KR20100124160A - Radiopacity poly(vinylpivalate/vinylacetate)/poly(vinylalcohol) microspheres embolic materials and manufacturing method thereof - Google Patents

Abstract

PURPOSE: A radiopacity poly(pivalic acid vinyl/acetic acid vinyl)/poly(vinyl alcohol) microsphere embolic material is provided to improve simplicity. CONSTITUTION: A poly(vinyl pivalate/acetic acid vinyl)/poly(vinyl alcohol) microsphere embolic material comprises: a 54-63% of syndiotactic dyad by copolymerizing mixture of pivalate monomer and acetic acid vinyl monomer; a core having poly(vinyl pivalate/acetic acid vinyl); and polyvinyl alcohol outer cover prepared by saponification of a part of core. A method for manufacturing the poly(vinyl pivalate/acetic acid vinyl)/poly(vinyl alcohol) microsphere embolic material comprises: a step of copolymerizing a mixture of vinyl pivalate monomer and acetic acid vinyl monomer to form the core; a step of adding 0.1-100 weight part of inorganic salt and milling; and a step of performing saponification.

Description

Microspherical embolic material of poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol with radiopaque impermeability and its manufacturing method {Radiopacity Poly (vinylpivalate / vinylacetate) / Poly (vinylalcohol) microspheres embolic materials and manufacturing method

The present invention relates to a microspherical embolic material of poly (vinylpivalate / vinylacetate) / polyvinyl alcohol (poly (vinylpivalate / vinylacetate)) having a radiopaque impermeability, and to a method of manufacturing the same, more specifically embolic Improved manufacturing to solve the difficulty in locating embolic material during computed tomography after granting silver iodide, a radiopaque material of polyvinyl alcohol used as a material, and performing imaging and embolization It is about a method.

Embolization injects a specific substance into the bloodstream of a lesion that is in a location that cannot be treated by surgical procedures, thereby treating the lesion by blocking blood flow, alleviating the symptoms caused by hyperblood flow, and preventing bleeding during surgery. As a treatment technique, a material used for such embolization is called an embolic material, and polyvinyl alcohol and the like are now commercially available. Embolization is used to treat vascular lesions such as hypervascular tumors with high vascular distribution, arteriovenous malformation (AVM), and inflammatory hemorrhages such as traumatic or tuberculosis.

The concept of cure by embolization is based on the fact that in 1952, when Markowitz received liver blood from the portal vein and arteries, the blood was doubled from the portal vein and arteries. It was first established by suggesting a method of treating liver tumors that blocked the blood supply to cancer cells via (see J.Markowitz, Surg. Gynecol Obstet. 95. 644 (1952)). It is necessary to know whether blood is supplied by the hepatic artery or the portal vein for selective embolism. In 1963, Hurley and Shena injected dyes and radioactive materials into the blood supply to liver cancer cells. It was confirmed entirely through the hepatic artery (see JE Healey and KS Sheena et al., S Surg. Forum, 14, 121 (1963)). Gerin et al. Also showed a 90% decrease in blood flow in malignant fields after hepatic artery removal, whereas 35-40% reduction in normal tissues (LE Gelin, DH Lewis and Nielsen (L.). Nilsson), Acta Hepatosplenol, 15, 21 (1968).

Embolization is also used to treat arteriovenous malformations in addition to liver cancer. Embolization of cerebral arteriovenous abnormalities has been reported to increase patient survival (LA Nisson and L. Zettergen, Acta Pathol.Microbiol). Scan., 71, 187 (1967)). In addition, recent studies have shown that uterine artery embolization is effective in the treatment of menstrual hyperplasia and pelvic pain in addition to the above lesions (SC Gookwin, S. Vedantham, B. Mclucas). , See AE Forno and R. Perrella, J. Vascular and Interventional Radiology, 8 (4), 517 (1997)). Occlusion has been reported to be used to prevent excessive bleeding, shorten the time of surgery, and reduce the risk of surgery (T. Tikkakoski, J. luotonen, Reynonene ( S. Leinonen, T. Siniluoto, O. Heikkila, M. Paivansalo and K. Hyrynkangas, LARYNGOSCOPE 107 (6), 821 (1997) Reference).

These embolizations include metal fiber coil type embolization materials using platinum and tungsten, liquid tissue adhesive embolization materials that cure and occlude blood vessels after being put into the body in a liquid state, and barium-impregnated plastic balls ( Particle embolic materials such as varium impregnated silasic balls, methacrylate, collagen-coated a crylic microsphere, and PVA are used. Particularly, PVA is a particulate and hydrogel. As a embolic material, it has been commercialized since the 1970s and used exclusively worldwide.

The ideal embolic material should be composed of a material with excellent biocompatibility due to the tissue response of the treatment area, and the physical size and size of the particles so as to effectively reach the target site of the lesion to give an excellent therapeutic effect and predict its predictability. The distribution should be standardized, ③ The surface should be smooth so as not to cause secondary lesions such as inflammation in occluded blood vessels, ④ It should be easy to handle and inject for universal clinical use, and ⑤ Without reopening of blood flow It should have a permanent embolic effect. ⑥ It must have X-ray radiopacity or form a uniform suspension in nonionic contrast agent to accurately evaluate vascular occlusion.

Currently, in order to develop an ideal embolic material, studies have been conducted to prepare particulate embolic materials for various polymer materials except polyvinyl alcohol, such as porous cellulose, gelatin, collagen, and collagen-coated acrylic. Natural polymer materials such as these are obtained directly from nature without undergoing synthesis, so their physical and chemical strength cannot be controlled, and the effective occlusion effect in blood vessels of various sizes and shapes is not well known.

