference to the experimental examples described below in detail in conjunction with the accompanying drawings.

"Hydrogel particles" are particles that can be used for embolization and can be swellable by water as one embolic material. The hydrogel particles may be sphere-shaped particles having a smooth spherical surface in order to prevent inflammation that may occur when long-term contact with the vessel wall after embolization. The size of the hydrogel particles is not particularly limited, but may be determined within a range of several μm or more to several hundred μm or less.

"Complex embolic material" means an embolic material in which two or more embolic materials are combined or an embolic material in which one embolic material and one contrast agent are combined. The complex embolic material includes, of course, a case in which the function of the embolic material and the contrast agent functions in a complex manner, such as when one embolic material has a function of a contrast agent.

A "biodegradable polymer" is a biomaterial that is replaced with autologous tissue that is slowly degraded and regenerated in the body after transplantation. For example, the biodegradable polymer may be made of a natural polymer compound, the natural polymer compound may be, for example, one or more of gelatin and chitosan. The gelatin and the chitosan may be used alone as the biodegradable polymer, respectively, or a combination thereof, that is, a combination of the gelatin and the chitosan may be used as the biodegradable polymer.

"C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative" is a derivative of aliphatic hydrocarbon having 18 to 26 carbon atoms.

“C ₁₈ to C ₂₆ alkyl amines” are amines having alkyl having 18 to 26 carbon atoms. “C ₁₈ to C ₂₆ alkyl amides” are amides having alkyl having 18 to 26 carbon atoms.

"C ₁₈ to C ₂₆ alkyl" refers to C ₁₈ to C ₂₆ n-alkyl and C ₁₈ to C ₂₆ iso-alkyl which do not have a branched carbon chain bonded to the main carbon chain, or alkyl having a branched carbon chain bonded to the main carbon chain, such as sec-alkyl and the like. "Amine" and "amide" include diamine and diamide, respectively.

An example of _C18 - _C26 n-alkyl amines is octadecyl amine.

An example of a C ₁₈ to C ₂₆ n-alkyl amide is octadecyl amine.

"Iodide C ₁₈ to C ₂₆ fatty acid ester" is a compound in which iodine is substituted for a fatty acid ester having an alkyl having from 18 to 26 carbon atoms. Examples of the iodide C ₁₈ ~ C ₂₆ fatty acid esters there may be mentioned lipiodol ^®, the lipiodol ^® may be a mono-iodo ethyl stearate (ethyl monoiodostearate).

"Iodide C ₁₈ ~ C ₂₆ average absorption of the fatty acid ester" is an amount of a C ₁₈ ~ C ₂₆ fatty acid ester, measured after having added the iodide C ₁₈ ~ C ₂₆ fatty acid ester of a predetermined amount of the embolic material and centrifuging the mixture .

"Iodide C ₁₈ ~ C ₂₆ average residual content of the fatty acid ester" is measured after a mixture of phosphate buffered saline (PBS) with a predetermined amount of the embolic material are the iodide C ₁₈ ~ C ₂₆ fatty acid esters absorbed and centrifuging the mixture The remaining content of one C ₁₈ to C ₂₆ fatty acid ester.

Hydrogel particles according to an embodiment of the present invention includes the biodegradable polymer and C ₁₈ ~ C ₂₆ aliphatic hydrocarbon derivative. The C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative may be, for example, C ₁₈ to C ₂₆ alkyl amine and / or C ₁₈ to C ₂₆ alkyl amide. In this specification, "A and / or B" means "A, B or A and B."

Each of the C ₁₈ to C ₂₆ alkyl amines and the C ₁₈ to C ₂₆ alkyl amides may include a linker bonded to the biodegradable polymer, and the linker may have a chemical structure derived from a crosslinking agent.

For example, the crosslinking agent may be formaldehyde, glutaraldehyde, genipin, or the like.

For example, when the formaldehyde is used as a crosslinking agent, each of C ₁₈ to C ₂₆ alkyl amine and C ₁₈ to C ₂₆ alkyl amide may include a methylene bridge bonded to the biodegradable polymer. . At this time, the methylene bridge may function as a linker.

The methylene bridge may be derived from the methylene of methylene glycol (HOCH ₂ OH) produced by the reaction of the formaldehyde and water, dehydration condensation reaction of the biodegradable polymer, the C ₁₈ ~ C ₂₆ aliphatic hydrocarbon derivative and methylene glycol As such, each of the C ₁₈ to C ₂₆ alkyl amines and the C ₁₈ to C ₂₆ alkyl amides may include the methylene bridge as a linker.

As an example, the methylene bridge may connect the nitrogen atom (N) of the gelatin and the nitrogen atom (N) of the C ₁₈ to C ₂₆ alkyl amine, or the nitrogen atom (N) of the gelatin and the C ₁₈ to C ₂₆ The nitrogen atom (N) of the alkyl amide may be connected.

