KR20080060463A - A preparing method for x-ray opaque embolic material and the x-ray opaque embolic material by using the method - Google Patents

Abstract

A preparation method of X-ray opaque embolic material is provided to prevent problems caused by in vivo resorption of liquid contrast medium, measure the quantitative blood flow and analyze the occlusion degree of blood vessel. A X-ray opaque embolic material is prepared by dipping a polymer particle in iodine or potassium iodide solution to form an iodine complex having X-ray opaque properties, wherein the polymer is a spherical PVAc(polyvinyl acetate) microparticle of which surface is modified by PVA(polyvinyl alcohol) and has the particle size of 100 nm-3000 mum, wherein the iodine complex is formed on both of a core and a surface of the polymer microparticles.

Description

A method of preparing an X-ray opaque embolic material and the X-ray opaque embolic material by using the method

1 is an optical micrograph of PVA / PVAc microspheres prepared by heterogeneous surface soaping reaction.

Figure 2 is an optical micrograph of the PVA microspheres prepared by the heterogeneous surface saponification reaction.

Figure 3 is an optical micrograph of the iodinated PVA / PVAc microspheres according to the present invention.

4 is a scanning electron micrograph of iodinated PVA / PVAc microspheres according to the present invention.

5 is an optical micrograph of the iodinated PVA microspheres according to the present invention.

Figure 6 is an optical micrograph of the PVA / PVAc microspheres removed by reducing the iodine complex on the surface according to the present invention.

Figure 7 is a photograph showing the image after X-ray contrast of the X-ray impermeable PVA / PVAc microspheres according to the present invention.

The present invention is a monodisperse polyvinyl acetate (hereinafter referred to as 'PVAc') which is a precursor of poly vinyl alcohol (hereinafter referred to as 'PVA') used as an embolic material. The present invention relates to a method for preparing microspheres and forming X-ray impermeability by forming an iodine complex on the surface and inside of the microspheres. More specifically, the present invention immersed and partially reduced PVA microspheres prepared by PVAc or surface hydrolysis method in aqueous solution of iodine (I2) and potassium iodide (KI) to suppress the release of iodine in water or in vivo X- A method for producing a line impermeable embolic material.

Embolization is the injection of certain substances into the bloodstream of a lesion where its location is incurable to surgery, thereby blocking blood flow, treating vascular diseases, and alleviating symptoms caused by hyperblood flow. This is a treatment technique to prevent bleeding during surgery. For example, embolization is widely used for the treatment of vascular lesions such as hypervascular tumors with high vascular distribution, arteriovenous malformation (AVM), uterine fibroid, or inflammatory bleeding such as traumatic or tuberculosis. Certain substances that are injected to block blood flow during embolization are called embolic materials.

Such embolic materials include metallic coils, liquid tissue adhesives, barium impregnated silastic balls, methacrylates, stainless steels, and muscles. ) And many other materials, including particulate material, have been developed. Since the 1970s, PVA has been widely used.

The ideal embolic material should be a highly biocompatible material, effectively reach the lesion vessel site for high therapeutic and predictable outcomes, be easy to handle and inject for universal clinical use, and have a permanent embolic effect and uniform size. It must have a distribution and form a uniform suspension in the nonionic molding agent. PVA particles are mainly used in clinical practice as materials satisfying the above requirements.

In the case of most particulate embolic materials, there is a problem that the appearance of the particles is irregular and the size distribution is uneven. To solve this problem, a method for producing spherical particles using various materials has been proposed. A method for producing microspheres such as alginate, gelatin and chitosan using natural materials has been proposed, but these materials cause problems of recanalization of blood due to in vivo resorption. Patents have been reported for the production of uniformly sized microspherical PVA embolic materials to solve the problem of blood communication. [Korean Patent No. 10-0205633-0000, 10-0335866-0000 Application No. 1998-0037498, US Patent No. 6,191,193 B1]

In general, unlike color-only coils composed of metals [US Patent No. 07 / 771,013, 806,979, 949,094], intravascular inserts made of polymers do not have self-contrast capability, and thus, silver nanomaterials [Korean Patent Application No. 2005-0032097, Registration] No. 20-0387797, tungsten filling [US Pat. No. 9 / 224,443], metal plating at the end of microcatheter [Italian Patent, 21123], material detectable by ultrasound [UK Patent, 9616301, US Patent, 08- 3956801], as a barium contrast agent for Citigraphy [Korean Patent, Publication No. 2000-0065649], large intestine, small intestine X-ray contrast agent [Japanese Patent, 92-302811], contrast enhancement [Korean Patent, Korean Patent No. 1993-0002789], It is used in combination with a composition such as a dental composition [Korean Patent Publication No. 2000-0067112] and an iodine compound-containing contrast agent [Germany Patents P3739098.8, P3739098.9, P3731542.0, US Patent, 443,869].