Polyvinyl alcohol (PVA), one of the most widely used embolic materials, was developed by Herrmann and Haehnel (WO Herrmann and W. Hachnel, German Patent, 450, 286 (1924) in 1924. Was first discovered during the saponification of poly (vinylacetate) (PVAc).

PVA used as a raw material of the PVA fibers, there are two kinds of hybrid array (atactic) PVA, such as the formula (1) and syndiotactic PVA, such as the formula (2).

However, the preparation of full-shift PVA, such as Formula 2, has not yet been made, and as disclosed in Japanese Patent Application Laid-open No. Hei 4-108,109, a monomer having a side chain group causing steric hindrance is polymerized and saponified again. Even the manufactured alternating PVA does not exceed 65% of the content of alternating diad groups.

In addition to polyvinyl acetate, PVA is a polymer produced by saponifying various types of polyvinylesters and polyvinylethers polymers, and has a molecular weight, stereoregularity and saponification. According to the drawing, it is a very useful polymer widely used in the manufacture of hosiery, clothing fibers, industrial fibers, food packaging films, liquid and gas separation membranes, polarizing films and medical polymer materials.

In addition, polyvinyl alcohol is used exclusively as an embolic material compared to other materials due to its biocompatibility, ease of procedure, control of molecular weight and stereoregularity by polymerization, and control of particle size.

In addition, polyvinyl alcohol particle embolism is mainly used for embolization of diseases such as malignant liver tumor, hepatic arteriovenous malformation, cerebral arteriovenous malformation and vascular tumors of various sites, and is the most widely used embolic material among the existing embolic materials. There is a lot of research going on.

In addition, polyvinyl alcohol, which is widely used as an embolic material, is currently sold in a variety of shapes and methods in the form of granular embolic materials, but these products do not have radiopaque impermeability, and thus, the embolism in the blood vessels after embolization is visually observed by X-ray fluoroscopy. Because of difficulty in observation, embolic materials containing radiopaque materials are required, and many studies have been conducted.

Existing studies on embolic materials reveal that polyvinyl alcohol is the most effective of the various embolic materials.However, polyvinyl alcohol's synthesis conditions (polymerization conditions of precursors) or molecular variables (molecular weight, saponification degree, branching degree, stericity) The manufacture of microspherical particles with uniform size and radiopaque imperfections by adjusting the regularity is hardly known.

In addition, the embolic material prepared from PVA by hydrolyzing polyvinyl acetate (PVAc) is loaded into a syringe and injected into the body through a microconduit, which makes it difficult to block or uniformly inject the conduit, that is, during embolization. In addition, clinical results have been reported in the case of dangerous embolism, such as the particle's strength is weak, the particle is crushed, the particle is pushed down by the blood flow to block the blood vessels of unwanted parts.

The technical problem to be achieved by the present invention is to increase the ease of embolization by producing a microsphere with high alternating arrangement.

In addition, the technical problem to be achieved by the present invention is to provide radiopaque impermeability to polyvinyl alcohol so that the embolic state in the blood vessel can be easily observed by X-ray irradiation.

In order to achieve the above object, a poly (vinyl pivalate / acetic acid) having a copolymerized mixture of a vinyl pivalate monomer and a vinyl acetate monomer having an alternating diad group content of 54 to 63% and a number average degree of polymerization of 2000 to 6000 Vinyl); And a polyvinyl alcohol shell formed by saponifying a part of the core (saponification ratio = 1: 9 to 9: 1 or 95% or less).

In addition, a core comprising a poly (vinyl pivalate / vinyl acetate) copolymerized with a mixture of a vinyl pivalate monomer and a vinyl acetate monomer having an alternating diad group content of 54 to 63% and a number average degree of polymerization of 2000 to 6000; And a polyvinyl alcohol shell formed by saponifying a part of the core (saponification ratio = 1: 1 to 9: 1 or 95% or less), wherein the polyvinyl alcohol shell is formed, and includes milling. Through the particle size is made within the range of 100 to 1000㎛, wherein the polyvinyl alcohol shell is characterized by forming an iodine complex by reaction with iodine and potassium iodide.

(1) A copolymer of a vinyl pivalate monomer and a vinyl acetate monomer is copolymerized to form a poly (vinyl pivalate / vinyl acetate) having an alternating diad group content of 54 to 63% and a number average degree of polymerization of 2000 to 6000. A core manufacturing step of manufacturing a core;

(2) 0.1 to 100 parts by weight of an inorganic salt as a dispersant and an antistatic agent based on 1 part by weight of the poly (vinyl pivalate / vinyl acetate) particles obtained in the core manufacturing step was added and milled to obtain a particle size of 100 to 1000 μm. Milling step of making the particles within the range; And

(3) a shell manufacturing step of forming a polyvinyl alcohol shell formed by saponifying a part of the core of the particles obtained in the milling step (saponification ratio = 1: 9 to 9: 1 or 95% or less); Characterized in that comprises a.

According to the present invention, the microspheres having high alternating arrangement are manufactured to increase the ease of embolization.

In addition, by imparting radiopacity to the polyvinyl alcohol, there is an effect that the embolic state in the blood vessel can be easily observed by X-ray irradiation.

