KR101667328B1

KR101667328B1 - Hydrogel particle and composite embolic material

Info

Publication number: KR101667328B1
Application number: KR1020150063816A
Authority: KR
Inventors: 차준회; 이지영
Original assignee: 주식회사 엔게인
Priority date: 2015-05-07
Filing date: 2015-05-07
Publication date: 2016-10-18
Also published as: WO2016178448A1

Abstract

At least one biodegradable polymer of at least one of gelatin and chitosan and at least one C ₁₈ -C ₂₆ aliphatic hydrocarbon derivative of an alkylamine and alkyl amide, wherein the methylene (CH ₂ ) of a C ₁₈ -C ₂₆ aliphatic hydrocarbon, of the CH stretching vibration (stretching vibration) 2850 cm ^-1 peak to 3000 cm ^- the composite embolic materials containing them with hydrogel particles having the FT-IR spectrum that appears in the wave number range of ¹ it is provided.

Description

[0001] HYDROGEL PARTICLE AND COMPOSITE EMBOLIC MATERIAL [0002]

The invention is directed to the hydrogel particles and complex embolization materials used in embolization.

Liver tissue is supplied by oxygen and nutrients by two blood vessels. One is the portal vein, which is the portal vein, and the other is the hepatic artery, which comes directly from the aorta. Normal liver tissue is mainly in the context, and tumor tissue is supplied mainly in the hepatic artery. Therefore, only the hepatic artery supplying the tumor is selected, and when the cancer drug is administered and the blood vessel is blocked after the administration of the anticancer drug, only the tumor can be selectively necrotized without significantly damaging the normal liver tissue.

Transarterial chemoembolization is a treatment for hepatocellular carcinoma (hepatocellular carcinoma) by administering anticancer drugs to find hepatic artery supplying hepatocellular carcinoma.

Through the femoral artery located in the groin (inguinal), a thin tube of about 2 ~ 3 mm called a catheter is inserted to approach the hepatic artery. When the catheter is inserted into the hepatic artery, an angiographic contrast agent is injected into the hepatic artery to obtain information on the position, size and blood supply of the tumor. When the treatment is decided, a thin tube of about 1 mm in thickness is used to find the hepatic artery to the hepatic tumor and to put an anticancer agent and an embolization substance into it.

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

Lipiodol ^® is an iodinated ethyl ester of poppy seed oil fatty acids derived from, when the anticancer agent and the mixed injection is selectively deposited in the liver tumor. Lipiodol ^® is a fat-soluble iodine based contrast media, it may serve as the embolic material having embolic effect of microvessels.

Excessive use of iodine contrast agents may cause side effects such as nausea, vomiting, urticaria, itching, hypotensive shock, respiratory arrest, cardiac arrest, and convulsions. Lipiodol ^® it can serve as embolic materials. However, since the fat-soluble iodine based contrast agents over-use of lipiodol ^® can cause side effects such as nausea, vomiting, urticaria, itching, hypotensive shock, respiratory arrest, cardiac arrest, convulsions.

Gelpom ^® is a block in the nutrients supplied to the liver tumors by promoting thrombus formation or blocking the flow of blood, and the main component is composed of proteins with excellent safety embolic material in the hepatic artery.

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 Which may result in the formation of 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 may occur in the arteries or veins connected to the same organs, such as forming blood clots or blocking blood flow.

The present invention aims to provide a composite embolization material in which the side effects of the iodine contrast agent are minimized and at the same time, the selective thrombus formation and blood flow blocking function of the embolization substance are improved and the embolization gel particles for embolization used therefor.

The present invention has been made in view of the above problems, and it is an object of the present invention to provide an apparatus and method for controlling the same.

The hydrogel particles according to one embodiment of the invention include at least one biodegradable polymer of gelatin and chitosan and at least one C ₁₈ -C ₂₆ aliphatic hydrocarbon derivative of an alkylamine and alkyl amide.

Hydrogel particles in accordance with one embodiment of the invention, C ₁₈ ~ C ₂₆ aliphatic hydrocarbon group of methylene (CH ₂₎ a CH stretching vibration (stretching vibration) 2850 cm ^-1 peak to 3000 cm ^- FT appears in the wave number range of from ¹ -IR spectra.

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 ~ C ₂₆ is in excess of 25% by weight, based on the addition amount of the fatty acid ester.

The complex embolization material according to an embodiment of the present invention includes the above-mentioned hydrogel particles and an iodinated C ₁₈ -C ₂₆ fatty acid ester.

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

The alkylamine may be a C ₁₈ -C ₂₆ n-alkylamine. The C ₁₈ -C ₂₆ n-alkylamine may be octadecylamine.

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

The iodinated 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.

