KR100835898B1 - Poly vinyl alcohol hydrogel particle by using acid hydrolysis and method the same - Google Patents

Abstract

Polyvinylalcohol hydrogel particles are provided to be amorphous irrespective of the degree of hydrolysis, to ensure relatively low specific gravity and increased surface unevenness, and to exhibit improved dispersibility in a contrast medium when the particles are used as an embolizing agent. Polyvinylalcohol hydrogel particles are prepared by dispersing poly(vinyl acetate) microspheres in an aqueous acid solution. The aqueous acid solution comprises 0.1-3 M of hydrochloric acid, 0.1-500 ml of alcohol, and 0.1-300 g of an inorganic salt, based on the aqueous acid solution 1L. The polyvinylalcohol hydrogel particle has an uneven surface. The alcohol is methanol or ethanol. The inorganic salt is sodium sulfate or sodium sulfite.

Description

Poly vinyl alcohol hydrogel particle by using acid hydrolysis and method the same}

1 is a thermogram of a differential scanning calorimeter (DSC) of hydrogel gel particles prepared by alkali and acid hydrolysis.

2a to 2b are scanning electron micrographs of the PVA hydrogel particles prepared in Example 1.

3 is a diagram showing a nuclear magnetic resonance spectra (NMR spectra) of hydrogel particles prepared by acid hydrolysis.

The present invention relates to polyvinyl alcohol hydrogel particles prepared by dispersing polyvinyl acetate microspheres in an aqueous acid solution, and a method for preparing the same. In particular, polyvinyl acetate (hereinafter referred to as 'PVAc') prepared by suspension polymerization. ) Polyvinyl alcohol (hereinafter referred to as 'PVA') prepared by separating microspheres into a standard network, controlling them to a uniform size, and immersing them in an aqueous solution containing an acid to hydrolyze ester groups of the polymer from the surface. It relates to a hydrogel particle and a method for producing the same.

Hydrogel particles are water-swellable structures that are nanoparticles or nanospheres with an average diameter of nanometers to submicrometers and microspheres ranging from micrometers to thousands of micrometers. ). Hydrogel particles of various polymer materials are characterized by their shape changing by external stimulation such as water, temperature, pH, and ionic strength, and are attracting attention as biomaterials because they are structurally similar to biological tissues.

From the late 1980s to the 1990s, research on hydrogel particles has been applied to fields such as embolization, enzyme fixation, and drug delivery by micronizing polymer materials and chemically modifying surfaces and interiors. Entering the 2000s, with the development of nanotechnology, researches on the production and application of nano-sized particles using water-soluble polymers are underway, and research on hydrogel particles using polymers sensitive to external stimuli has begun to become active. In particular, polymers such as poly (N-isopropylacylamide), poly (N-vinyl caprolactam), and poly (acrylamide) are accompanied by a change in volume at a specific temperature, that is, above a critical lower limit temperature, and form a hydrogel in a certain concentration range as the temperature increases. There is an increasing interest in thermally responsive particles utilizing such functionality. In addition, the results of using a polymer electrolyte to prepare particles having different swelling behaviors according to pH changes and using them for drug delivery were reported.

In general, a method of preparing particles using a polymer is as follows. In the first method, spherical particles are prepared by emulsion polymerization, suspension polymerization, dispersion polymerization and precipitation polymerization of monomers. However, in order to prepare the hydrogel particles, the water-soluble monomer must be polymerized by emulsifying, dispersing, or suspending it in an organic solvent harmful to the human body. Particularly, in the case of suspension polymerization, the size and distribution of particles are determined by the equilibrium of collision and separation of monomer droplets. However, it is not easy to prepare monodisperse particles and the phenomenon is very complicated and is not completely understood theoretically. The second method is a process using a polymer solution, which is mainly used for preparing particles containing drugs. In particular, the solvent evaporation method is a very advantageous method for easily dissolving hydrophobic polymers in volatile solvents such as methylene dichloride to make monodisperse particles. There is a problem. In addition, in the obtaining of particles, a high energy consumption process such as lyophilization is required, and thus an improvement method is required.

In order to prepare hydrogel particles, PVA or gelatin is dissolved in an aqueous solution, and gelated using the reactivity of the side chain —OH and —NH ₂ groups. Dehydrated by addition, centrifuged, washed with acetone and alcohol and dried to obtain uncrosslinked particles. The obtained non-crosslinked particles are dispersed in an aqueous solution containing glutaraldehyde to introduce crosslinking from the surface to prepare structurally stabilized hydrogel particles. In the case of alginate, the dispersed particles are dispersed in an aqueous solution of calcium chloride and converted into hydrogel particles by introducing crosslinks by ions inside the droplets, and human serum albumin can be converted into hydrogel particles by using carbodiimide.