As another example, the methylene bridge may connect the nitrogen atom (N) of the chitosan and the nitrogen atom (N) of the C ₁₈ to C ₂₆ alkyl amine, or the nitrogen atom (N) of the chitosan and the C ₁₈ to C The nitrogen atom (N) of the ₂₆ alkyl amide may be connected.

For example, when the glutaraldehyde is used as a crosslinking agent, each of C ₁₈ to C ₂₆ alkyl amines and C ₁₈ to C ₂₆ alkyl amides may include a shift base bonded to the biodegradable polymer. have. At this time, the seed base may function as a linker.

By dehydration condensation of the biodegradable polymer, the C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative, and methylene glycol, each of the C ₁₈ to C ₂₆ alkyl amines and the C ₁₈ to C ₂₆ alkyl amides may include the seed base as a linker. Can be.

As an example, the sipebase may connect a nitrogen atom (N) of one of the gelatin and the chitosan and a nitrogen atom (N) of the C ₁₈ to C ₂₆ alkyl amine, or a nitrogen atom of one of the gelatin and the chitosan. (N) and the nitrogen atom (N) of the C ₁₈ ~ C ₂₆ alkyl amide may be connected.

For example, when the nippin is used as a crosslinking agent, each of the C ₁₈ to C ₂₆ alkyl amines and the C ₁₈ to C ₂₆ alkyl amides may include a linker represented by the following Formula (1).

In formula (1), the nitrogen atom (N) of the heterocyclic amine may be a nitrogen atom (N) of one of the gelatin and the chitosan, and the nitrogen atom (N) of the amine next to the carbonyl group is It may be a nitrogen atom (N) of one of the C ₁₈ ~ C ₂₆ alkyl amine and the C ₁₈ ~ C ₂₆ alkyl amide.

<Formula (1)>

The C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative may be uniformly mixed with the biodegradable polymer within the range of C ₁₈ to C ₂₆ , and may generate a lot of foam during whipping. Hereinafter, as can be seen through the experimental example, when hexadecylamine was used as the C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative, the mixing was not well performed, and foam was not visually confirmed even during whipping. This will be described in more detail in the experimental example described later.

Complex embolic material according to an embodiment of the invention comprises the hydrogel particles and iodide fatty acid ester. It is assumed that the iodide fatty acid ester is bound through hydrophilic interaction with the aliphatic hydrocarbon derivative.

That is, the complex embolic material according to an embodiment of the present invention is due to the hydrophobic interaction between the carbon chain of the C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative and the carbon chain of the iodide fatty acid ester, and two embolic materials are chemically bonded. It is assumed to be.

For example, the iodide fatty acid ester may be an iodide fatty acid ester having a carbon chain of C ₁₈ to C ₂₆ n-alkyl. The carbon chain of the C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative may include n-alkyl to increase hydrophobic interaction between alkyl. For example, the C ₁₈ to C ₂₆ alkyl amine may be C ₁₈ to C ₂₆ n-alkyl amine, and the C ₁₈ to C ₂₆ alkyl amide may be C ₁₈ to C ₂₆ n-alkyl amide.

From the experimental examples described below, it can be seen that the hydrogel particles and the composite embolic material according to the embodiment of the present invention have excellent absorption or binding strength to the iodide C ₁₈ to C ₂₆ fatty acid ester, respectively.

Hereinafter, the hydrogel gel particles and the composite embolic material according to an embodiment of the present invention will be described in more detail through experimental examples using experimental samples and comparative samples.

<Preparation Example of Experimental Sample 1>

6% gelatin aqueous solution was prepared by dissolving gelatin in water at 60 ° C. Octadecyl amine was dissolved in ethanol to prepare a 2.5% octadecyl amine ethanol solution.

100 mL of 6% gelatin aqueous solution and 10 mL of 2.5% octadecyl amine ethanol solution were respectively taken and mixed, followed by stirring until uniformly mixed. Thereafter, 11.75 mL of a 3% aqueous solution of formaldehyde was added to the stirred product, and the test sample 1 was prepared by stirring at 2000 rmp for 15 minutes using a foam maker.

<Preparation Example of Experimental Sample 2>

6% gelatin aqueous solution was prepared by dissolving gelatin in water at 60 ° C. Octadecyl amine was dissolved in ethanol to prepare a 5% octadecyl amine ethanol solution.

100 mL of 6% gelatin aqueous solution and 10 mL of 5% octadecyl amine ethanol solution were respectively taken and mixed, followed by stirring until uniformly mixed. Thereafter, 11.75 mL of glutaraldehyde was added to the agitated product and stirred for 15 minutes at 2000 rmp using a bubble maker to prepare Experimental Sample 2.

<Preparation Example of Experimental Sample 3>

Chitosan was dissolved in water at 60 ° C. to prepare 6% gelatin aqueous solution. Octadecyl amine was dissolved in ethanol to prepare a 5% octadecyl amine ethanol solution.

100 mL of 6% gelatin aqueous solution and 10 mL of 5% octadecyl amine ethanol solution were respectively taken and mixed, followed by stirring until uniformly mixed. Thereafter, 11.75 mL of a 3% aqueous solution of formaldehyde was added to the stirred product, and the test sample 1 was prepared by stirring at 2000 rmp for 15 minutes using a foam maker.