The iodide C ₁₈ ~ C ₂₆ is the average value of the average absorption of the fatty acid ester can be less than the iodide C ₁₈ ~ C ₂₆ exceeds 85% by weight, based on the amount of fatty acid ester to 88% by weight.

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 By weight to 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 To less than 77% by weight based on the total weight of the composition.

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

The hydrogel particles and the complex embolization agent according to an embodiment of the present invention can minimize the use of the iodine contrast agent, thereby reducing the side effects of the iodine contrast agent and preventing the formation of a thrombus selectively in the blood vessel, 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 specification.

1 is a photomicrograph of an experimental sample 1 according to an embodiment of the invention.
2 is a photomicrograph of an experimental sample 2 according to an embodiment of the invention.
3 is a photomicrograph of an experimental sample 3 according to an embodiment of the invention.
4 is a photomicrograph of an experimental sample 4 according to an embodiment of the invention.
5 is a photomicrograph of an experimental sample 5 according to an embodiment of the invention.
6 is a photomicrograph of an experimental sample 6 according to an embodiment of the 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 for the gas content of the test compound lipiodol ^® embolic material sample in accordance with one embodiment of the invention, chromatographic (GC) analysis results are graphs.
15 and 16 are gas chromatography for the content of the comparison compound lipiodol ^® embolic material samples (GC) analysis result graphs are
17 is a graph of gas chromatography (GC) analysis results of a standard product.
18 to 20 are FT-IR spectra of the hydrogel particles of an experimental sample according to an embodiment of the present invention.
21 and 22 are FT-IR spectra of the hydrogel particles of the comparative sample.

BRIEF DESCRIPTION OF THE DRAWINGS The features and advantages of the present invention will become more apparent from the following detailed description taken in conjunction with the accompanying drawings, in which: FIG.

A "hydrogel particle" is a particle that can be used for embolization and can be swollen by water as a kind of embolization substance. The hydrogel particles may be sphere-shaped particles having a smooth spherical surface in order to prevent inflammation that may occur when they are in contact with the blood vessel wall for a long time after embolization. The size of the hydrogel particles is not particularly limited, but may be determined within a range of several μm to several hundreds of μm.

The term "composite embolization substance" means an embolus material in which two or more types of embolization materials are combined, or an embolus material in which one type of embolization material and one type of contrast agent are combined. The complex embolization material also includes a case where the function of the embolus substance and the function of the contrast agent function in a complex manner, such as when one kind of embolization substance has the function of the contrast agent.

A "biodegradable polymer" is a biomaterial that is gradually degraded in the body after transplantation and replaced with a regenerating autologous tissue. For example, the biodegradable polymer may be a natural polymeric compound, and the natural polymeric compound may be at least one of gelatin and chitosan, for example. The gelatin and the chitosan may be used alone as the biodegradable polymer, or a combination thereof, that is, a combination of the gelatin and the chitosan may be used as the biodegradable polymer.

The " _C18 to _C26 aliphatic hydrocarbon derivative" is a derivative of an aliphatic hydrocarbon having from 18 to 26 carbon atoms.

"C ₁₈ -C ₂₆ alkylamine" is an amine having alkyl having from 18 to 26 carbon atoms. "C ₁₈ -C ₂₆ alkyl amide" is an amide having alkyl having from 18 to 26 carbon atoms.

"C ₁₈ -C ₂₆ alkyl" refers to C ₁₈ -C ₂₆ n-alkyl and C ₁₈ -C ₂₆ iso-alkyl, which do not have side-chain carbon chains attached to the main carbon chain, or alkyl having a side chain carbon chain attached to the main carbon chain such as < RTI ID = 0.0 > sec-alkyl. < / RTI >"Amines" and "amides " include diamines and diamides, respectively.

An example of the C ₁₈ to C ₂₆ n-alkylamine is octadecyl amine.

An example of the C ₁₈ to C ₂₆ n-alkyl amide includes octadecyl amine.

The "iodinated C ₁₈ -C ₂₆ fatty acid ester" is a compound in which iodine is substituted for a fatty acid ester having an alkyl of 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 residual content of one C ₁₈ to C ₂₆ fatty acid ester.

The hydrogel particles according to an embodiment of the present invention include the biodegradable polymer and a C ₁₈ -C ₂₆ aliphatic hydrocarbon derivative. The C ₁₈ -C ₂₆ aliphatic hydrocarbon derivative may be, for example, a C ₁₈ -C ₂₆ alkylamine and / or a C ₁₈ -C ₂₆ alkylamide. As used herein, "A and / or B" means "A, B or A and B".

The C ₁₈ -C ₂₆ alkylamine and the C ₁₈ -C ₂₆ alkylamide may each 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, and the like.

For example, where the formaldehyde is used as a crosslinking agent, each of the C ₁₈ -C ₂₆ alkylamine and the C ₁₈ -C ₂₆ alkylamide may comprise a methylene bridge bonded to the biodegradable polymer . At this time, the methylene bridge can function as a linker.