In particular, PVA particulate embolic materials, which are widely used, are suspended and used in contrast media consisting of iodine compounds. Suspension instability due to the difference in specific gravity between embolic materials and contrast media, biosafety of iodine compounds, and embolic substances swell in contrast media. There is a problem of melting. In particular, swelling / dissolution behavior in the contrast medium of the PVA increases the adhesion of the surface of the particles and causes frequent association between the particles and finally, blockage of the conduit during arterial injection through the micro-catheter. In order to solve this problem, a crosslinking agent such as formaldehyde or glutaraldehyde is used to cure the surface of the PVA particles to control the swelling / dissolution behavior to relieve the blockage of the microtubules. There is a problem that causes it.

An object of the present invention is to provide a method for producing an X-ray impermeable embolic material characterized by imparting X-ray impermeability by forming an iodine complex in monodisperse PVAc or PVA microspheres.

Another object of the present invention is to provide an X-ray impermeable embolic material prepared by a method of forming an iodine complex in monodisperse PVAc or PVA microspheres.

Method for producing an X-ray impermeable embolic material according to the present invention for achieving the above object is to impart X-ray impermeability by immersing the polymer particles in aqueous solution of iodine or potassium iodide or aqueous solution of iodine and potassium iodide to form an iodine complex It is characterized by.

In addition, the X-ray impermeable embolic material according to the present invention for achieving the object is characterized in that it is prepared by a method of forming an iodine complex by immersing the polymer particles in aqueous solution of iodine or potassium iodide or aqueous solution of iodine and potassium iodide .

Hereinafter, specific embodiments of the present invention will be described in detail with reference to the accompanying drawings.

Depending on the type of vascular disease, particulate embolic material should be adjusted in diameter from tens of micrometers to hundreds of micrometers and have a very narrow distribution of sizes for selective occlusion of blood vessels. In addition, the surface should be composed of a material that is biocompatible to minimize the inflammatory response of the vessel wall. To give radiopacity to these materials, substances with different densities from the surroundings are mixed (ultrasound diagnosis), electron densities for X-ray impermeability, or radioisotopes are used for diagnosis using PET. There is a way.

The present invention, unlike the existing method to form an iodine complex in the polymer particles to impart X-ray impermeability, the polymer particles used are hundreds of nanometers can be produced by emulsion polymerization, dispersion polymerization and suspension polymerization or dispersion method in the polymerization method can be a particle having thousands of micrometers in diameter and I ₃ is immersed in the iodine / potassium iodide solution at ^- should be capable of forming a particle, such as a composite ^{_{-, I 5 -, I 7}} .

Examples include PVA, PVAc, polyethylene vinyl alcohol copolymer, polylactic acid, polylactide glycolide copolymer, polyethylene oxide, cellulose acetate, polymethacrylate, polyethylene-vinylacetate copolymer, polyvinylpyrrolidone, polycapro Lactones, polyhydroxyethylmethacrylates and copolymers, collagen, gelatin, keratin, alginate and alginic acid, chitin and chitosan and the like.

Hereinafter, the present invention will be described in more detail through examples using polyvinyl acetate (PVAc) or polyvinyl alcohol (PVA) particles. However, this is to help the understanding of the present invention is not limited only to the following examples.

Example 1

In a 250 ml two-necked flask equipped with a thermometer and a cooling tower, 100 ml of an aqueous alkali solution containing 8.75 g of sodium hydroxide, 8.75 sodium sulfate, and 8 g of methanol was added, and polyvinyl acetate particles separated using sodium sulfate (particle diameter: 100 ~ 125 ㎛, polydispersity index: 1.03, number average degree of polymerization: 8,300) 0.5g was suspended and saponified for 4 hours with stirring using a magnetic stirrer at 40 ℃. After completion of the reaction, the reaction solution was poured into supercooled distilled water, stirred for 1 hour, filtered through a glass filter, and the filtrate was washed three times with excess distilled water and filtered. Spherical polyvinyl acetate particles in which the surface of Fig. 38%, the particle diameter of 100 to 125 µm and the polydispersity index 1.03 were converted to polyvinyl alcohol were obtained.

Example 1 shows a method for producing a polymer particle used in the method for producing an X-ray impermeable embolic material according to the present invention, wherein the surface of the polyvinyl acetate particles is partially hydrolyzed and the surface is converted into polyvinyl alcohol. The method of obtaining vinyl acetate particles is shown, and FIG. 1 is an optical micrograph of the PVA / PVAc microspheres prepared in Example 1. FIG.

Example 2

In a 250 ml two-necked flask equipped with a thermometer and a cooling tower, 100 ml of an aqueous alkaline solution containing 8.75 g of sodium hydroxide, 8.75 sodium sulfate, and 8 g of methanol was added and polyvinyl acetate particles separated using sodium sulfate (particle diameter: 100 ~ 125 ㎛, polydispersity index: 1.03, number average degree of polymerization: 8,300) 0.5g was suspended and saponified for 48 hours with stirring using a magnetic stirrer at 40 ℃. After the reaction was completed, the reaction solution was poured into supercooled distilled water, stirred for 1 hour, filtered through a glass filter, the filtrate was washed with excess distilled water, filtered three times, and dried under vacuum at 40 ° C. for 1 day. PVA particles having a saponification degree of 99% or more, a particle diameter of 100 to 125 µm and a polydispersity index of 1.03 were obtained.