However, in the case of PVA, crosslinking agents such as aldehydes, which are used as toxic substances, are limited in use when used in a living body, and the dehydration process is complicated and it is very difficult to prepare a uniform size sphere. Therefore, new methods have been proposed to solve this problem. The double heterogeneous hydrolysis method [US Pat. No. 6,191,193 B1] disperses monodisperse PVAc microspheres as precursors in an aqueous alkali solution and saponifies the surface. Therefore, the surface of the PVA inside the particles composed of PVAc or the surface and the inside of the PVA particles are completely prepared a method for producing.

In addition, as a method of preparing particles through gelation, various mechanisms of hydrogel formation, such as raising the temperature of a poly (N-isopropyl acrylamide) dispersion solution or irradiating gamma rays to a polymer aqueous solution, are generally applied to a heterogeneous system. It is utilized for manufacture.

Among various applications of hydrogel particles, there is increasing interest in embolization. Embolization is a treatment technique that blocks blood flow by injecting certain substances into the blood stream when the location can be expected to have a better result than the lesion or surgical procedure that is present in the area that cannot be treated by surgery. In other words, the embolization through blood vessels collectively refers to a technique for blocking the blood flow of the lesion by selectively blocking pathological vessels. Therefore, embolization is particularly used for the treatment of vascular lesions such as hypervascular tumors, arteriovenous malformations, arteriovenous varices, and traumatic or tuberculosis.

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.

When PVA is used for medical purposes, it is used in various forms such as hydrogel particles, foams, gel sheets, and films. Especially, hydrogel particles can be injected into the body using microcatheters and syringes when they have diameters ranging from tens of um to hundreds of um. Can be. This procedure has the advantages of minimizing the pain of the patient and increasing the therapeutic effect and preventing the infection of the wound during the treatment of the disease.

PVA having many of the above advantages is very difficult to polymerize directly because vinyl alcohol, which is a monomer, exists in aldehyde form by tautomerization, unlike other biocompatible synthetic polymer materials. Therefore, a polymer such as vinyl ester or vinyl ether is polymerized and PVA is prepared by using a catalyst such as alkali, acid or amine. In this case, the precursor polyvinyl ester or polyvinyl ether is completely dissolved in an alcohol solvent and a catalyst is added to the reaction. This method is a method in which the form of the precursor disappears completely. impossible.

Therefore, conventionally, PVA has been prepared by hydrolyzing PVAc using alkali as a catalyst. However, in the case of PVA particles prepared using an alkali catalyst, the crystal melting temperature was observed at around 237 ° C., and the higher the saponification, the higher the heat of crystal melting, the lower the solubility in water and the lower the adhesion. In addition, the particles produced by hydrolysis with alkali have a high specific gravity, so that when the particles are dispersed in the contrast medium, the particles settle to the bottom, and loaded into a syringe, there is a problem that it is difficult to block or uniformly inject the conduit when injected into the body through a micro-conduit.

An object of the present invention is to provide a polyvinyl alcohol hydrogel particles prepared by dispersing polyvinyl acetate microspheres in an acid aqueous solution.

An object of the present invention is to provide a method for producing polyvinyl alcohol hydrogel particles by dispersing polyvinyl acetate microspheres in an acid aqueous solution.

Polyvinyl alcohol hydrogel particles according to the present invention for achieving the above object is characterized by being prepared by dispersing polyvinyl acetate microspheres in an acid aqueous solution.

When hydrolyzing PVAc using alkali as a catalyst, the prepared PVA is somewhat different depending on the reaction conditions, but the reactivity is very high, so that the saponification degree can be made to be 99% or more in a short time. In the case of PVA hydrolyzed using an acid as a catalyst, hydrogen generated adjacent to -OH groups reacts to cause dehydration, and double bonds are introduced into the main chain or the main chain is cleaved.

In the two kinds of catalyst The main difference in the case of alkali catalyst to react with the side chain ester sort of group chain-ester reaction adjacent to dissociate continuously obtained a copolymer of vinyl alcohol and vinyl esters present in a block form an acid catalyst H ⁺ Attack occurs in a random form against the polymer backbone, resulting in a polymer having a random copolymer.

This phenomenon can be identified by analyzing the particles produced using a differential scanning calorimeter and observing the melting point and heat of fusion of PVA crystals inside the produced particles.

1 is a thermogram of a differential scanning calorimeter (DSC) of hydrogel gel particles prepared by alkali and acid hydrolysis. As shown in FIG. 1, in the case of PVA particles prepared using an alkali catalyst, the crystal melting temperature was observed at around 237 ° C., and the heat of fusion increased as the degree of saponification increased.