<Production Example of Experimental Sample 4>

Chitosan and gelatin were mixed at a mass ratio of 3: 7 to prepare a chitosan-gelatin mixture. The chitosan-gelatin mixture was dissolved in water at 60 ° C. to prepare a 6% chitosan-gelatin mixture aqueous solution. Octadecyl amine was dissolved in ethanol to prepare a 5% octadecyl amine ethanol solution.

100 mL of a 6% chitosan-gelatin mixture aqueous solution and 10 mL of a 5% octadecyl amine ethanol solution were taken, mixed, and stirred until uniformly mixed. Thereafter, 11.75 mL of an aqueous 3% formaldehyde solution was added to the stirred product, and stirred for 15 minutes at 2000 rmp using a foam maker.

<Production Example of Experimental Sample 5>

Chitosan and gelatin were mixed at a mass ratio of 7: 3 to prepare a chitosan-gelatin mixture. The chitosan-gelatin mixture was dissolved in water at 60 ° C. to prepare a 6% chitosan-gelatin mixture aqueous solution. Octadecyl amine was dissolved in ethanol to prepare a 5% octadecyl amine ethanol solution.

100 mL of a 6% chitosan-gelatin mixture aqueous solution and 10 mL of a 5% octadecyl amine ethanol solution were taken, mixed, and stirred until uniformly mixed. Thereafter, 11.75 mL of an aqueous 3% formaldehyde solution was added to the stirred product, and stirred for 15 minutes at 2000 rmp using a foam maker.

<Preparation Example of Experimental Sample 6>

6% gelatin aqueous solution was prepared by dissolving gelatin in water at 60 ° C. Octadecyl amine was dissolved in ethanol to prepare a 5.0% octadecyl amine ethanol solution.

100 mL of a 6% gelatin aqueous solution and 10 mL of a 5.0% octadecyl amine ethanol solution were respectively taken, mixed, and stirred until uniformly mixed. Thereafter, 11.75 mL of an aqueous 3% formaldehyde solution was added to the stirred product, and stirred for 15 minutes at 2000 rmp using a foam maker.

<Production Example of Comparative Sample 1>

6% gelatin aqueous solution was prepared by dissolving gelatin in water at 60 ° C. Octadecyl amine was dissolved in ethanol to prepare a 5% hexadecyl amine ethanol solution.

100 mL of a 6% gelatin aqueous solution and 10 mL of a 5% hexadecyl amine ethanol solution were respectively taken and mixed, followed by stirring until uniformly mixed. Thereafter, 11.75 mL of an aqueous 3% formaldehyde solution was added to the stirred product, and a comparative sample 1 was prepared by stirring at 2000 rmp for 15 minutes using a foam maker.

<Production Example of Comparative Sample 2>

Chitosan was dissolved in water at 60 ° C. to prepare 6% gelatin aqueous solution. Octadecyl amine was dissolved in ethanol to prepare a 5% hexadecyl amine ethanol solution.

100 mL of a 6% gelatin aqueous solution and 10 mL of a 5% hexadecyl amine ethanol solution were respectively taken and mixed, followed by stirring until uniformly mixed. Thereafter, 11.75 mL of an aqueous 3% formaldehyde solution was added to the stirred product, and a comparative sample 2 was prepared by stirring at 2000 rmp for 15 minutes using a foam maker.

Experimental Example 1: Comparison of Properties

Using the microscope, the degree of foaming of the test samples 1 to 3 and the comparative sample 1 was compared. The results are shown in Table 1.

Table 1 sample Whether the bubble can be visually checked Bubbles occur Experimental Sample 1 possible Occur Experimental Sample 2 possible Occur Experimental Sample 3 possible Occur Experimental Sample 4 possible Occur Experimental Sample 5 possible Occur Experimental Sample 6 possible Occur Comparative Sample 1 impossible Unknown Comparative Sample 2 impossible Unknown

1 is a micrograph of a test sample 1 according to an embodiment of the present invention. 2 is a micrograph of a test sample 2 according to an embodiment of the present invention. 3 is a micrograph of a test sample 3 according to an embodiment of the present invention. 4 is a photomicrograph of Experimental Sample 4 according to an embodiment of the invention. 5 is a micrograph of an experimental sample 5 according to an embodiment of the present invention. 6 is a micrograph of a test sample 6 according to an embodiment of the present invention.

Referring to Figures 1 to 6 and Table 1, it can be seen that the experimental samples 1 to 6, unlike the comparative samples 1 and 2, the bubbles were visually confirmed. In contrast, Comparative Samples 1 and 2 did not visually confirm bubbles. Comparative Samples 1 and 2 are not considered to be homogeneous with gelatin and hexadecyl amine and chitosan and hexadecyl amine, respectively.