Example 2 shows a method for producing a polymer particle used in the method for producing an X-ray impermeable embolic material according to the present invention to obtain spherical polyvinyl alcohol particles converted to polyvinyl alcohol by hydrolyzing polyvinyl acetate particles. 2 is an optical micrograph of the PVA microspheres prepared in Example 2.

Example 3

0.5 g of hydrolyzed particles (38% soap degree) are immersed in 50 ml of an aqueous solution of iodine concentration 2x10 ^-3 mol / L and potassium iodide concentration 4x10 ^-3 mol / L and stirred for 48 hours using a magnetic stirrer at room temperature. The iodinated particles are filtered and stirred for 1 hour with distilled water at room temperature to remove the iodine adsorbed on the surface. Thereafter, the mixture is refiltered and the filtrate is left to dry at room temperature for 24 hours.

Example 3 shows a method for preparing an X-ray impermeable embolic material by iodinating the spherical polyvinyl acetate particles prepared in Example 1, and FIGS. 3 and 4 show the iodinated PVA / PVAc prepared in Example 3. Optical micrograph of microspheres.

Example 4

0.5 g of hydrolyzed particles (more than 99% soap) are immersed in 50 ml of iodine concentration 2x10 ^-3 mol / L and potassium iodide concentration 4x10 ^-3 mol / L aqueous solution, and stirred for 48 hours using a magnetic stirrer at room temperature. . The iodinated particles are filtered and stirred for 1 hour with distilled water at room temperature to remove the iodine adsorbed on the surface. Thereafter, the mixture is refiltered and the filtrate is left to dry at room temperature for 24 hours.

Example 4 shows a method for producing an X-ray impermeable embolic material by iodinating the spherical polyvinyl alcohol particles prepared in Example 2 and Figure 5 is an optical micrograph of the iodinated PVA microspheres prepared in Example 4 to be.

Example 5

0.5 g of particles having an iodide saponification degree of 38% are immersed in 100 ml aqueous sodium sulfite (10 wt%) solution at room temperature for 48 hours and stirred. After the iodine complex of the PVA layer was completely reduced and removed, washing and filtration were repeated three times with distilled water, and the obtained filtrate was dried at room temperature for 24 hours.

It was confirmed that particles imparted with radiopacity were made from FIG. 6, which is an optical micrograph of the particles prepared in Example 5, and FIG. 7, which shows an image obtained after X-ray imaging.

The technical spirit of the present invention has been described above with reference to the accompanying drawings. However, the present invention has been described by way of example only, and is not intended to limit the present invention. In addition, it is apparent that any person having ordinary knowledge in the technical field to which the present invention belongs may make various modifications and imitations without departing from the scope of the technical idea of the present invention.

According to the manufacturing method of the X-ray impermeable embolic material according to the present invention, by forming a iodine complex in a polymer material with a simple method and preparing the particles, the blood vessels when used as a material for embolization, which is a non-invasive method of arteriovenous malformation, cancer, myoma The degree of occlusion, hyperselective embolism, and it can be verified that it is always occluded without using a liquid contrast agent.They contain functional drugs such as anti-cancer agent, growth factor / semi-growth factor, hormone, protein, etc. There is an advantage that it is possible to simply evaluate whether the phosphor particles have reached properly.

In addition, the use of liquid contrast agents avoids the problem of diffusion and recirculation into the tissues, and eliminates the need for rapid diagnosis immediately after ingestion or thinning of the contrast medium, and visually monitors the spraying of the tissue on the particles. It is possible to measure the exact quantitative blood flow.

Claims (7)

A method for producing an X-ray impermeable embolic material, wherein the polymer particles are impregnated in an aqueous solution of iodine or potassium iodide to form an iodine complex. The method of claim 1, wherein the polymer PVA, PVAc, polyethylene vinyl alcohol copolymer, polylactic acid, polylactide glycolide copolymer, polyethylene oxide, cellulose acetate, polymethacrylate, polyethylene-vinylacetate copolymer, polyvinylpyrrolidone, polycaprolactone, poly Hydroxyethyl methacrylate and copolymer, collagen, gelatin, keratin, alginate and alginic acid, chitin and chitosan. The method of claim 1, wherein the polymer Method for producing an X-ray impermeable embolic material, characterized in that the surface is spherical PVAc particles converted to PVA. The method of claim 1, wherein the polymer Method for producing an X-ray impermeable embolic material, characterized in that the particle size of 100 nm ~ 3000 um. The method of claim 1, wherein the iodine complex is Method for producing an X-ray impermeable embolic material, characterized in that formed only on the core of the polymer particles. The method of claim 1, wherein the iodine complex is Method for producing an X-ray impermeable embolic material, characterized in that formed on both the surface and the core of the polymer particles. X-ray impermeable embolic material prepared by the method according to any one of claims 1 to 6.

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