The microspherical embolic material of poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol for producing a microspherical embolic agent having radiopaque impermeability according to the present invention is arranged by copolymerizing a mixture of a vinyl pivalate monomer and a vinyl acetate monomer. A core made of poly (vinyl pivalate / vinyl acetate) having a diad group content of 54 to 63% and a number average degree of polymerization of 2000 to 6000; And a polyvinyl alcohol shell formed by saponifying a part of the core (saponification ratio = 1: 9 to 9: 1 or 95% or less), and including a particle size within a range of 100 to 1000 μm through milling. It features.

The microspherical embolic agent having radiopaque impermeability according to the present invention is a poly copolymer having a mixture of vinyl pivalate monomer and vinyl acetate monomer having an alternating diad group content of 54 to 63% and a number average degree of polymerization of 2000 to 6000. A core made of (vinyl pivalate / vinyl acetate); And a polyvinyl alcohol shell formed by saponifying a part of the core (saponification ratio = 1: 9 to 9: 1 or 95% or less), and including a particle size within a range of 100 to 1000 μm through milling. Herein, the polyvinyl alcohol shell is characterized in that the iodine complex is formed by reaction with iodine and potassium iodide.

The method for producing a microspherical embolic material of poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol for producing a microspherical embolic agent having radiopaque impermeability according to the present invention comprises the steps of (1) a vinyl pivalate monomer and a vinyl acetate monomer. A core manufacturing step of preparing a core made of poly (vinyl pivalate / vinyl acetate) having an alternating diad group content of 54 to 63% and a number average degree of polymerization of 2000 to 6000 by copolymerizing the mixture; (2) 0.1 to 100 parts by weight of an inorganic salt as a dispersant and an antistatic agent based on 1 part by weight of the poly (vinyl pivalate / vinyl acetate) particles obtained in the core manufacturing step was added and milled to obtain a particle size of 100 to 1000 μm. Milling step of making the particles within the range of; And (3) a shell manufacturing step of forming a polyvinyl alcohol shell formed by saponifying a part of the core of the particles obtained in the milling step (saponification ratio = 1: 9 to 9: 1 or 95% or less). Characterized in that made.

The copolymerization of the mixture of the vinyl pivalate monomer and the vinyl acetate monomer in the core manufacturing step is carried out in the presence of azobisdimethylvaleronitrile as a catalyst at a concentration between 1 × 10 −5 and 1 × 10 −1 mol / monomer mole. It may be carried out by suspension copolymerization within a temperature range of 20 to 60 ℃.

In the method for producing a radiosphere impermeable microspherical embolic agent according to the present invention, (1) copolymerization of a mixture of a vinyl pivalate monomer and a vinyl acetate monomer has an alternating diad group content of 54 to 63%, and a number average degree of polymerization A core manufacturing step of preparing a core made of poly (vinyl pivalate / vinyl acetate) having an amount of 2000 to 6000; (2) 0.1 to 100 parts by weight of an inorganic salt as a dispersant and an antistatic agent based on 1 part by weight of the poly (vinyl pivalate / vinyl acetate) particles obtained in the core manufacturing step was added and milled to obtain a particle size of 100 to 1000 μm. Milling step of making the particles within the range; (3) a shell manufacturing step of forming a polyvinyl alcohol shell formed by saponifying a part of the core of the particles obtained in the milling step (saponification ratio = 1: 9 to 9: 1 or 95% or less); And (4) a complex forming step of reacting the polyvinyl alcohol shell formed in the milling step with iodine and potassium iodide to form an iodine complex.

In the milling step, milling is performed by adding 0.1 to 100 parts by weight of an inorganic salt as a dispersant and an antistatic agent based on 1 part by weight of microspherical poly (pivalate / vinyl acetate) particles having various particle diameters prepared according to the suspension polymerization method. The method may be used, and the method may use the method disclosed in Korean Patent Registration No. 10-0335866, which is incorporated herein by reference. By performing the milling step, particles having a uniform particle diameter distribution having a polydispersity index of 1.00 to 1.60 can be obtained.

Therefore, monodisperse poly (vinyl pivalate / vinyl acetate) microspheres, which are precursors, are prepared in an aqueous alkali solution in order to produce radiopaque impermeable particle embolic materials having excellent embolic ability (US Patent No. 6,191,193 B1). According to the reaction time, the surface of the polyvinyl alcohol contains radiopaque material through the method of producing particles composed of poly (vinyl pivalate / vinyl acetate), and the vinyl pivalate monomer and The mixture of vinyl acetate monomers was copolymerized to have a high alternating arrangement of 54 to 63% of the alternating diad group content. The present invention was completed by discovering a new saponification method capable of maintaining particle shape and preventing association. Was done. It is possible to increase the physical properties, particularly the strength of the particles, by high alternating arrangement.

The object of the present invention is to adjust the monomer feed ratio of vinyl pivalate and vinyl acetate by varying the concentration of azobisdimethylvaleronitrile from 1 × 10 −5 to 1 × 10 −1 mol / monomer mol. Suspension copolymerization at 20-60 ° C., the polymerization temperature, at optimum conditions between the various types of alternating poly (vinyl pivalate / vinyl acetate) copolymers with alternating diad group content of up to 54-63% and radioactive thereto A method of imparting impermeability is provided.

When the concentration of the initiator of the present invention is less than 1 × 10 −5 mol / monomer mol, polymerization does not occur at the polymerization temperature of the present invention, and when it exceeds 1 × 10 −1 mol / monomer mol, the polymerization reaction rate is The sudden rise in molecular weight occurs.