From Experimental Example 1, Comparative Samples 1 and 2 were confirmed to be difficult to prepare porous hydrogel particles that can be used as an embolic material. In addition, it was confirmed from Experimental Example 1 that a hydrogel particle including a mixture of two or more biodegradable polymers and including a C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative was possible.

<Preparation Example of Experimental Sample 7>

6% gelatin aqueous solution was prepared by dissolving gelatin in water at 60 ° C. Octadecyl amine was dissolved in ethanol to prepare a 0.5% octadecyl amine ethanol solution.

100 mL of a 6% gelatin aqueous solution and 10 mL of a 0.5% octadecyl amine ethanol solution were respectively taken and mixed, followed by stirring until uniformly mixed. Thereafter, 11.75 mL of an aqueous 3% formaldehyde solution was added to the stirred product, and stirred for 15 minutes at 2000 rmp using a foam maker.

After the stirring product was naturally dried at room temperature, the natural drying result was crushed finely, and the test sample 7 was prepared by selecting hydrogel particles having a size of 560 μm or more and 710 μm or less.

<Preparation Example of Experimental Sample 8>

Dissolve octadecyl amine in ethanol to prepare 1.0% octadecyl amine ethanol solution, take 100 mL of 6% gelatin aqueous solution and 10 mL of 1.0% octadecyl amine ethanol solution, mix them, and stir until uniform mixing. Except for one, the experimental sample 8 was prepared according to the preparation example of the experimental sample 7.

<Preparation Example of Experimental Sample 9>

Dissolve octadecyl amine in ethanol to prepare 2.0% octadecyl amine ethanol solution, take 100 mL of 6% gelatin aqueous solution and 10 mL of 2.0% octadecyl amine ethanol solution, mix them, and stir until uniformly mixed. Except for one, the experimental sample 9 was prepared according to the preparation example of the experimental sample 7.

<Preparation Example of Experimental Sample 10>

Dissolve octadecyl amine in ethanol to prepare 2.5% octadecyl amine ethanol solution, take 100 mL of 6% gelatin aqueous solution and 10 mL of 2.5% octadecyl amine ethanol solution, mix them, and stir until uniformly mixed. Except for one, the experimental sample 10 was prepared according to the preparation example of the experimental sample 7.

<Preparation Example of Experimental Sample 11>

Dissolve octadecyl amine in ethanol to prepare a 5.0% octadecyl amine ethanol solution, take 100 mL of 6% gelatin aqueous solution and 10 mL of 5.0% octadecyl amine ethanol solution, mix them, and stir until uniformly mixed. Except for one, the experimental sample 11 was prepared according to the preparation example of the experimental sample 7.

<Preparation Example of Experimental Sample 12>

Dissolve octadecyl amine in ethanol to prepare a 10.0% octadecyl amine ethanol solution, take 100 mL of 6% gelatin aqueous solution and 10 mL of 10.0% octadecyl amine ethanol solution, mix them, and stir until uniformly mixed. Except one, the experimental sample 12 was prepared according to the preparation example of the experimental sample 7.

<Preparation Example of Experimental Sample 13>

Dissolve octadecane amide in ethanol to prepare 2.5% octadecane amide ethanol solution, take 100 mL of 6% gelatin aqueous solution and 10 mL of 2.5% octadecane amide ethanol solution, mix them, and stir until uniform mixing Except one, the experimental sample 13 was prepared according to the preparation example of the experimental sample 7.

<Production Example of Comparative Sample 3>

6% gelatin aqueous solution was prepared by dissolving gelatin in water at 60 ° C. 11.75 mL of an aqueous 3% formaldehyde solution was added to 100 mL of an aqueous 6% gelatin solution, and stirred for 15 minutes at 2000 rmp using a foam maker.

After the stirring product was naturally dried at room temperature, the natural drying product was crushed finely, and hydrogel particles having a size of 560 μm or more and 710 μm or less were selected.

<Production Example of Comparative Sample 4>

As the embolization gelatin Prime Material curry was used for gel ^® (Cali-Gel ^®). Kali-Gel ^® was purchased from EMBOGENIC.

Experimental Example 2: Comparison of Absorption Capacity of Lipiodol ^®

Using a test sample 7 to 12, and comparative samples 3 and 4 was compared to absorption of lipiodol ^® according to the concentration of octadecylamine.

50 mg of each of the test samples 7-12 were taken and then placed in separate 15 mL centrifuge tubes. In the same manner, 50 mg of Comparative Samples 3 and 4 were each taken, and then placed in a 15 mL centrifuge tube.

After the experiment samples 7 to 12 and Comparative samples 3 and 4 in the lipiodol each centrifuge tube containing each ^® (ethyl mono-iodo stearate) into ssikeul 2 mL (2.560g) were mixed for 30 minutes.

Thereafter, the mixture was centrifuged at 4000 rpm for 1 minute, and after removing the supernatant, the mass was measured. Lipiodol ^® mass was converted from the measured values. The above experimental procedure was repeated three times.