The methylene bridge may be derived from the methylene of methylene glycol (HOCH ₂ OH) produced by the reaction of formaldehyde with water, and may be a dehydration condensation reaction of the biodegradable polymer, the C ₁₈ -C ₂₆ aliphatic hydrocarbon derivative and methylene glycol Each of the C ₁₈ -C ₂₆ alkylamine and the C ₁₈ -C ₂₆ alkyl amide may comprise the methylene bridge as a linker.

As an example, the methylene bridge may link the nitrogen atom (N) of the gelatin with the nitrogen atom (N) of the C ₁₈ -C ₂₆ alkylamine, or the nitrogen atom (N) of the gelatin and the C ₁₈ -C ₂₆ The nitrogen atom (N) of the alkyl amide can be connected.

As another example, the methylene bridge may link the nitrogen atom (N) of the chitosan with the nitrogen atom (N) of the C ₁₈ -C ₂₆ alkylamine, or the nitrogen atom (N) of the chitosan and the C ₁₈ -C _Lt; RTI ID = 0.0 > (N) < / RTI >

For example, where the glutaraldehyde is used as the crosslinking agent, each of the C ₁₈ -C ₂₆ alkylamine and the C ₁₈ -C ₂₆ alkylamide may comprise a Shiff base bound to the biodegradable polymer have. At this time, the Schiff base may function as a linker.

By the dehydration condensation reaction of the biodegradable polymer, the C ₁₈ -C ₂₆ aliphatic hydrocarbon derivative and the methylene glycol, the C ₁₈ -C ₂₆ alkylamine and the C ₁₈ -C ₂₆ alkylamide each contain the Schiff base as a linker .

As an example, the Schiff base may link one nitrogen atom (N) of the gelatin and the chitosan to the nitrogen atom (N) of the C ₁₈ -C ₂₆ alkylamine, or one nitrogen atom of the gelatin and the chitosan (N) and the nitrogen atom (N) of the C ₁₈ -C ₂₆ alkylamide.

For example, where the Jenin fins are used as the crosslinking agent, each of the C ₁₈ -C ₂₆ alkylamine and the C ₁₈ -C ₂₆ alkylamide may include a linker represented by the following formula (1).

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

&Lt; Formula (1) >

The C ₁₈ -C ₂₆ aliphatic hydrocarbon derivative can be uniformly mixed with the biodegradable polymer within the range of C ₁₈ -C ₂₆ , and can produce many bubbles during whipping. As can be seen from the following experimental examples, when hexadecylamine was used as the C ₁₈ -C ₂₆ aliphatic hydrocarbon derivative, mixing was not performed well, and bubbles could not be visually confirmed even when whipped. This will be described more specifically in the following experimental examples.

The composite embolization material according to an embodiment of the present invention includes the hydrogel particles and an iodinated fatty acid ester. It is presumed that the iodinated fatty acid ester is bonded through the hydrophilic interaction with the aliphatic hydrocarbon derivative.

That is, since the complex embolization substance according to an embodiment of the present invention has a hydrophobic interaction between the carbon chain of the C ₁₈ -C ₂₆ aliphatic hydrocarbon derivative and the carbon chain of the iodinated fatty acid ester, .

For example, the iodinated fatty acid ester may be an iodinated fatty acid ester in which the carbon chain is C ₁₈ to C ₂₆ n-alkyl. The carbon chain of the C ₁₈ -C ₂₆ aliphatic hydrocarbon derivative may include n-alkyl to increase the hydrophobic interaction between the alkyls. For example, the C ₁₈ -C ₂₆ alkylamine may be a C ₁₈ -C ₂₆ n-alkylamine, and the C ₁₈ -C ₂₆ alkylamide may be a C ₁₈ -C ₂₆ n-alkylamide.

From the experimental examples described below, it can be confirmed that the hydrogel particles and the complex embolization substance according to one embodiment of the present invention each have an excellent absorption or binding force for the iodinated C ₁₈ -C ₂₆ fatty acid ester.

Hereinafter, the hydrated gel particles and the complex embolization substance according to one embodiment of the present invention will be described in more detail through experimental examples using experimental samples and comparative samples.

Gelatin was dissolved in water at 60 ° C to prepare a 6% gelatin aqueous solution. Octadecylamine was dissolved in ethanol to prepare a 2.5% octadecylamine ethanol solution.

100 mL of a 6% gelatin aqueous solution and 10 mL of a 2.5% octadecylamine ethanol solution were taken and mixed, followed by stirring until uniformly mixed. Then, 11.75 mL of a 3% formaldehyde aqueous solution was added to the resultant, and stirred at 2000 rpm for 15 minutes using a foam maker to prepare an experimental sample 1.