On the other hand, when acid is used as a catalyst, crystals do not appear to melt even if the degree of hydrolysis increases. This is because the acetate group randomly present in the side chain prevents the polymer chain from crystallizing and no crystal region is formed inside the particle.

In addition, unlike PVA hydrogel particles prepared using an alkali catalyst, particles prepared using an acid have a very sticky surface. Although PVA is a water-soluble polymer, it has a high crystallinity due to its high hydrogen bonding force between -OH groups in the side chain, and also has a relatively low hydration phenomenon by water. However, hydrogel particles by acid catalyst have higher solubility in water and higher adhesion than alkali-based particles because the bulky side chain acetate groups interfere with hydrogen bonding to some extent.

Increased tackiness causes the problem that after the acid hydrolysis reaction has ended, separation is impossible once the particles are associated and dried upon obtaining the particles. Therefore, in the present invention, after the reaction is completed, the particles were washed with distilled water several times and lyophilized in water to obtain separated particles.

2a to 2b are scanning electron micrographs of the PVA hydrogel particles prepared in Example 1.

2A to 2B, the scanning electron micrographs of the lyophilized hydrogel gel particles, which are completely lyophilized, show a very rough surface of the particles. These maximized surface irregularities have a very beneficial effect on the adsorption and activation of fibrinogen associated with platelet, or blood coagulation, which causes the initial coagulation of blood upon occlusion of blood vessels.

PVA hydrogel particles prepared using an acid catalyst are polymers having no crystallinity as described above, and have a higher degree of hydration for water and relatively lower specific gravity than hydrogel particles prepared using an alkali catalyst. This will improve the dispersibility of nonionic contrast medium when the particles are used as embolic.

3 is a diagram showing a nuclear magnetic resonance spectra (NMR spectra) of hydrogel particles prepared by acid hydrolysis.

The acid catalyst was used to determine the conversion of PVAc to PVA, and the reactivity over time was subjected to NMR analysis. As shown in FIG. 3, it was confirmed that complete PVA hydrogel particles were prepared through the 70 hour reaction by disappearing all the characteristic peaks of PVAc and only the characteristic peaks of PVA.

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

Example 1

52 ml of 35 wt% HCl aqueous solution, 100 g of sodium sulfate, and 100 ml of methanol are added to a 1 L volumetric flask, and distilled water is added so that the total volume is 1 L. In a 250 ml two-necked flask equipped with a thermometer and a cooling tower, 100 ml of an aqueous HCl solution was added, and polyvinyl acetate particles separated using sodium sulfate (particle diameter: 300 to 350 µm, polydispersity index: 1.03, number average degree of polymerization) : 8,300) 0.5g was suspended and hydrolyzed for 7 hours with stirring using a magnetic stirrer at 50 ° C. 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 using a freeze dryer for 1 day. Hydrogel particles having a degree of hydrolysis of 30% were obtained.

Example 2

52 ml of 35 wt% HCl aqueous solution and 100 ml of methanol are added to a 1 liter volumetric flask, and distilled water is added so that the total volume is 1 L. In a 250 ml two-necked flask equipped with a thermometer and a cooling tower, 100 ml of an aqueous HCl solution was added, and polyvinyl acetate particles separated using sodium sulfate (particle diameter: 300 to 350 µm, polydispersity index: 1.03, number average degree of polymerization) : 8,300) 0.5g was suspended and hydrolyzed for 7 hours with stirring using a magnetic stirrer at 50 ° C. 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 using a freeze dryer for 1 day. Hydrogel particles having a degree of hydrolysis of 23% were obtained.

Example 3

52 ml of 35 wt% aqueous HCl solution, 100 g of sodium sulfate, and 300 ml of methanol are added to a 1 L volumetric flask, and distilled water is added so that the total volume is 1 L. In a 250 ml two-necked flask equipped with a thermometer and a cooling tower, 100 ml of an aqueous HCl solution was added, and polyvinyl acetate particles separated using sodium sulfate (particle diameter: 300 to 350 µm, polydispersity index: 1.03, number average degree of polymerization) : 8,300) 0.5g was suspended and hydrolyzed for 7 hours with stirring using a magnetic stirrer at 50 ° C. 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 using a freeze dryer for 1 day. Hydrogel particles having a degree of hydrolysis of 42% were obtained.