The embolic material particles of the poly (vinyl pivalate / vinyl acetate) core / polyvinyl alcohol envelope double structure of the present invention have a uniform particle diameter distribution of 1.0 to 1.60 of the polydispersity index separated according to the method of the present invention. Uneven surface saponification reaction so that the microspherical poly (vinyl pivalate / vinyl acetate) particles having is suspended in an aqueous alkali solution and saponification occurs only at the surface of the poly (vinyl pivalate / vinyl acetate) particles at a temperature of 0 to 90 ° C. It is prepared by making.

In the method for producing an embolic material particle having a poly (vinyl pivalate / vinyl acetate) core / polyvinyl alcohol shell double structure according to the present invention, an aqueous solution containing sodium hydroxide, sodium sulfate, and ethanol is used as the aqueous alkali solution, and is preferably separated. An aqueous solution dissolved in 0.1 to 100 parts by weight of sodium hydroxide, 0.1 to 100 parts by weight of sodium sulfate and 0.1 to 100 parts by weight of ethanol in 10 to 1000 parts by weight of water based on 1 part by weight of the poly (vinyl pivalate / vinyl acetate) particles Used.

In the method for producing an embolic material according to the present invention, the heterogeneous surface saponification reaction of poly (vinyl pivalate / vinyl acetate) particles is carried out at a reaction temperature of 0 ° C. to 90 ° C. in the aqueous alkali solution, and the surface is polyvinyl alcohol. An embolic material particle having a double structure of poly (vinyl pivalate / vinyl acetate) is provided.

An embolic material particle provided with radiopaque impermeability is provided to an embolic material particle according to the present invention by ion reaction between a composite of an aqueous solution of iodine and silver nitrate and a poly (vinyl pivalate / vinyl acetate) core / polyvinyl alcohol shell particle.

The method for preparing embolic particles of a radiopaque poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol double structure having a uniform size distribution and a size available for embolization according to the present invention has the following characteristics: Have.

First, in the case of non-uniform surface saponification, ethanol which is harmless to human body instead of methanol is added to alkaline aqueous solution to reduce inflammatory reaction during embolism. It reduces the blockage of the catheter due to the difference in particle size with the treatment time, and also reduces the morphological change of the particle surface over time.

Second, the polyvinyl alcohol particles imparting radiopaque properties facilitate the X-ray perspective of the embolic state in the hallway after embolization.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited only to the following examples.

Example 1

In a 250 ml four-necked flask equipped with a thermometer, nitrogen inlet, cooling tower, and anchor type stirrer, 120 ml of polyvinyl alcohol (1.18 × 10-5 mol, saponification degree: 88%, number average molecular weight with 120 ml of distilled water and suspension stabilizer) : Place 127,000 and dissolve while stirring at 70 ° C, cool to room temperature, pass through pyrogallol-alkali aqueous solution trap and dryer light trap to remove oxygen by passing through oxygen-free nitrogen for 2 hours and remove oxygen, vinyl pivalate 14.6 After adding 1 mL (0.1 mol) and 83.1 mL (0.9 mol) of vinyl acetate, oxygen was removed for 1 hour, 0.0248 g (1 × 10 -4 mol / monomer mol) of azobisisobutyronitrile was added thereto. After the polymerization temperature was raised to 30 ° C., the mixture was polymerized for 1 day at a stirring speed of 250 rpm under nitrogen stream, precipitated in the cooled distilled water, precipitated with a glass filter, and the filtrate was washed several times with distilled water. percolation Repeated by one days drying the residual monomer and the back to remove the suspension stabilizer, 40 ℃ under vacuum to give the particles.

The polydispersity of the particle diameter was defined as the weight average particle diameter divided by the number average particle diameter for 500 particles, and the weight average particle diameter and the number average particle diameter were measured using a particle size analyzer. It is known that when the polydispersity value of the particle diameter is in the range of 1.0 to 1.2, it may be defined as almost monodisperse.

[Example 2]

29.6 mL (0.2 mol) of vinyl pivalate and 73.9 mL (0.8 mol) of vinyl acetate were added to the same device as Example 1, followed by oxygen removal for 1 hour, followed by 0.0248 g (1 × 10 −) of azobisisobutyronitrile. 4 mol / monomer mole), the temperature was raised to 30 ° C., the polymerization temperature, and then polymerized for 1 day at a stirring speed of 250 rpm under a nitrogen stream, and then the precipitated polymer was precipitated in a cooled distilled water, followed by a glass filter. The filtrate was washed several times with distilled water and filtered repeatedly to remove residual monomer and suspension stabilizer, and then dried under vacuum at 40 ° C. for 1 day to obtain particles.

Example 3

44.4 ml (0.3 mol) of vinyl pivalate and 64.6 ml (0.7 mol) of vinyl acetate were placed in the same device as Example 1, followed by oxygen removal for 1 hour, followed by 0.0248 g (1 × 10 −) of azobisisobutyronitrile. 4 moles / monomer mole), the temperature was raised to 30 ° C., the polymerization temperature, and then polymerized for 1 day at a stirring speed of 250 rpm under a nitrogen stream, and the mixture was poured into cooled distilled water to precipitate a polymer, followed by a glass filter. The filtrate was washed several times with distilled water and filtered repeatedly to remove residual monomer and suspension stabilizer, and then dried under vacuum at 40 ° C. for 1 day to obtain particles.