&Lt; Production example of test sample 2 >

Gelatin was dissolved in water at 60 ° C to prepare a 6% gelatin aqueous solution. Octadecylamine was dissolved in ethanol to prepare a 5% octadecylamine ethanol solution.

100 mL of a 6% gelatin aqueous solution and 10 mL of a 5% octadecylamine ethanol solution were taken and mixed, followed by stirring until uniformly mixed. Then, 11.75 mL of glutaraldehyde was added to the resultant of the stirring, and stirred at 2000 rpm for 15 minutes using a foam maker to prepare an experimental sample 2.

The chitosan was dissolved in water at 60 ° C to prepare a 6% aqueous chitosan solution. Octadecylamine was dissolved in ethanol to prepare a 5% octadecylamine ethanol solution.

100 mL of a 6% aqueous chitosan solution and 10 mL of a 5% octadecylamine ethanol solution were taken and mixed, followed by stirring until uniformly mixed. Then, 11.75 mL of a 3% formaldehyde aqueous solution was added to the resultant, and stirred at 2000 rpm for 15 minutes using a foam maker to prepare an experimental sample 3.

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% aqueous chitosan-gelatin mixture solution. Octadecylamine was dissolved in ethanol to prepare a 5% octadecylamine ethanol solution.

100 mL of the 6% chitosan-gelatin mixture aqueous solution and 10 mL of the 5% octadecylamine ethanol solution were taken and mixed, and the mixture was stirred until uniformly mixed. Then, 11.75 mL of a 3% formaldehyde aqueous solution was added to the resultant, and the mixture was stirred at 2000 rpm for 15 minutes using a foam maker.

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% aqueous chitosan-gelatin mixture solution. Octadecylamine was dissolved in ethanol to prepare a 5% octadecylamine ethanol solution.

Gelatin was dissolved in water at 60 ° C to prepare a 6% gelatin aqueous solution. Octadecylamine was dissolved in ethanol to prepare a 5.0% octadecylamine ethanol solution.

100 mL of a 6% gelatin aqueous solution and 10 mL of a 5.0% octadecylamine ethanol solution were taken and mixed, followed by stirring until uniformly mixed. Then, 11.75 mL of a 3% formaldehyde aqueous solution was added to the resultant, and the mixture was stirred at 2000 rpm for 15 minutes using a foam maker.

Gelatin was dissolved in water at 60 ° C to prepare a 6% gelatin aqueous solution. Hexadecylamine was dissolved in ethanol to prepare a 5% hexadecylamine ethanol solution.

100 mL of a 6% gelatin aqueous solution and 10 mL of a 5% hexadecylamine ethanol solution were taken and mixed, followed by stirring until uniformly mixed. Then, 11.75 mL of a 3% formaldehyde aqueous solution was added to the resultant, and the mixture was stirred at 2000 rpm for 15 minutes using a foam maker to prepare a comparative sample 1.

The chitosan was dissolved in water at 60 ° C to prepare a 6% aqueous chitosan solution. Hexadecylamine was dissolved in ethanol to prepare a 5% hexadecylamine ethanol solution.

100 mL of a 6% aqueous solution of chitosan and 10 mL of a 5% hexadecylamine ethanol solution were taken, mixed, and stirred until uniformly mixed. Then, 11.75 mL of 3% formaldehyde aqueous solution was added to the resultant, and the mixture was stirred at 2000 rpm for 15 minutes using a foam maker to prepare a comparative sample 2.

&Lt; Experimental Example 1: Characteristic comparison >

The degree of foaming of the experimental samples 1 to 3 and the comparative sample 1 was compared using a microscope. The results are shown in Table 1.

sample Visibility of bubbles Whether bubbles are generated 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 photomicrograph of an experimental sample 1 according to an embodiment of the invention. 2 is a photomicrograph of an experimental sample 2 according to an embodiment of the invention. 3 is a photomicrograph of an experimental sample 3 according to an embodiment of the invention. 4 is a photomicrograph of an experimental sample 4 according to an embodiment of the invention. 5 is a photomicrograph of an experimental sample 5 according to an embodiment of the invention. 6 is a photomicrograph of an experimental sample 6 according to an embodiment of the invention.

Referring to FIGS. 1 to 6 and Table 1, it can be seen that the test samples 1 to 6, unlike the comparative samples 1 and 2, were visually confirmed to have a bubble. On the contrary, the comparative samples 1 and 2 were not visually confirmed as bubbles. In Comparative Samples 1 and 2, it is presumed that a mixture of gelatin and hexadecylamine and a mixture of chitosan and hexadecylamine were not homogeneously mixed.

It was confirmed that it was difficult to prepare the porous hydrogel particles from Experimental Example 1 in which Comparative Samples 1 and 2 could be used as embolization materials. It was also confirmed from Experimental Example 1 that preparation of hydrogel particles containing a mixture of two or more biodegradable polymers and containing a C ₁₈ -C ₂₆ aliphatic hydrocarbon derivative was possible.