7 is a graph comparing experimental samples 7 to 12 of the comparative samples and the hydrogel particles of the hydrogel particles of the third and lipiodol 4 ^® absorption. Table 2 summarizes Lipiodol ^® mass conversion values of FIG. 7 and summarizes it as a percentage of Lipiodol ^® addition.

TABLE 2 No. sample A B B / A × 100 (%) Lipiodol ^{® Addition} (g) Lipiodol ^® Mass Conversion Value (g) 7 Sample 7 2.560 1.873 73.2 8 Experimental Sample 8 2.318 90.5 9 Sample 9 2.226 87.0 10 Experimental Sample 10 2.439 95.3 11 Test Sample 11 2.000 78.1 12 Test Sample 12 2.260 88.3 3 Comparative Sample 3 0.623 24.3 4 Comparative Sample 4 1.553 45.0

On the other hand, Figure 7 and Referring to Table 2, even considering the experimental error detection hydrogel particles of the samples 3 and 4 is less than 50% by weight, based on the amount of ^® an average uptake of lipiodol ^® lipiodol, the test samples 7 to 12 Hydrogel gel particles can be confirmed that the average absorption of Lipiodol ^® is greater than 50% by weight based on the amount of Lipiodol ^® added.

In addition, the hydrogel particles of the test samples 7 to 12 was confirmed that the average absorption amount of Lipiodol ^® is greater than 70% by weight based on the amount of Lipiodol ^® added.

Referring to FIG. 7 and Table 2, unlike Comparative Samples 3 and 4, in which the content of octadecyl amine is 0% by weight relative to the total weight of the hydrogel particles, Experimental Samples 7 to 12 have the total amount of octadecyl amine content of the hydrogel particles. From 0.5% by weight to weight, it can be seen that the average absorption of Lipiodol ^® is rapidly increased and then maintained even when the content of octadecyl amine is increased.

In terms of numerical values, the average absorption of Lipiodol ^® in Experimental Samples 7-12 was 85.4 wt%, and the average absorption of Lipiodol ^® in Experimental Samples 8-12 was 87.8 wt%. From this, it can be seen that the hydrogel particles of the test samples 7 to 12 have an average of the average absorption of Lipiodol ^® at least 85 wt% and less than 88 wt%.

Experimental Example 3: Comparison of Absorption Capacity of Lipiodol ^®

Experimental samples 13 and comparative sample 4 lipiodol ^® each (mono-iodo ethyl stearate) were converted to the lipiodol ^® mass in the same manner as in Experimental Example 2, except that insert ssikeul 2.5 mL (3.200g).

8 is a graph comparing Lipiodol® absorption of hydrogel particles of Experimental Sample 13 and hydrogel particles of Comparative Sample 4. FIG. Table 3 summarizes Lipiodol ^® mass conversion values of FIG. 8 and summarizes it as a percentage of Lipiodol ^® addition.

TABLE 3 No. sample A B ' B '/ A × 100 (%) Lipiodol ^{® Addition} (g) Lipiodol ^® Mass Conversion Value (g) 13 Experimental Sample 13 3.200 2.271 71.0 4 Comparative Sample 4 1.358 42.4

Hydrogel particles of Figure 8 and Table Referring to Figure 3, compare hydrogel particles of the sample 4 on the other hand, the average uptake of lipiodol ^® is less than 50% by weight, based on the amount of lipiodol ^®, test sample 13 is the average amount of water absorption of lipiodol ^® It can be seen that it is more than 50% by weight based on the amount of Lipiodol ^® added.

In addition, the hydrogel particles of the test sample 13 was confirmed that the average absorption amount of Lipiodol ^® is greater than 70% by weight based on the amount of Lipiodol ^® added.

Experimental Example 4: Residual Content Comparison of Lipiodol ^®

In order to simulate the actual embolization, 5 mL of phosphate buffered saline (PBS) was added to each tube of the experiment samples 7 to 12 and the tubes of the comparative samples 3 and 4 in which the supernatant was separated after centrifugation in Experimental Example 2, respectively. And mixed for 10 minutes in a rolling mixer.

Then, after centrifuging for 1 minute at 4000 rpm, the supernatant was removed, and the mass was measured. Lipiodol ^® mass was converted from the measured values. The above experimental procedure was repeated three times.

Figure 9 shows the hydrogel particles and Lipiodol ^® of the test samples 7 to 12 Hydrogel particles of samples 3 and 4 and Lipiodol ^® were compared with experimental composite embolic samples containing Lipiodol ^® residual content comparison graph of comparative complex embolic samples containing. Table 4 summarizes Lipiodol ^® mass conversion values of FIG. 9 and summarizes it as a percentage of Lipiodol ^® addition.