Example 4

59.2 ml (0.4 mol) of vinyl pivalate and 55.4 ml (0.6 mol) of vinyl acetate were placed in the same device as in Example 1, followed by oxygen removal for 1 hour, followed by 0.0248 g (1 × 10 −) of azobisisobutyronitrile. 4 moles / monomer mole), the temperature was raised to 30 ° C., the polymerization temperature, and then polymerized for 1 day at a stirring speed of 250 rpm under a nitrogen stream, and the mixture was poured into cooled distilled water to precipitate a polymer, followed by a glass filter. The filtrate was washed several times with distilled water and filtered repeatedly to remove residual monomer and suspension stabilizer, and then dried under vacuum at 40 ° C. for 1 day to obtain particles.

Example 5

74.0 mL (0.5 mol) of vinyl pivalate and 46.2 mL (0.5 mol) of vinyl acetate were placed in the same device as in Example 1, followed by oxygen removal for 1 hour, followed by 0.0248 g (1 × 10 −) of azobisisobutyronitrile. 4 moles / monomer mole), the temperature was raised to 30 ° C., the polymerization temperature, and then polymerized for 1 day at a stirring speed of 250 rpm under a nitrogen stream, and the mixture was poured into cooled distilled water to precipitate a polymer, followed by a glass filter. The filtrate was washed several times with distilled water and filtered repeatedly to remove residual monomer and suspension stabilizer, and then dried under vacuum at 40 ° C. for 1 day to obtain particles.

Example 6

88.8 ml (0.6 mol) of vinyl pivalate and 36.9 ml (0.4 mol) of vinyl acetate were placed in the same device as Example 1, followed by oxygen removal for 1 hour, followed by 0.0248 g (1 × 10 −) of azobisisobutyronitrile. 4 moles / monomer mole), the temperature was raised to 30 ° C., the polymerization temperature, and then polymerized for 1 day at a stirring speed of 250 rpm under a nitrogen stream, and the mixture was poured into cooled distilled water to precipitate a polymer, followed by a glass filter. The filtrate was washed several times with distilled water and filtered repeatedly to remove residual monomer and suspension stabilizer, and then dried under vacuum at 40 ° C. for 1 day to obtain particles.

Example 7

103.6 mL (0.7 mol) of vinyl pivalate and 27.7 mL (0.3 mol) of vinyl acetate were placed in the same device as Example 1, followed by oxygen removal for 1 hour, followed by 0.0248 g of azobisisobutyronitrile (1 × 10 −). 4 mol / monomer mole), the temperature was raised to 30 ° C., the polymerization temperature, and then polymerized for 1 day at a stirring speed of 250 rpm under a nitrogen stream, and then the precipitated polymer was precipitated in a cooled distilled water, followed by a glass filter. The filtrate was washed several times with distilled water and filtered repeatedly to remove residual monomer and suspension stabilizer, and then dried under vacuum at 40 ° C. for 1 day to obtain particles.

Example 8

118.4 ml (0.8 mol) of vinyl pivalate and 18.5 ml (0.2 mol) of vinyl acetate were placed in the same device as in Example 1, followed by oxygen removal for 1 hour, followed by 0.0248 g (1 × 10 −1) of azobisisobutyronitrile. 4 moles / monomer mole), the temperature was raised to 30 ° C., the polymerization temperature, and then polymerized for 1 day at a stirring speed of 250 rpm under a nitrogen stream, and the mixture was poured into cooled distilled water to precipitate a polymer, followed by a glass filter. The filtrate was washed several times with distilled water and filtered repeatedly to remove residual monomer and suspension stabilizer, and then dried under vacuum at 40 ° C. for 1 day to obtain particles.

Example 9

133.2 ml (0.9 mol) of vinyl pivalate and 9.2 ml (0.1 mol) of vinyl acetate were placed in the same device as in Example 1, followed by oxygen removal for 1 hour, and then 0.0248 g (1 × 10 −1) of azobisisobutyronitrile. 4 moles / monomer mole), the temperature was raised to 30 ° C., the polymerization temperature, and then polymerized for 1 day at a stirring speed of 250 rpm under a nitrogen stream, and the mixture was poured into cooled distilled water to precipitate a polymer, followed by a glass filter. The filtrate was washed several times with distilled water and filtered repeatedly to remove residual monomer and suspension stabilizer, and then dried under vacuum at 40 ° C. for 1 day to obtain particles.

Example 10

100 g of sodium hydroxide, 100 g of sodium sulfate, and 100 ml of ethanol were added to a 1-l volumetric flask (35 ml by weight) in an aqueous alkaline solution, and distilled water was added so that the total volume was 1 liter. In a 250 mL two-necked flask equipped with a thermometer and a cooling tower, 100 mL of an aqueous alkali solution was prepared, and poly (vinyl pivalate / vinyl acetate) separated using sodium sulfate (using the prepared particles of Example 1, particle diameter : 300 to 350㎛, polydispersity index: 1.05) 0.5g was suspended and stirred for 1 day while stirring using a magnetic stirrer at 50 ° C., filtered through a glass filter, and the filtrate was washed with excess distilled water and filtered. The procedure was repeated three times, followed by drying for 1 day using a vacuum dryer to obtain hydrogel particles having a degree of hydrolysis of 80%.