Gelatin was dissolved in water at 60 ° C to prepare a 6% gelatin aqueous solution. Octadecylamine was dissolved in ethanol to prepare a 0.5% octadecylamine ethanol solution.

100 mL of a 6% gelatin aqueous solution and 10 mL of a 0.5% octadecylamine ethanol solution were taken and mixed, followed by stirring until uniformly mixed. Then, 11.75 mL of a 3% formaldehyde aqueous solution was added to the resultant, and the mixture was stirred at 2000 rpm for 15 minutes using a foam maker.

The resultant mixture was naturally dried at room temperature, and the natural dried product was finely crushed. The hydrogel particles having a size of 560 쨉 m to 710 쨉 m were selected to prepare Test Sample 7.

&Lt; Production example of test sample 8 >

Octadecylamine was dissolved in ethanol to prepare a 1.0% octadecylamine ethanol solution. Then, 100 mL of a 6% gelatin aqueous solution and 10 mL of a 1.0% octadecylamine ethanol solution were taken and mixed. Then, the mixture was stirred until homogeneous mixing , An experimental sample 8 was prepared according to the production example of the experimental sample 7.

Octadecylamine was dissolved in ethanol to prepare a 2.0% octadecylamine ethanol solution. Then, 100 mL of a 6% gelatin aqueous solution and 10 mL of a 2.0% octadecylamine ethanol solution were taken and mixed. Then, the mixture was stirred until uniformly mixed , An experimental sample 9 was prepared according to the production example of the experimental sample 7.

Octadecylamine was dissolved in ethanol to prepare a 2.5% octadecylamine ethanol solution. Then, 100 mL of a 6% gelatin aqueous solution and 10 mL of a 2.5% octadecylamine ethanol solution were taken and mixed. Then, the mixture was stirred until uniformly mixed , An experimental sample 10 was prepared according to the production example of the experimental sample 7.

Octadecylamine was dissolved in ethanol to prepare a 5.0% octadecylamine ethanol solution. Then, 100 mL of a 6% gelatin aqueous solution and 10 mL of 5.0% octadecylamine ethanol solution were taken and mixed. Then, the mixture was stirred until uniformly mixed , An experimental sample 11 was prepared according to the production example of the experimental sample 7.

&Lt; Production example of experimental sample 12 >

Octadecylamine was dissolved in ethanol to prepare a 10.0% octadecylamine ethanol solution. Then, 100 mL of a 6% gelatin aqueous solution and 10 mL of 10.0% octadecylamine ethanol solution were taken and mixed. Then, the mixture was stirred until uniformly mixed , An experimental sample 12 was prepared according to the production example of the experimental sample 7.

&Lt; Production example of experimental sample 13 >

Octadecanamide was dissolved in ethanol to prepare a 2.5% octadecanamide ethanol solution. Then, 100 mL of a 6% gelatin aqueous solution and 10 mL of a 2.5% octadecanamide ethanol solution were taken and mixed. Then, the mixture was stirred until homogeneous mixing , An experimental sample 13 was prepared according to the production example of the experimental sample 7.

Gelatin was dissolved in water at 60 ° C to prepare a 6% gelatin aqueous solution. To 100 mL of 6% gelatin aqueous solution was added 11.75 mL of 3% formaldehyde aqueous solution and stirred at 2000 rpm for 15 minutes using a foam maker.

The resultant agitated product was naturally dried at room temperature, the naturally dried product was finely crushed, and hydrogel particles having a size of 560 쨉 m to 710 쨉 m were selected.

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

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 each of the experimental samples 7 to 12 was taken and placed in separate 15-mL centrifuge tubes. In the same manner, 50 mg of each of the comparative samples 3 and 4 was taken and 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.

After centrifugation at 4000 rpm for 1 min, the supernatant was removed and the mass was measured. It was converted to lipiodol ^® mass in the measure. The above 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 is a table summarizing the lipiodol ^® by mass in terms of the value of 7, and organize them as a percentage of the amount lipiodol ^®.

No. sample A B B / A x 100 (%) Lipiodol ^®
Addition amount (g) Lipiodol ^®
Mass conversion value (g) 7 Experimental Sample 7 2.560 1.873 73.2 8 Experimental Sample 8 2.318 90.5 9 Experimental Sample 9 2.226 87.0 10 Experimental Sample 10 2.439 95.3 11 Experimental Sample 11 2.000 78.1 12 Experimental 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 particles may be found that the average absorption of lipiodol ^® is more than 50% by weight, based on the amount of lipiodol ^®.

The experimental samples 7 to 12 of the hydrogel particles was confirmed that the average absorption of lipiodol ^® greater than 70% by weight, based on the amount of lipiodol ^®.