Table 4 No. sample A C C / A × 100 (%) Lipiodol ^{® Addition} (g) Lipiodol ^® Mass Conversion Value (g) 7 Sample 7 2.5600 1.3440 52.5 8 Experimental Sample 8 1.9850 77.5 9 Sample 9 1.9300 75.4 10 Experimental Sample 10 2.0685 80.8 11 Test Sample 11 2.0000 78.1 12 Test Sample 12 1.7860 69.8 3 Comparative Sample 3 0.4570 17.9 4 Comparative Sample 4 0.4970 19.4

9 and referring to Table 4, even considering the experimental error detection hydrogel particles of the samples 3 and 4 on the other hand, the average residual content of lipiodol ^® less than 25% by weight, based on the amount of lipiodol ^®, test samples 7 to 12 of hydrogel particles it may be found that the average residual content of lipiodol ^® exceeds 25% by weight, based on the amount of lipiodol ^®.

The experimental hydrogel particles of the sample 7 to 12 were found to be an average residual content of lipiodol ^® is more than 50% by weight, based on the amount of lipiodol ^®.

Referring to FIG. 9 and Table 4, Experimental Samples 7 to 12 show that the content of octadecyl amine is 0.5% by weight relative to the total weight of the hydrogel particles, and the content of octadecyl amine is 0% by weight relative to the total weight of the hydrogel particles. unlike the comparative samples 3 and 4, it can be seen that maintaining a certain level even if the average residual content of lipiodol ^® significantly increased after increasing the content of octadecylamine.

In terms of the numerical value, the average of the self-sustained content of Lipiodol ^® of the test samples 7-12 was 72.4% by weight, and the average absorption of Lipiodol ^® of the test samples 8-12 was 76.3% by weight. From this, it can be seen that the hydrogel particles of the test samples 7 to 12 have an average value of the average residual content of Lipiodol ^® at least 72 wt% and less than 77 wt%.

Experimental Example 5: Residual Content Comparison of Lipiodol ^®

Lipiodol ^® mass was converted in the same manner as in Experiment 4, except that 2.5 mL (3.200 g) of Lipiodol ^® (ethyl monoiodostearate) was added to each of Experimental Sample 13 and Comparative Sample 4.

Figure 10 is a comparison graph of lipiodol ^® absorbent hydrogel particles in the experimental sample and the comparative sample 13, the hydrogel particles 4. Table 5 summarizes Lipiodol ^® mass conversion values of FIG. 10 and summarizes it as a percentage of Lipiodol ^® addition.

Table 5 No. sample A C ' C '/ A × 100 (%) Lipiodol ^{® Addition} (g) Lipiodol ^® Mass Conversion Value (g) 13 Experimental Sample 13 3.200 1.18 36.9 4 Comparative Sample 4 0.60 18.8

With reference to Table 5 and FIG. 10, in consideration of the experimental error, the hydrogel particles of Comparative Sample 4, whereas the average residual content of lipiodol ^® is less than 20% by weight, based on the amount of lipiodol ^®, hydrogels of the experimental samples 13 the particles can be confirmed that the average residual content of lipiodol ^® is more than 20% by weight, based on the amount of lipiodol ^®.

In addition, the hydrogel particles of the test sample 13 was confirmed that the average residual content of lipiodol ^® than 35% by weight, based on the amount of lipiodol ^®.

Experimental Example 6: GC / MS

50 mg of each of the test samples 10-12 was taken and then placed in separate 15 mL centrifuge tubes. In the same manner, 50 mg of Comparative Samples 3 and 4 were each taken, and then placed in a 15 mL centrifuge tube.

After the test samples 10 to 12 and Comparative lipiodol the samples 3 and 4 to each of the centrifuge tubes containing each ^® (ethyl mono-iodo stearate) into ssikeul 2 mL (2.560g) were mixed for 30 minutes. Thereafter, the mixture was centrifuged at 4000 rpm for 1 minute, and after removing the supernatant, 1 mL of hexane was added to each centrifuge tube and ultrasonically dispersed at room temperature (23 ° C.) for 10 minutes. Thereafter, after centrifugation at 4000 rpm for 1 minute, 200 μm each of the supernatant was filtered, and then the content of Lipiodol® was analyzed using GC / MS analysis. Standard (STD) was 1 mL of hexane.

Table 5 provides a comparison of lipiodol ^® content of experimental sample embolic materials for lipiodol ^® content of the comparison compound embolic material sample.

Table 6 No. sample Lipiodol ^® Content 10 Experimental Sample 10 1.423 11 Test Sample 11 1.458 12 Test Sample 12 1.519 3 Comparative Sample 3 1.151 4 Comparative Sample 4 1.000

Referring to Table 6 and Figure 11, the test composite sample embolic materials can see this amount of water absorption of 150% of lipiodol ^® plenty compared to comparative compound embolic material sample.

A summary of the GC analysis results of FIGS. 12 to 17 is shown in Table 7 below. 12 is a gas chromatography (GC) analysis result graph of an experimental composite embolic material sample including hydrogel particles and Lipiodol ^® of Experimental Sample 10.

FIG. 13 is a graph of gas chromatography (GC) analysis of an experimental composite embolic material sample including hydrogel particles and Lipiodol ^® of Experimental Sample 11. FIG.

FIG. 14 is a gas chromatographic (GC) analysis result graph of an experimental composite embolic material sample including hydrogel particles and Lipiodol ^® of Experimental Sample 12. FIG.