Example 11

100 g of sodium hydroxide, 100 g of sodium sulfate, and 100 ml of ethanol were added to a 1-volume flask with 35 wt% alkaline aqueous solution, and distilled water was added so that the total volume was 1 liter. In a 250 mL two-necked flask equipped with a thermometer and a cooling tower, 100 mL of an aqueous alkali solution was prepared, and poly (vinyl pivalate / vinyl acetate) separated using sodium sulfate (using the prepared particles of Example 2, particle diameter : 300 to 350㎛, polydispersity index: 1.05) 0.5g was suspended and stirred for 1 day while stirring using a magnetic stirrer at 50 ° C., filtered through a glass filter, and the filtrate was washed with excess distilled water and filtered. The procedure was repeated three times, followed by drying for 1 day using a vacuum dryer to obtain hydrogel particles having a degree of hydrolysis of 75%.

Example 12

100 g of sodium hydroxide, 100 g of sodium sulfate, and 100 ml of ethanol were added to a 1-volume flask with 35 wt% alkaline aqueous solution, and distilled water was added so that the total volume was 1 liter. In a 250 ml two-necked flask equipped with a thermometer and a cooling tower, 100 ml of an aqueous alkali solution was added, and poly (vinyl pivalate / vinyl acetate) separated using sodium sulfate (using the prepared particles of Example 3, particle diameter : 300 to 350㎛, polydispersity index: 1.05) 0.5g was suspended and stirred for 1 day while stirring using a magnetic stirrer at 50 ° C., filtered through a glass filter, and the filtrate was washed with excess distilled water and filtered. The procedure was repeated three times, followed by drying for 1 day using a vacuum dryer to obtain hydrogel particles having a degree of hydrolysis of 65%.

Example 13

100 g of sodium hydroxide, 100 g of sodium sulfate, and 100 ml of ethanol were added to a 1-volume flask with 35 wt% alkaline aqueous solution, and distilled water was added so that the total volume was 1 liter. In a 250 mL two-necked flask equipped with a thermometer and a cooling tower, 100 mL of an aqueous alkali solution was prepared, and poly (vinyl pivalate / vinyl acetate) separated using sodium sulfate (using the prepared particles of Example 4, particle diameter : 300 to 350㎛, polydispersity index: 1.05) 0.5g was suspended and stirred for 1 day while stirring using a magnetic stirrer at 50 ° C., filtered through a glass filter, and the filtrate was washed with excess distilled water and filtered. The procedure was repeated three times, followed by drying for 1 day using a vacuum dryer to obtain hydrogel particles having a degree of hydrolysis of 60%.

Example 14

100 g of sodium hydroxide, 100 g of sodium sulfate, and 100 ml of ethanol were added to a 1-volume flask with 35 wt% alkaline aqueous solution, and distilled water was added so that the total volume was 1 liter. In a 250 mL two-necked flask equipped with a thermometer and a cooling tower, 100 mL of an aqueous alkali solution was prepared, and poly (vinyl pivalate / vinyl acetate) separated using sodium sulfate (using the prepared particles of Example 5, particle diameter : 300 to 350㎛, polydispersity index: 1.05) 0.5g was suspended and stirred for 1 day while stirring using a magnetic stirrer at 50 ° C., filtered through a glass filter, and the filtrate was washed with excess distilled water and filtered. The procedure was repeated three times, followed by drying for one day using a vacuum dryer to obtain hydrogel particles having a degree of hydrolysis of 50%.

Example 15

100 g of sodium hydroxide, 100 g of sodium sulfate, and 100 ml of ethanol were added to a 1-volume flask with 35 wt% alkaline aqueous solution, and distilled water was added so that the total volume was 1 liter. In a 250 ml two-necked flask equipped with a thermometer and a cooling tower, 100 ml of an aqueous alkali solution was added, and poly (vinyl pivalate / vinyl acetate) separated using sodium sulfate (using the prepared particles of Example 6, particle diameter : 300 to 350㎛, polydispersity index: 1.05) 0.5g was suspended and stirred for 1 day while stirring using a magnetic stirrer at 50 ° C., filtered through a glass filter, and the filtrate was washed with excess distilled water and filtered. The procedure was repeated three times, followed by drying for 1 day using a vacuum dryer to obtain hydrogel particles having a degree of hydrolysis of 45%.

Example 16

100 g of sodium hydroxide, 100 g of sodium sulfate, and 100 ml of ethanol were added to a 1-volume flask with 35 wt% alkaline aqueous solution, and distilled water was added so that the total volume was 1 liter. In a 250 mL two-necked flask equipped with a thermometer and a cooling tower, 100 mL of an aqueous alkali solution was prepared, and poly (vinyl pivalate / vinyl acetate) separated using sodium sulfate (using the prepared particles of Example 7, particle diameter : 300 to 350㎛, polydispersity index: 1.05) 0.5g was suspended and stirred for 1 day while stirring using a magnetic stirrer at 50 ° C., filtered through a glass filter, and the filtrate was washed with excess distilled water and filtered. The procedure was repeated three times, followed by drying for 1 day using a vacuum dryer to obtain hydrogel particles having a degree of hydrolysis of 35%.

Example 17

100 g of sodium hydroxide, 100 g of sodium sulfate, and 100 ml of ethanol were added to a 1-volume flask with 35 wt% alkaline aqueous solution, and distilled water was added so that the total volume was 1 liter. In a 250 ml two-necked flask equipped with a thermometer and a cooling tower, 100 ml of an aqueous alkali solution was prepared, and poly (vinyl pivalate / vinyl acetate) separated using sodium sulfate (using the prepared particles of Example 8, particle diameter : 300 to 350㎛, polydispersity index: 1.05) 0.5g was suspended and stirred for 1 day while stirring using a magnetic stirrer at 50 ° C., filtered through a glass filter, and the filtrate was washed with excess distilled water and filtered. The procedure was repeated three times, followed by drying for 1 day using a vacuum dryer to obtain hydrogel particles having a degree of hydrolysis of 30%.