7 and Table 2, unlike the comparative samples 3 and 4 in which the content of octadecylamine was 0 wt% based on the total weight of the hydrogel particles, the test samples 7 to 12 showed that the octadecylamine content was higher than the total from the time of 0.5% by weight, based on the weight of, it can be confirmed that after that the average absorption of lipiodol ^® significantly increased, maintaining a certain level even when the amount of octadecylamine increased.

The average absorbed amount of Lipiodol ( ^R) in Experimental Samples 7 to 12 was 85.4% by weight, and the average amount of Lipiol ( ^R) in Experimental Samples 8 to 12 was 87.8% by weight. And from this, experimental samples hydrogel particles of 7 to 12 is greater than the average of the average absorption of at least 85% by weight of lipiodol ^®, it can be seen that less than 88% by weight.

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).

Fig. 8 is a graph showing a comparison of absorption of lipidol with the hydrated gel particles of Experimental Sample 13 and the hydrated gel particles of Comparative Sample 4. Fig. Table 3 is a table summarizing the lipiodol ^® by mass in terms of the value of 8, and organize them as a percentage of the amount lipiodol ^®.

No. sample A B ' B '/ A x 100 (%) Lipiodol ^®
Addition amount (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 ^® based on the amount of lipiodol ^® can confirm that more than 50% by weight.

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

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

After centrifugation at 4000 rpm for 1 minute, the supernatant was removed, and the mass was measured. It was converted to lipiodol ^® mass in the measure. The above procedure was repeated three times.

Figure 9 is an experimental samples 7 to 12, the hydrogel particles and in lipiodol ^® The test compound comprises embolization material samples and the comparative samples 3 and 4, the hydrogel particles and lipiodol ^® in which Lipiodol of comparison compound embolic material samples containing a residual content ^® comparison graph. Table 4 summarizes the Lipidol ^占 mass conversion values in FIG. 9, and summarizes them as a percentage with respect to the Lipidol ^占 addition amount.

No. sample A C C / A x 100 (%) Lipiodol ^®
Addition amount (g) Lipiodol ^®
Mass conversion value (g) 7 Experimental Sample 7 2.5600 1.3440 52.5 8 Experimental Sample 8 1.9850 77.5 9 Experimental Sample 9 1.9300 75.4 10 Experimental Sample 10 2.0685 80.8 11 Experimental Sample 11 2.0000 78.1 12 Experimental 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 ^®.

9 and Table 4, the test samples 7 to 12 show that the content of octadecylamine was 0 wt% based on the total weight of the hydrogel particles from 0.5 wt% of 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.

Haebomyeon translates to a numerical value, the experiment sample average of the mean content of the self-esteem of 7 to 12 lipiodol ^® was the average of the average uptake of lipiodol ^® of a 72.4% by weight, 8 to 12 test samples is 76.3% by weight. And from this, experimental samples 7 to 12 of the hydrogel particles is greater than the average of the residual content of lipiodol ^® average at least 72% by weight, it can be seen that less than 77% by weight.

Experimental Example 5: Comparison of Residual Content of Lipiodol ^占 ?

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 Example 4 except that into ssikeul 2.5 mL (3.200g).

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 the Ripiodol ^占 mass conversion values shown in FIG. 10 and summarizes them as a percentage of Lipidol ^占 addition amount.

No. sample A C ' C '/ A x 100 (%) Lipiodol ^®
Addition amount (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 each of the test samples 10 to 12 were taken and placed in separate 15-mL centrifuge tubes. In the same manner, 50 mg of each of the comparative samples 3 and 4 was taken and 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. After centrifugation at 4000 rpm for 1 minute, the supernatant was removed, 1 mL of hexane was added to each tube for centrifugation, and the mixture was ultrasonically dispersed at room temperature (23 ° C) for 10 minutes. After centrifugation at 4000 rpm for 1 minute, 200 ㎛ of the supernatant was filtered, and the content of lipiodol was analyzed by GC / MS. Standard product (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.

No. sample Lipiodol ^® content 10 Experimental Sample 10 1.423 11 Experimental Sample 11 1.458 12 Experimental 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.

The GC analysis results of FIGS. 12 to 17 are summarized in Table 7 below. 12 is a gas chromatograph of the experimental composite samples embolic materials Photography (GC) is an analysis result graph including a test specimen 10 of the hydrogel particles and lipiodol ^®.

13 is a gas chromatogram of the experimental sample composite embolic materials Photography (GC) is an analysis result graph containing hydrogel particles, and lipiodol ^® of experimental samples 11.

14 is a test sample of 12 experimental composite embolic material sample containing the hydrogel particles and lipiodol ^® gas chromatography (GC) analysis graph.

Figure 15 is a comparison of three samples of the comparative compound embolic material sample containing the hydrogel particles and lipiodol ^® gas chromatography (GC) analysis graph.