Example 4

52 ml of 35 wt% HCl aqueous solution, 100 g of sodium sulfate, and 100 ml of methanol are added to a 1 L volumetric flask, and distilled water is added so that the total volume is 1 L. In a 250 ml two-necked flask equipped with a thermometer and a cooling tower, 100 ml of an aqueous HCl solution was added, and polyvinyl acetate particles separated using sodium sulfate (particle diameter: 300 to 350 µm, polydispersity index: 1.03, number average degree of polymerization) : 8,300) was suspended and hydrolyzed for 40 hours with stirring using a magnetic stirrer at 50 ° C. 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 using a freeze dryer for 1 day. Hydrogel particles having a degree of hydrolysis of at least 99% were obtained.

Comparative Example 1

In a 250 ml four-necked flask equipped with a thermometer, a nitrogen inlet, a cooling tower, and an angle stirrer, 100 ml of distilled water and 1.5 g of polyvinyl alcohol (saturation degree: 88%, number average molecular weight: 127,000) were added as a suspension stabilizer at 70 ° C. After melting with stirring at room temperature, the mixture was cooled to room temperature, and passed through a pyrrogalol-alkali aqueous solution trap and a dryer light trap to pass oxygen-free nitrogen strongly for 2 hours to remove dissolved oxygen, and to 50 ml of vinyl acetate and azobisisobutyro as an initiator. Nitrile was removed by adding 1.5x10-3 mol / mol of VAc to the molar number of vinyl acetate for 1 hour to remove oxygen and raising the temperature to 50 ° C, the polymerization temperature, and then stirring at 200 rpm under nitrogen stream for 4 hours. Polymerized. After the polymerization was completed, the resultant was filtered with a glass filtration apparatus, and the filtrate was washed with excess distilled water and filtered. Then, the resultant was dried under vacuum at 40 ° C. for 1 day to obtain particles. PVAc particles were milled in a mortar with 0.1 g sodium sulfate as a dispersant and an antistatic agent per 1.0 g and then separated using a standard mesh. The separated particles were washed with 100 ml of distilled water for 4 hours while stirring using a magnetic alternator in a 250 ml beaker, filtered through a glass filter, and dried in vacuo for 1 day at 40 ° C. to obtain particles of various sizes. The polydispersity index of the obtained particles is 1.01 to 1.1.

Comparative 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 g of sodium sulfate, and 8 g of methanol was added. um) 0.5g was suspended and hydrolyzed for 30 minutes with stirring using a magnetic stirrer at 40 ° C. After the reaction, the reaction solution was poured into distilled water, stirred for 1, 2, 3, 4 hours, filtered through a glass filtration apparatus, the filtrate was washed with excess distilled water and filtered three times. It dried for 1 day and obtained the hydrogel particle.

The composition of the acid aqueous solution used in the present invention can be used in the range of 0.1 ~ 3M of hydrochloric acid (HCl) with respect to 1L of the acid aqueous solution, in addition to those described in the above examples, the volume of alcohol 0.1 ~ 500ml, inorganic salt 0.1 It can be used as appropriately mixed in the range of ~ 300g.

Alcohol also includes ethanol in addition to methanol and the inorganic salt may include sodium sulfate or sodium sulfite.

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.

Polyvinyl alcohol hydrogel gel particles according to the present invention is an amorphous, regardless of the degree of hydrolysis, the specific gravity is relatively low, the surface irregularities are increased to improve the dispersibility of contrast medium when used as an embolic agent and has the advantage of inducing effective blood vessel occlusion .

Claims (8)

In polyvinyl alcohol (PVA) hydrogel particles prepared by dispersing polyvinyl acetate (PVAc) microspheres in an aqueous acid solution, the acid aqueous solution is Polyvinyl alcohol (PVA) hydrogel particles, characterized in that the hydrochloric acid (HCl) 0.1 ~ 3M, alcohol volume 0.1 ~ 500ml, inorganic salt 0.1 ~ 300g with respect to 1L of the aqueous acid solution. delete delete According to claim 1, wherein the polyvinyl alcohol (PVA) hydrogel particles are Polyvinyl alcohol (PVA) hydrogel particles, characterized in that irregularities are formed on the surface. In the method for producing polyvinyl alcohol (PVA) hydrogel particles prepared by dispersing polyvinyl acetate (PVAc) microspheres in an aqueous acid solution, the acid aqueous solution is A method for producing polyvinyl alcohol (PVA) hydrogel particles, characterized in that the hydrochloric acid (HCl) 0.1 ~ 3M, alcohol volume 0.1 ~ 500ml, inorganic salt 0.1 ~ 300g with respect to 1L of the aqueous acid solution. delete The method of claim 5, wherein the alcohol Method for producing polyvinyl alcohol (PVA) hydrogel particles, characterized in that methanol or ethanol. The method of claim 5, wherein the inorganic salt is Method for producing polyvinyl alcohol (PVA) hydrogel particles, characterized in that the sodium sulfate or sodium sulfite.

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