Example 18

100 g of sodium hydroxide, 100 g of sodium sulfate, and 100 ml of ethanol were added to a 1-volume flask with 35 wt% alkaline aqueous solution, and distilled water was added so that the total volume was 1 liter. In a 250 ml two-necked flask equipped with a thermometer and a cooling tower, 100 ml of an aqueous alkali solution was prepared, and poly (vinyl pivalate / vinyl acetate) separated using sodium sulfate (using the prepared particles of Example 9, particle diameter : 300 to 350㎛, polydispersity index: 1.05) 0.5g was suspended and stirred for 1 day while stirring using a magnetic stirrer at 50 ° C., filtered through a glass filter, and the filtrate was washed with excess distilled water and filtered. The procedure was repeated three times, followed by drying for 1 day using a vacuum dryer to obtain hydrogel particles having a degree of hydrolysis of 20%.

Example 19

The poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol particles prepared in Example 10 were dissolved in 10 ml of distilled water in an aqueous solution prepared by dissolving potassium iodide (0.7 g) and iodide (0.45 g) for 48 hours. It was immersed. Immediately after filtration with a glass filter, 30% of silver nitrate was immersed in the solution for 24 hours, filtered through a glass filter, and the filtrate was washed with distilled water, acetone, and diethyl ether. Dried.

Example 20

The poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol particles prepared in Example 11 were dissolved in 10 ml of distilled water in an aqueous solution prepared by dissolving potassium iodide (0.7 g) and iodide (0.45 g) for 48 hours. It was immersed. Immediately after filtration with a glass filter, 30% of silver nitrate was immersed in the solution for 24 hours, filtered through a glass filter, and the filtrate was washed with distilled water, acetone, and diethyl ether. Dried.

Example 21

The poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol particles prepared in Example 12 were dissolved in 10 ml of distilled water in an aqueous solution prepared by dissolving potassium iodide (0.7 g) and iodide (0.45 g) for 48 hours. It was immersed. Immediately after filtration with a glass filter, 30% of silver nitrate was immersed in the solution for 24 hours, filtered through a glass filter, and the filtrate was washed with distilled water, acetone, and diethyl ether. Dried.

[Example 22]

The poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol particles prepared in Example 13 were dissolved for 48 hours in an aqueous solution prepared by dissolving potassium iodide (0.7 g) and iodine (0.45 g) in 10 ml of distilled water. It was immersed. Immediately after filtration with a glass filter, 30% of silver nitrate was immersed in the solution for 24 hours, filtered through a glass filter, and the filtrate was washed with distilled water, acetone, and diethyl ether. Dried.

[Example 23]

The poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol particles prepared in Example 14 were dissolved in 10 ml of distilled water in an aqueous solution prepared by dissolving potassium iodide (0.7 g) and iodide (0.45 g) for 48 hours. It was immersed. Immediately after filtration with a glass filter, 30% of silver nitrate was immersed in the solution for 24 hours, filtered through a glass filter, and the filtrate was washed with distilled water, acetone, and diethyl ether. Dried.

Example 24

The poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol particles prepared in Example 15 were dissolved in 10 ml of distilled water in an aqueous solution prepared by dissolving potassium iodide (0.7 g) and iodide (0.45 g) for 48 hours. It was immersed. Immediately after filtration with a glass filter, 30% of silver nitrate was immersed in the solution for 24 hours, filtered through a glass filter, and the filtrate was washed with distilled water, acetone, and diethyl ether. Dried.

[Example 25]

The poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol particles prepared in Example 16 were dissolved in 10 ml of distilled water in an aqueous solution prepared by dissolving potassium iodide (0.7 g) and iodide (0.45 g) for 48 hours. It was immersed. Immediately after filtration with a glass filter, 30% of silver nitrate was immersed in the solution for 24 hours, filtered through a glass filter, and the filtrate was washed with distilled water, acetone, and diethyl ether. Dried.

Example 26

The poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol particles prepared in Example 17 were dissolved in 10 ml of distilled water in an aqueous solution prepared by dissolving potassium iodide (0.7 g) and iodide (0.45 g) for 48 hours. It was immersed. Immediately after filtration with a glass filter, 30% of silver nitrate was immersed in the solution for 24 hours, filtered through a glass filter, and the filtrate was washed with distilled water, acetone, and diethyl ether. Dried.

[Example 27]

The poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol particles prepared in Example 18 were dissolved in an aqueous solution made by dissolving potassium iodide (0.7 g) and iodide (0.45 g) in 10 ml of distilled water for 48 hours. It was immersed. Immediately after filtration with a glass filter, 30% of silver nitrate was immersed in the solution for 24 hours, filtered through a glass filter, and the filtrate was washed with distilled water, acetone, and diethyl ether. Dried.

1 shows the reaction of poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol microspheres (NT-PVA) prepared in Example 10 with polyvinyl alcohol shell prepared in Example 19 with iodine and potassium iodide Computed tomography (CT) photographs between the microspheres (AgI / PVA) in which the iodine complex was formed are shown. As shown in FIG. 1, it was confirmed that the microspheres forming the iodine complex according to the present invention as in Example 19 exhibited radiopacity.