Figure 16 is a comparative sample 4 of the hydrogel particles and the gas chromatographic comparison of the composite material sample embolism Photography (GC) containing lipiodol ^® analysis result graph.

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

sample Area 23.4 (min) 27.0 (min) 33.0 (min) 33.4 (min) Standard (STD) 57475654 13826631 51466977 88767611 Experimental Sample 10 321461373 86026365 513523050 597348080 Experimental Sample 11 328639405 85737125 535488767 605572583 Experimental 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 confirmed that ethyl stearate was detected near 27.0 minutes, and it can be confirmed that 98% of the concordance is observed. 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.

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

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

18 is an FT-IR spectrum of the hydrogel particles of the comparative sample 10. Fig.

19 is an FT-IR spectrum of the hydrogel particles of the comparative sample 11.

20 is an FT-IR spectrum of the hydrogel particles of the comparative sample 12. Fig.

21 is FT-IR spectra of the hydrated gel particles of the comparative sample 3. Fig.

22 is FT-IR spectra of the hydrated gel particles of Comparative Sample 4.

18 to 22, the hydrogel particles of Experimental Samples 10 to 12 exhibit CH stretching vibration peaks in the wave number range of about 2850 cm- ¹ to about 3000 cm ^- ¹ , while 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.

About 2850 cm ^-1 to about 3000 cm ^- CH stretching vibrations in the wave number range from ¹ (stretching vibration) peak is C ₁₈ ~ C ₂₆ as the CH stretching vibration peak of a methylene (CH ₂₎ an aliphatic hydrocarbon, 18 to 22 It was confirmed that C ₁₈ -C ₂₆ aliphatic hydrocarbons were chemically bonded to gelatin. The stretching vibration of CH is about 2920 cm ^-1 at CH The asymmetrical stretch vibration peak and the CH symmetrical stretch vibration peak at about 2,853 cm ^-1 are analyzed. The wave number in the FT-IR spectrum may have an error range in the range of ± 8 cm ^-1 .

It was confirmed that the FT-IR spectra of the hydrogel particles of comparative samples 3 and 4, which did not contain octadecylamine and were mainly composed of gelatin, were almost the same.

The production examples and the experimental examples of the above-mentioned experimental samples are provided for the purpose of understanding the invention and the technical idea of the invention is not limited to the production examples and the experimental examples of the above-mentioned experimental samples. Substitutions, additions, deletions, and the like of other elements within the scope of not hurting the technical idea of the invention will still be included in the present invention and constitute the contents of the invention.

Claims

At least one biodegradable polymer selected from the group consisting of gelatin and chitosan; And
At least one C ₁₈ aliphatic hydrocarbon derivative of an alkylamine and alkyl amide combined with the biodegradable polymer,
A hydrogel particle having an FT-IR spectrum in which a CH stretching vibration peak of methylene (CH ₂ ) in a C ₁₈ aliphatic hydrocarbon appears in a wave number range of 2850 cm ^-1 to 3000 cm ^-1 .

The method according to claim 1,
Wherein said C ₁₈ aliphatic hydrocarbon derivative is a derivative of C ₁₈ n-alkyl.

The method according to claim 1,
Wherein said alkylamine is a C ₁₈ n-alkylamine.

The method of claim 3,
Wherein the C ₁₈ n-alkylamine is octadecylamine.

The method according to claim 1,
Wherein the alkyl amide is a C ₁₈ n-alkyl amide.

6. The method of claim 5,
Wherein the C ₁₈ n-alkyl amide is octadecane amide.

The method according to claim 1,
When 5120 parts by weight of iodinated C ₁₈ fatty acid ester is added to 100 parts by weight of the hydrogel particles,
The hydrogel particles, the average amount of water absorption of the iodide C ₁₈ fatty acid ester to be absorbed into the hydrogel particle is more than 50% by weight, based on the amount of the iodide C ₁₈ fatty acid esters.

The method according to claim 1,
When 5120 parts by weight of iodinated C ₁₈ fatty acid ester is added to 100 parts by weight of the hydrogel particles,
The hydrogel particles, the average amount of water absorption of the iodide C ₁₈ fatty acid ester to be absorbed into the hydrogel particles exceeds 70% by weight, based on the amount of the iodide C ₁₈ fatty acid esters.

The method according to claim 1,
When 5120 parts by weight of iodinated C ₁₈ fatty acid ester is added to 100 parts by weight of the hydrogel particles,
Wherein the average value of the average absorption amount of the iodinated C ₁₈ fatty acid ester absorbed by the hydrogel particles is more than 85% by weight and less than 88% by weight based on the added amount of the iodinated C ₁₈ fatty acid ester.