FIG. 15 is a graph of gas chromatography (GC) analysis of a comparative composite embolic material sample including hydrogel particles and Lipiodol ^® of Comparative Sample 3. FIG.

FIG. 16 is a graph of gas chromatography (GC) analysis of comparative composite embolic material samples including hydrogel particles and Lipiodol ^® of Comparative Sample 4. FIG.

17 is a graph of gas chromatography (GC) analysis results of a standard product.

TABLE 7 sample Area 23.4 (min) 27.0 (min) 33.0 (min) 33.4 (min) Standard product (STD) 57475654 13826631 51466977 88767611 Experimental Sample 10 321461373 86026365 513523050 597348080 Test Sample 11 328639405 85737125 535488767 605572583 Test Sample 12 317148280 83173444 643952322 605572583 Comparative Sample 3 261770662 70794233 400609249 494974190 Comparative Sample 4 227328208 62007876 341203153 436546480

Table 8 below is a mass spectrometry (MS) result table. Referring to Table 8 below, it can be seen that ethyl stearate is detected at around 27.0 minutes, showing a concordance rate of 98%. Figure 11 is a comparison of the relative content of gas chromatography lipiodol ^® 27.0 minutes based on the peak area units and based on a (GC) analysis of the 12 to 16.

Table 8 No. Runtime (RT) (min) Compound name % Match One 23.4 Ethyl palmitate 97 2 27.0 Ethyl stearate 98 3 33.0 1-hexadecanol 47 4 33.4 1-octadecanol 55

Experimental Example 7: FT-IR Spectrum

The chemical structures of the hydrogel particles of the test sample and the chemical structures of the hydrogel particles of the comparative sample were analyzed using the test samples 10 to 12 and the comparative samples 3 and 4. Experimental Samples 10-12, Comparative Samples 3 and 4 hydrogel particles were mixed with potassium bromide (Kbr) to produce pellets, and then FT-FT spectrometer (Spectrum GX, Perkin Elmer) -IR spectrum was obtained. Analysis range is 4,000 ㎝ ^-1 to 400 ㎝ ^- was ^one, it was scanned six times repeated with a resolution of 1 ㎝ ^-1.

FIG. 18 is an FT-IR spectrum of hydrogel particles of Comparative Sample 10.

19 is an FT-IR spectrum of hydrogel particles of Comparative Sample 11. FIG.

20 is an FT-IR spectrum of the hydrogel particles of Comparative Sample 12.

21 are FT-IR spectra of the hydrogel particles of Comparative Sample 3. FIG.

FIG. 22 is FT-IR spectra of hydrogel particles of Comparative Sample 4. FIG.

Referring to Figure 18 to Figure 22, the experimental sample of hydrogel particles from 10 to 12 are about 2850 cm ^-1 to about 3000 cm ^- in the wave number range of ^1, whereas the CH stretching vibration (stretching vibration) peak appears, the comparative sample 3 and hydrogel particles 4 are approximately 2850 cm ^-1 to about 3000 cm ^- was no CH stretching vibrations in the wave number range from ¹ (stretching vibration) peak.

The CH stretching vibration peak in the frequency range of about 2850 cm ⁻¹ to about 3000 cm ^{− 1} is the CH stretching vibration peak of methylene (CH ₂ ) of C ₁₈ to C ₂₆ aliphatic hydrocarbon, FIGS. 18 to 22. It was confirmed that the C ₁₈ ~ C ₂₆ aliphatic hydrocarbon is chemically bonded to gelatin. CH stretching vibration is about 2920 cm ^-1 at CH Asymmetrical stretch vibration peaks and CH symmetrical stretch vibration peaks at about 2,853 cm ⁻¹ are analyzed. The number of waves in the FT-IR spectrum can have an error range within the range of ± 8 cm ⁻¹ .

It was confirmed that the FT-IR spectra of the hydrogel particles of Comparative Samples 3 and 4, in which octadecyl amine was not included and gelatin was the main substance, were almost identical.

The preparation examples, experimental examples, and the like of the experimental samples are for the purpose of understanding the invention, and the technical spirit of the present invention is not limited to the above-described preparation examples, experimental examples, and the like. Substitution of equivalents, addition of other components, deletion, and the like within the scope of not impairing the technical idea of the present invention will still be incorporated in the present specification to constitute the present invention.

Hydrogel gel particles and complex embolic material according to an embodiment of the present invention can minimize the use of iodine-based contrast agent to reduce the side effects of the iodine-based contrast agent, to selectively form blood clots in the blood vessels or to block blood flow As a result, the accuracy of embolization can be increased.

The effects according to the present invention are not limited by the contents exemplified above, and more various effects are included in the present specification.