Figure 2 shows the nuclear magnetic resonance spectrum (NMR spectra) instrumental analysis (left) of the conventional general polyvinyl acetate microspheres (right), the NMR instrumental analysis (right) of the microspheres prepared in Example 4. As shown in Figure 2, it can be seen that the microspheres obtained by copolymerizing the polyvinyl polyvinyrate together according to the present invention compared to the general polyvinyl acetate microspheres can further increase the alternating arrangement.

3 is poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol microspheres (Me-PVA) as a saponification solution using methanol and poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol fine as a saponification solution using ethanol. It is a graph which shows the result of the swelling degree experiment of the sphere (Et-PVA). As shown in FIG. 3, the swelling ratio of the particles with time is lower than that of the conventional methanol using polyvinyl alcohol (Me-PVA), and the ethanol using polyvinyl alcohol (Et-PVA) according to the present invention was found to be lower. Can be.

The present invention can be used in industries related to the manufacture of medical embolic materials.

Although the present invention has been described in detail only with respect to the described embodiments, it will be apparent to those skilled in the art that various modifications and variations are possible within the technical scope of the present invention, and such modifications and modifications are within the scope of the appended claims.

1 is poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol microspheres of particles prepared in Example 10 and poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol fine particles containing silver iodide composite prepared in Example 19; Computed tomography (CT) images.

Figure 2 is a nuclear magnetic resonance spectrum (NMR spectra) instrumental analysis (left) of the general polyvinyl acetate microspheres, the NMR instrumental analysis (right) of the microspheres prepared in Example 4.

3 is poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol microspheres (Me-PVA) as a saponification solution using methanol and poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol fine as a saponification solution using ethanol. It is a graph which shows the result of the swelling degree experiment of the sphere (Et-PVA).

Claims (6)

A core made of a poly (vinyl pivalate / vinyl acetate) copolymerized with a mixture of a vinyl pivalate monomer and a vinyl acetate monomer having an alternating diad group content of 54 to 63% and a number average degree of polymerization of 2000 to 6000; And a polyvinyl alcohol shell formed by saponifying a part of the core (saponification ratio = 1: 9 to 9: 1 or 95% or less). Microspherical embolic material of poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol. A core made of a poly (vinyl pivalate / vinyl acetate) copolymerized with a mixture of a vinyl pivalate monomer and a vinyl acetate monomer having an alternating diad group content of 54 to 63% and a number average degree of polymerization of 2000 to 6000; And a polyvinyl alcohol shell formed by saponifying a part of the core (saponification ratio = 1: 1 to 9: 1 or 95% or less), wherein the polyvinyl alcohol shell is formed, and includes milling. The particle size is made within the range of 100 to 1000 ㎛, wherein the polyvinyl alcohol shell is a microspherical color having radiopaque impermeability, characterized in that the iodine complex is formed by reaction with iodine and potassium iodide Premise. (1) A mixture of a vinyl pivalate monomer and a vinyl acetate monomer is copolymerized to form a core made of poly (vinyl pivalate / vinyl acetate) having an alternating diad group content of 54 to 63% and a number average degree of polymerization of 2000 to 6000. Manufacturing core manufacturing step; (2) 0.1 to 100 parts by weight of an inorganic salt as a dispersant and an antistatic agent based on 1 part by weight of the poly (vinyl pivalate / vinyl acetate) particles obtained in the core manufacturing step was added and milled to obtain a particle size of 100 to 1000 μm. Milling step of making the particles within the range; And (3) a shell manufacturing step of forming a polyvinyl alcohol shell formed by saponifying a part of the core of the particles obtained in the milling step (saponification ratio = 1: 9 to 9: 1 or 95% or less); A method for producing a microspherical embolic material of poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol for producing a microspherical embolic agent having a radiopaque impermeability, characterized by comprising a. The method of claim 3, wherein The mixture of the vinyl pivalate monomer and the vinyl acetate monomer in the core manufacturing step is copolymerized in the presence of azobisdimethylvaleronitrile as a catalyst at a concentration between 1-10-5 to 1-10-1 mol / monomer mol. Preparation of microspherical embolic material of poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol for preparation of microspherical color whole with radiopaque impermeability, characterized by suspension co-polymerization within a temperature range of 20 to 60 ° C Way. (1) A mixture of a vinyl pivalate monomer and a vinyl acetate monomer is copolymerized to form a core made of poly (vinyl pivalate / vinyl acetate) having an alternating diad group content of 54 to 63% and a number average degree of polymerization of 2000 to 6000. Manufacturing core manufacturing step; (2) 0.1 to 100 parts by weight of an inorganic salt as a dispersant and an antistatic agent based on 1 part by weight of the poly (vinyl pivalate / vinyl acetate) particles obtained in the core manufacturing step was added and milled to obtain a particle size of 100 to 1000 μm. Milling step of making the particles within the range; (3) a shell manufacturing step of forming a polyvinyl alcohol shell formed by saponifying a part of the core of the particles obtained in the milling step (saponification ratio = 1: 9 to 9: 1 or 95% or less); And (4) a complex forming step of forming a iodine complex by reacting the polyvinyl alcohol shell formed in the milling step with iodine and potassium iodide; Method for producing a microspherical embolic agent having a radiopaque impermeability, characterized in that made. After the preparation of microspheres having an endothelial / enveloped double structure of poly (vinyl pivalate / vinyl acetate) / polyvinyl alcohol, ionic reaction between an aqueous solution of iodine and an aqueous solution of AgNO3 using the particles, and a method of washing using reducing properties A method for producing a silver iodide (AgI) composite having radiopaque impermeability to a.

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