At least one biodegradable polymer selected from the group consisting of gelatin and chitosan; And
At least one _C18 aliphatic hydrocarbon derivative of an alkylamine and an alkylamide bonded to the biodegradable polymer,
When 5120 parts by weight of iodinated C ₁₈ fatty acid ester is added to 100 parts by weight of the hydrogel particles,
The hydrogel particles, the average amount of water absorption of the iodide C ₁₈ fatty acid ester to be absorbed into the hydrogel particle is more than 50% by weight, based on the amount of the iodide C ₁₈ fatty acid esters.

11. The method of claim 10,
The hydrogel particles, the average amount of water absorption of the iodide C ₁₈ fatty acid ester to be absorbed into the hydrogel particles exceeds 70% by weight, based on the amount of the iodide C ₁₈ fatty acid esters.

11. The method of claim 10,
Wherein the average value of the average absorption amount of the iodinated C ₁₈ fatty acid ester absorbed by the hydrogel particles is more than 85% by weight and less than 88% by weight based on the added amount of the iodinated C ₁₈ fatty acid ester.

A composition comprising at least one biodegradable polymer of gelatin and chitosan and at least one C ₁₈ aliphatic hydrocarbon derivative of an alkylamine and alkyl amide combined with the biodegradable polymer and is characterized by stretching CH of methylene (CH ₂ ) in a C ₁₈ aliphatic hydrocarbon hydrographic peaks having an FT-IR spectrum in the range of wave numbers of 2850 cm ^-1 to 3000 cm ^-1 ; And
Iodinated C ₁₈ fatty acid esters;
&Lt; / RTI >

14. The method of claim 13,
Wherein the iodinated _C18 fatty acid ester is ethyl monoiodostearate.

14. The method of claim 13,
To 100 parts by weight of the hydrogel particles, 5120 parts by weight of iodinated C ₁₈ fatty acid ester was added to absorb the iodinated C ₁₈ fatty acid ester to the hydrogel particles. Then, phosphate buffered saline (PBS) was added thereto and centrifuged to remove the supernatant If you do,
The C ₁₈ average iodide content of the residual iodide C ₁₈ A composite embolic material exceeding 25% by weight based on the amount of fatty acid ester of a fatty acid ester remaining in the hydrogel particles.

14. The method of claim 13,
To 100 parts by weight of the hydrogel particles, 5120 parts by weight of iodinated C ₁₈ fatty acid ester was added to absorb the iodinated C ₁₈ fatty acid ester to the hydrogel particles, followed by addition of phosphate buffered saline (PBS), centrifugation, If you do,
The C ₁₈ average iodide content of the residual iodide C ₁₈ A composite embolic material exceeding 35% by weight, based on the amount of fatty acid ester of a fatty acid ester remaining in the hydrogel particles.

14. The method of claim 13,
To 100 parts by weight of the hydrogel particles, 5120 parts by weight of iodinated C ₁₈ fatty acid ester was added to absorb the iodinated C ₁₈ fatty acid ester to the hydrogel particles. Then, phosphate buffered saline (PBS) was added thereto and centrifuged to remove the supernatant If you do,
Wherein the average residual amount of the iodinated C ₁₈ fatty acid ester remaining on the hydrogel particles is more than 72% by weight and less than 77% by weight based on the amount of the iodinated C ₁₈ fatty acid ester added.

Hydrogel particles comprising at least one biodegradable polymer of gelatin and chitosan and at least one C ₁₈ aliphatic hydrocarbon derivative of alkylamines and alkyl amides bonded to the biodegradable polymer; And
Iodinated C ₁₈ fatty acid ester,
The addition of iodide C ₁₈ fatty acid ester 5120 parts by weight to 100 parts by weight of the hydrogel particles, greater than 50% by weight of the average amount of water absorption of the iodide C ₁₈ fatty acid ester to be absorbed into the hydrogel particles, based on the amount of the iodide C ₁₈ fatty acid ester ego,
To 100 parts by weight of the hydrogel particles, 5120 parts by weight of iodinated C ₁₈ fatty acid ester was added to absorb the iodinated C ₁₈ fatty acid ester to the hydrogel particles. Then, phosphate buffered saline (PBS) was added thereto and centrifuged to remove the supernatant the C ₁₈ average iodide content of the residual composite embolic material exceeding 25% by weight, based on the amount of the iodide C ₁₈ fatty acid ester of a fatty acid ester remaining in the hydrogel particles if.

19. The method of claim 18,
The C ₁₈ average iodide content of the residual iodide C ₁₈ A composite embolic material exceeding 35% by weight, based on the amount of fatty acid ester of a fatty acid ester remaining in the hydrogel particles.

19. The method of claim 18,
Wherein the average residual amount of the iodinated C ₁₈ fatty acid ester remaining on the hydrogel particles is more than 72% by weight and less than 77% by weight based on the amount of the iodinated C ₁₈ fatty acid ester added.