Claims (20)

Biodegradable polymers of at least one of gelatin and chitosan; And And at least one C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative of an alkyl amine and an alkyl amide; C ₁₈ ~ C ₂₆ CH stretching vibration (stretching vibration) 2850 cm ^-1 peak to 3000 cm of methylene (CH ₂₎ an aliphatic ^{hydrocarbon-hydrogel} particles having the FT-IR spectrum that appears in the wave number range in ^Fig. According to claim 1, The C ₁₈ ~ C ₂₆ aliphatic hydrocarbon derivative is a hydrogel particle that is a derivative of C ₁₈ ~ C ₂₆ n-alkyl. According to claim 1, The alkyl amine is a C ₁₈ ~ C ₂₆ n-alkyl amine hydrogel particles. The method of claim 3, wherein The C ₁₈ ~ C ₂₆ n-alkyl amine is octadecylamine hydrogel particles. According to claim 1, The alkyl amide is C ₁₈ ~ C ₂₆ n-alkyl amide hydrogel particles. The method of claim 5, The C ₁₈ ~ C ₂₆ n-alkyl amide is octadecane amide (octadecane amide) hydrogel particles. According to claim 1, Hydrogel gel particles having an average absorbed amount of iodide C ₁₈ ~ C ₂₆ fatty acid ester greater than 50% by weight based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid ester. According to claim 1, Hydrogel gel particles having an average absorbed amount of iodide C ₁₈ ~ C ₂₆ fatty acid ester greater than 70% by weight based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid ester. According to claim 1, Hydrogel gel particles having an average value of the average absorption of the iodide C ₁₈ to C ₂₆ fatty acid ester is greater than 85% to less than 88% by weight based on the amount of the iodide C ₁₈ to C ₂₆ fatty acid ester added. Biodegradable polymers of at least one of gelatin and chitosan; And And at least one C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative of an alkyl amine and an alkyl amide; Hydrogel gel particles having an average absorbed amount of iodide C ₁₈ ~ C ₂₆ fatty acid ester greater than 50% by weight based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid ester. The method of claim 10, Hydrogel gel particles having an average absorbed amount of iodide C ₁₈ ~ C ₂₆ fatty acid ester greater than 70% by weight based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid ester. The method of claim 10, Hydrogel gel particles having an average value of the average absorption of the iodide C ₁₈ to C ₂₆ fatty acid ester is greater than 85% to less than 88% by weight based on the amount of the iodide C ₁₈ to C ₂₆ fatty acid ester added. CH stretching vibration of methylene (CH ₂ ) of C ₁₈ to C ₂₆ aliphatic hydrocarbons comprising at least one biodegradable polymer of gelatin and chitosan and at least one C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative of alkyl amines and alkyl amides the peak 2850 cm ^-1 to 3000 cm ^- hydrogel particles having the FT-IR spectrum that appears in the wave number range of from ^1; And Iodide C ₁₈ -C ₂₆ fatty acid esters; Complex embolic material comprising a. The method of claim 13, The iodide C ₁₈ ~ C ₂₆ fatty acid ester is ethyl monoiodostearate (ethyl monoiodostearate) complex embolic material. The method of claim 13, The average residual content after the addition of phosphate buffered saline (PBS) centrifugation was separated measured after removing the supernatant the iodide C ₁₈ ~ C ₂₆ fatty acid esters are based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid ester Complex embolic material greater than 25% by weight. The method of claim 13, The average residual content after the addition of phosphate buffered saline (PBS) centrifugation was separated measured after removing the supernatant the iodide C ₁₈ ~ C ₂₆ fatty acid esters are based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid ester Complex embolic material greater than 35% by weight. The method of claim 13, After the addition of phosphate buffered saline (PBS) and centrifugation, the average value of the average residual content of the iodide C ₁₈ to C ₂₆ fatty acid ester measured after removing the supernatant was determined by the amount of the iodide C ₁₈ to C ₂₆ fatty acid ester added. A composite embolic material that is greater than 72% and less than 77% by weight based. Hydrogel particles comprising at least one biodegradable polymer of gelatin and chitosan and at least one C ₁₈ to C ₂₆ aliphatic hydrocarbon derivative of alkyl amine and alkyl amide; And Iodide C ₁₈ -C ₂₆ fatty acid ester; The hydrogel particles have an average amount of water absorption of the iodide C ₁₈ ~ C ₂₆ fatty acid ester exceeds 50% by weight, based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid ester, The average residual content after the addition of phosphate buffered saline (PBS) centrifugation was separated measured after removing the supernatant the iodide C ₁₈ ~ C ₂₆ fatty acid esters are based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid ester Complex embolic material greater than 25% by weight. The method of claim 18, The average residual content after the addition of phosphate buffered saline (PBS) centrifugation was separated measured after removing the supernatant the iodide C ₁₈ ~ C ₂₆ fatty acid esters are based on the amount of the iodide C ₁₈ ~ C ₂₆ fatty acid ester Complex embolic material greater than 35% by weight. The method of claim 18, After the addition of phosphate buffered saline (PBS) and centrifugation, the average value of the average residual content of the iodide C ₁₈ to C ₂₆ fatty acid ester measured after removing the supernatant was determined by the amount of the iodide C ₁₈ to C ₂₆ fatty acid ester added. A composite embolic material that is greater than 72% and less than 77% by weight based.

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